bims-kracam 2021-10-03 papers

on K-Ras in cancer metabolism

Issue of 2021‒10‒03
forty-eight papers selected by
Yasmin Elkabani
Egyptian Foundation for Research and Community Development

Cancer Signaling Drives Cancer Metabolism: AKT and the Warburg Effect.
Metabolic Flexibility Is a Determinant of Breast Cancer Heterogeneity and Progression.
Small Molecules Targeting Programmed Cell Death in Breast Cancer Cells.
Ketogenic Diets in Pancreatic Cancer and Associated Cachexia: Cellular Mechanisms and Clinical Perspectives.
Glucose and Amino Acid Metabolic Dependencies Linked to Stemness and Metastasis in Different Aggressive Cancer Types.
Glutamine Metabolism Regulators Associated with Cancer Development and the Tumor Microenvironment: A Pan-Cancer Multi-Omics Analysis.
The Evolving Role of Ferroptosis in Breast Cancer: Translational Implications Present and Future.
HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells.
Inhibition of Metabolism as a Therapeutic Option for Tamoxifen-Resistant Breast Cancer Cells.
Moringa Oleifera Seed Extract Concomitantly Supplemented with Chemotherapy Worsens Tumor Progression in Mice with Triple Negative Breast Cancer and Obesity.
Calcitriol Suppresses Warburg Effect and Cell Growth in Human Colorectal Cancer Cells.
An Updated Comprehensive Review on Vitamin A and Carotenoids in Breast Cancer: Mechanisms, Genetics, Assessment, Current Evidence, and Future Clinical Implications.
Multi-Omic Approaches to Breast Cancer Metabolic Phenotyping: Applications in Diagnosis, Prognosis, and the Development of Novel Treatments.
Ferroptosis Meets Cell-Cell Contacts.
Targeting Histone Modifications in Breast Cancer: A Precise Weapon on the Way.
Anti-Cancer Activity of Phytochemicals Targeting Hypoxia-Inducible Factor-1 Alpha.
Dietary Polyphenols: Promising Adjuvants for Colorectal Cancer Therapies.
Liposome Photosensitizer Formulations for Effective Cancer Photodynamic Therapy.
Wild-Type KRAS Allele Effects on Druggable Targets in KRAS Mutant Lung Adenocarcinomas.
Galectins in Cancer and the Microenvironment: Functional Roles, Therapeutic Developments, and Perspectives.
Mediterranean Diet Food Components as Possible Adjuvant Therapies to Counteract Breast and Prostate Cancer Progression to Bone Metastasis.
Combining histone deacetylase inhibitors (HDACis) with other therapies for cancer therapy.
Regulatory role of acetylation on enzyme activity and fluxes of energy metabolism pathways.
Delivery of Various Cargos into Cancer Cells and Tissues via Cell-Penetrating Peptides: A Review of the Last Decade.
Understanding Nanotechnology in the Treatment of Oral Cancer: A Comprehensive Review.
Targeted Photodynamic Therapy Using Alloyed Nanoparticle-Conjugated 5-Aminolevulinic Acid for Breast Cancer.
Photodynamic Therapy Review: Principles, Photosensitizers, Applications, and Future Directions.
Synergistic effect of anethole and doxorubicin alleviates cell proliferation, cell cycle arrest, and ER stress and promotes ROS-mediated apoptosis in triple-negative breast cancer cells.
A genetic model of methionine restriction extends Drosophila health- and lifespan.
Clinical Targeting of Altered Metabolism in High-Grade Glioma.
Retinoids Delivery Systems in Cancer: Liposomal Fenretinide for Neuroectodermal-Derived Tumors.
Marine Power on Cancer: Drugs, Lead Compounds, and Mechanisms.
Antioxidant Role of Kaempferol in Prevention of Hepatocellular Carcinoma.
Applications of Aptamer-Bound Nanomaterials in Cancer Therapy.
Metformin and sodium dichloroacetate effects on proliferation, apoptosis, and metabolic activity tested alone and in combination in a canine prostate and a bladder cancer cell line.
Metformin and Dichloroacetate Suppress Proliferation of Liver Cancer Cells by Inhibiting mTOR Complex 1.
Anticipating resistance to KRAS inhibition: a novel role for USP21 in macropinocytosis regulation.
Oncogenes, Proto-Oncogenes, and Lineage Restriction of Cancer Stem Cells.
Recent Advances in Phenolic Metabolites and Skin Cancer.
Targeting Autophagy with Natural Products as a Potential Therapeutic Approach for Cancer.
Cancer Biology, Epidemiology, and Treatment in the 21st Century: Current Status and Future Challenges From a Biomedical Perspective.
Photodynamic cancer therapy using liposomes as an advanced vesicular photosensitizer delivery system.
Intermittent and Periodic Fasting, Hormones, and Cancer Prevention.
Peptide-Conjugated Nano Delivery Systems for Therapy and Diagnosis of Cancer.
Targeting Tumor Cells with Nanoparticles for Enhanced Co-Drug Delivery in Cancer Treatment.
Bioactive Compounds of Arthrospira spp. (Spirulina) with Potential Anticancer Activities: A Systematic Review.
The Pro-Health Benefits of Morusin Administration-An Update Review.
Potential of Bioactive Food Components against Gastric Cancer: Insights into Molecular Mechanism and Therapeutic Targets.

Cancer Res. 2021 Oct 01. 81(19): 4896-4898

Cancer Signaling Drives Cancer Metabolism: AKT and the Warburg Effect.

Aaron M Hosios, Brendan D Manning.

The Warburg effect, the propensity of some cells to metabolize glucose to lactate in the presence of oxygen (also known as aerobic glycolysis), has long been observed in cancer and other contexts of cell proliferation, but only in the past two decades have significant gains been made in understanding how and why this metabolic transformation occurs. In 2004, Cancer Research published a study by Elstrom and colleagues that provided one of the first connections between a specific oncogene and aerobic glycolysis. Studying hematopoietic and glioblastoma cell lines, they demonstrated that constitutive activation of AKT promotes an increased glycolytic rate without altering proliferation or oxygen consumption in culture. They proposed that it is this effect that allows constitutive AKT activation to transform cells and found that it sensitizes cells to glucose deprivation. In the years since, mechanistic understanding of oncogenic control of metabolism, and glycolysis specifically, has deepened substantially. Current work seeks to understand the benefits and liabilities associated with glycolytic metabolism and to identify inhibitors that might be of clinical benefit to target glycolytic cancer cells.See related article by Elstrom and colleagues, Cancer Res 2004;64:3892-9.

DOI: https://doi.org/10.1158/0008-5472.CAN-21-2647
Cancers (Basel). 2021 Sep 19. pii: 4699. [Epub ahead of print]13(18):

Metabolic Flexibility Is a Determinant of Breast Cancer Heterogeneity and Progression.

Marina Fukano, Morag Park, Geneviève Deblois.

  Breast cancer progression is characterized by changes in cellular metabolism that contribute to enhanced tumour growth and adaptation to microenvironmental stresses. Metabolic changes within breast tumours are still poorly understood and are not as yet exploited for therapeutic intervention, in part due to a high level of metabolic heterogeneity within tumours. The metabolic profiles of breast cancer cells are flexible, providing dynamic switches in metabolic states to accommodate nutrient and energy demands and further aggravating the challenges of targeting metabolic dependencies in cancer. In this review, we discuss the intrinsic and extrinsic factors that contribute to metabolic heterogeneity of breast tumours. Next, we examine how metabolic flexibility, which contributes to the metabolic heterogeneity of breast tumours, can alter epigenetic landscapes and increase a variety of pro-tumorigenic functions. Finally, we highlight the difficulties in pharmacologically targeting the metabolic adaptations of breast tumours and provide an overview of possible strategies to sensitize heterogeneous breast tumours to the targeting of metabolic vulnerabilities.

Keywords:  adaptive capacity; breast cancer; epigenetic reprogramming; metabolic flexibility; metabolic heterogeneity; metabolic plasticity; tumour microenvironment

DOI:  https://doi.org/10.3390/cancers13184699
Int J Mol Sci. 2021 Sep 08. pii: 9722. [Epub ahead of print]22(18):

Small Molecules Targeting Programmed Cell Death in Breast Cancer Cells.

Subashani Maniam, Sandra Maniam.

  Targeted chemotherapy has become the forefront for cancer treatment in recent years. The selective and specific features allow more effective treatment with reduced side effects. Most targeted therapies, which include small molecules, act on specific molecular targets that are altered in tumour cells, mainly in cancers such as breast, lung, colorectal, lymphoma and leukaemia. With the recent exponential progress in drug development, programmed cell death, which includes apoptosis and autophagy, has become a promising therapeutic target. The research in identifying effective small molecules that target compensatory mechanisms in tumour cells alleviates the emergence of drug resistance. Due to the heterogenous nature of breast cancer, various attempts were made to overcome chemoresistance. Amongst breast cancers, triple negative breast cancer (TNBC) is of particular interest due to its heterogeneous nature in response to chemotherapy. TNBC represents approximately 15% of all breast tumours, however, and still has a poor prognosis. Unlike other breast tumours, signature targets lack for TNBCs, causing high morbidity and mortality. This review highlights several small molecules with promising preclinical data that target autophagy and apoptosis to induce cell death in TNBC cells.

Keywords:  apoptosis; autophagy; breast cancer; programmed cell death; small molecule

DOI:  https://doi.org/10.3390/ijms22189722
Nutrients. 2021 Sep 15. pii: 3202. [Epub ahead of print]13(9):

Ketogenic Diets in Pancreatic Cancer and Associated Cachexia: Cellular Mechanisms and Clinical Perspectives.

Natalia E Cortez, Gerardo G Mackenzie.

  Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and extremely therapy-resistant cancer. It is estimated that up to 80% of PDAC patients present with cachexia, a multifactorial disorder characterized by the involuntary and ongoing wasting of skeletal muscle that affects therapeutic response and survival. During the last decade, there has been an increased interest in exploring dietary interventions to complement the treatment of PDAC and associated cachexia. Ketogenic diets (KDs) have gained attention for their anti-tumor potential. Characterized by a very low carbohydrate, moderate protein, and high fat composition, this diet mimics the metabolic changes that occur in fasting. Numerous studies report that a KD reduces tumor growth and can act as an adjuvant therapy in various cancers, including pancreatic cancer. However, research on the effect and mechanisms of action of KDs on PDAC-associated cachexia is limited. In this narrative review, we summarize the evidence of the impact of KDs in PDAC treatment and cachexia mitigation. Furthermore, we discuss key cellular mechanisms that explain KDs' potential anti-tumor and anti-cachexia effects, focusing primarily on reprogramming of cell metabolism, epigenome, and the gut microbiome. Finally, we provide a perspective on future research needed to advance KDs into clinical use.

Keywords:  cancer cachexia; cell metabolism; ketogenic diet; ketone bodies; microbiome; pancreatic cancer; pancreatic ductal adenocarcinoma

DOI:  https://doi.org/10.3390/nu13093202
Front Pharmacol. 2021 ;12 723798

Glucose and Amino Acid Metabolic Dependencies Linked to Stemness and Metastasis in Different Aggressive Cancer Types.

Andrea Chisari, Irene Golán, Sabrina Campisano, Caroline Gélabert, Aristidis Moustakas, Patricia Sancho, Laia Caja.

  Malignant cells are commonly characterised by being capable of invading tissue, growing self-sufficiently and uncontrollably, being insensitive to apoptosis induction and controlling their environment, for example inducing angiogenesis. Amongst them, a subpopulation of cancer cells, called cancer stem cells (CSCs) shows sustained replicative potential, tumor-initiating properties and chemoresistance. These characteristics make CSCs responsible for therapy resistance, tumor relapse and growth in distant organs, causing metastatic dissemination. For these reasons, eliminating CSCs is necessary in order to achieve long-term survival of cancer patients. New insights in cancer metabolism have revealed that cellular metabolism in tumors is highly heterogeneous and that CSCs show specific metabolic traits supporting their unique functionality. Indeed, CSCs adapt differently to the deprivation of specific nutrients that represent potentially targetable vulnerabilities. This review focuses on three of the most aggressive tumor types: pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC) and glioblastoma (GBM). The aim is to prove whether CSCs from different tumour types share common metabolic requirements and responses to nutrient starvation, by outlining the diverse roles of glucose and amino acids within tumour cells and in the tumour microenvironment, as well as the consequences of their deprivation. Beyond their role in biosynthesis, they serve as energy sources and help maintain redox balance. In addition, glucose and amino acid derivatives contribute to immune responses linked to tumourigenesis and metastasis. Furthermore, potential metabolic liabilities are identified and discussed as targets for therapeutic intervention.

Keywords:  GBM-glioblastoma multiforme; HCC-hepatocellular carcinoma; PDAC-pancreatic ductal adenocarcinoma; amino acid; cancer stem cell (CSC); glucose; therapy

DOI:  https://doi.org/10.3389/fphar.2021.723798
Genes (Basel). 2021 Aug 25. pii: 1305. [Epub ahead of print]12(9):

Glutamine Metabolism Regulators Associated with Cancer Development and the Tumor Microenvironment: A Pan-Cancer Multi-Omics Analysis.

Jingwen Zou, Kunpeng Du, Shaohua Li, Lianghe Lu, Jie Mei, Wenping Lin, Min Deng, Wei Wei, Rongping Guo.

  BACKGROUND: In recent years, metabolic reprogramming has been identified as a hallmark of cancer. Accumulating evidence suggests that glutamine metabolism plays a crucial role in oncogenesis and the tumor microenvironment. In this study, we aimed to perform a systematic and comprehensive analysis of six key metabolic node genes involved in the dynamic regulation of glutamine metabolism (referred to as GLNM regulators) across 33 types of cancer.METHODS: We analyzed the gene expression, epigenetic regulation, and genomic alterations of six key GLNM regulators, including SLC1A5, SLC7A5, SLC3A2, SLC7A11, GLS, and GLS2, in pan-cancer using several open-source platforms and databases. Additionally, we investigated the impacts of these gene expression changes on clinical outcomes, drug sensitivity, and the tumor microenvironment. We also attempted to investigate the upstream microRNA-mRNA molecular networks and the downstream signaling pathways involved in order to uncover the potential molecular mechanisms behind metabolic reprogramming.
RESULTS: We found that the expression levels of GLNM regulators varied across cancer types and were related to several genomic and immunological characteristics. While the immune scores were generally lower in the tumors with higher gene expression, the types of immune cell infiltration showed significantly different correlations among cancer types, dividing them into two clusters. Furthermore, we showed that elevated GLNM regulators expression was associated with poor overall survival in the majority of cancer types. Lastly, the expression of GLNM regulators was significantly associated with PD-L1 expression and drug sensitivity.
CONCLUSIONS: The elevated expression of GLNM regulators was associated with poorer cancer prognoses and a cold tumor microenvironment, providing novel insights into cancer treatment and possibly offering alternative options for the treatment of clinically refractory cancers.

Keywords:  PD-L1; glutamine; immune; metabolism; multi-omics; pan-cancer

DOI:  https://doi.org/10.3390/genes12091305
Cancers (Basel). 2021 Sep 12. pii: 4576. [Epub ahead of print]13(18):

The Evolving Role of Ferroptosis in Breast Cancer: Translational Implications Present and Future.

Hung-Yu Lin, Hui-Wen Ho, Yen-Hsiang Chang, Chun-Jui Wei, Pei-Yi Chu.

  Breast cancer (BC) is the most common malignancy among women worldwide. The discovery of regulated cell death processes has enabled advances in the treatment of BC. In the past decade, ferroptosis, a new form of iron-dependent regulated cell death caused by excessive lipid peroxidation has been implicated in the development and therapeutic responses of BC. Intriguingly, the induction of ferroptosis acts to suppress conventional therapy-resistant cells, and to potentiate the effects of immunotherapy. As such, pharmacological or genetic modulation targeting ferroptosis holds great potential for the treatment of drug-resistant cancers. In this review, we present a critical analysis of the current understanding of the molecular mechanisms and regulatory networks involved in ferroptosis, the potential physiological functions of ferroptosis in tumor suppression, its potential in therapeutic targeting, and explore recent advances in the development of therapeutic strategies for BC.

Keywords:  antioxidant defense; breast cancer; ferroptosis; iron metabolism; lipid peroxidation; therapy

DOI:  https://doi.org/10.3390/cancers13184576
Cells. 2021 Sep 09. pii: 2371. [Epub ahead of print]10(9):

HIF-1-Independent Mechanisms Regulating Metabolic Adaptation in Hypoxic Cancer Cells.

Shen-Han Lee, Monika Golinska, John R Griffiths.

  In solid tumours, cancer cells exist within hypoxic microenvironments, and their metabolic adaptation to this hypoxia is driven by HIF-1 transcription factor, which is overexpressed in a broad range of human cancers. HIF inhibitors are under pre-clinical investigation and clinical trials, but there is evidence that hypoxic cancer cells can adapt metabolically to HIF-1 inhibition, which would provide a potential route for drug resistance. Here, we review accumulating evidence of such adaptions in carbohydrate and creatine metabolism and other HIF-1-independent mechanisms that might allow cancers to survive hypoxia despite anti-HIF-1 therapy. These include pathways in glucose, glutamine, and lipid metabolism; epigenetic mechanisms; post-translational protein modifications; spatial reorganization of enzymes; signalling pathways such as Myc, PI3K-Akt, 2-hyxdroxyglutarate and AMP-activated protein kinase (AMPK); and activation of the HIF-2 pathway. All of these should be investigated in future work on hypoxia bypass mechanisms in anti-HIF-1 cancer therapy. In principle, agents targeted toward HIF-1β rather than HIF-1α might be advantageous, as both HIF-1 and HIF-2 require HIF-1β for activation. However, HIF-1β is also the aryl hydrocarbon nuclear transporter (ARNT), which has functions in many tissues, so off-target effects should be expected. In general, cancer therapy by HIF inhibition will need careful attention to potential resistance mechanisms.

Keywords:  2-hydroxyglutarate; AMP-activated protein kinase (AMPK); Myc; cancer metabolism; creatine metabolism; glutamine metabolism; glycolysis; hypoxia; hypoxia-inducible factor-1 (HIF-1); lipid metabolism; phosphatidylinositol 3-kinase (PI3K)

DOI:  https://doi.org/10.3390/cells10092371
Cells. 2021 Sep 12. pii: 2398. [Epub ahead of print]10(9):

Inhibition of Metabolism as a Therapeutic Option for Tamoxifen-Resistant Breast Cancer Cells.

Friederike Steifensand, Julia Gallwas, Gerd Bauerschmitz, Carsten Gründker.

  Cancer cells have an increased need for glucose and, despite aerobic conditions, obtain their energy through aerobic oxidation and lactate fermentation, instead of aerobic oxidation alone. Glutamine is an essential amino acid in the human body. Glutaminolysis and glycolysis are crucial for cancer cell survival. In the therapy of estrogen receptor α (ERα)-positive breast cancer (BC), the focus lies on hormone sensitivity targeting therapy with selective estrogen receptor modulators (SERMs) such as 4-hydroxytamoxifen (4-OHT), although this therapy is partially limited by the development of resistance. Therefore, further targets for therapy improvement of ERα-positive BC with secondary 4-OHT resistance are needed. Hence, increased glucose requirement and upregulated glutaminolysis in BC cells could be used. We have established sublines of ERα-positive MCF7 and T47D BC cells, which were developed to be resistant to 4-OHT. Further, glycolysis inhibitor 2-Deoxy-D-Glucose (2-DG) and glutaminase inhibitor CB-839 were analyzed. Co-treatments using 4-OHT and CB-839, 2-DG and CB-839, or 4-OHT, 2-DG and CB-839, respectively, showed significantly stronger inhibitory effects on viability compared to single treatments. It could be shown that tamoxifen-resistant BC cell lines, compared to the non-resistant cell lines, exhibited a stronger reducing effect on cell viability under co-treatments. In addition, the tamoxifen-resistant BC cell lines showed increased expression of proto-oncogene c-Myc compared to the parental cell lines. This could be reduced depending on the treatment. Suppression of c-Myc expression using specific siRNA completely abolished resistance to 4OH-tamoxifen. In summary, our data suggest that combined treatments affecting the metabolism of BC are suitable depending on the cellularity and resistance status. In addition, the anti-metabolic treatments affected the expression of the proto-oncogene c-Myc, a key player in the regulation of cancer cell metabolism.

Keywords:  breast cancer; estrogen receptor α; glutaminolysis; glycolysis; tamoxifen resistance

DOI:  https://doi.org/10.3390/cells10092398
Nutrients. 2021 Aug 24. pii: 2923. [Epub ahead of print]13(9):

Moringa Oleifera Seed Extract Concomitantly Supplemented with Chemotherapy Worsens Tumor Progression in Mice with Triple Negative Breast Cancer and Obesity.

Elizabeth R M Zunica, Shengping Yang, Ann Coulter, Christy White, John P Kirwan, Linda A Gilmore.

  Triple negative breast cancer (TNBC) is an aggressive and highly metastatic breast cancer subtype with limited treatment options. Obesity and insulin resistance are associated with a worse prognosis in those with TNBC. Moringa oleifera (moringa) is a tropical edible plant used for both food and medicinal purposes and found to have anti-obesity and anti-cancer effects in vitro and in preclinical models. The anti-cancer effects of moringa seed extract alone and in combination with chemotherapy were evaluated in immunocompromised female mice with diet-induced obesity bearing MDA-MB-231-derived xenograft tumors. Moringa supplementation protected against high-fat diet- and chemotherapy-induced increases in fasting glucose and improved insulin sensitivity. Moringa supplementation alone did not attenuate tumor growth relative to chemotherapy alone, and in combination worsened tumor progression. Moringa supplementation alone reduced angiogenesis, but this effect was abrogated in combination with chemotherapy. Moringa supplementation may be an effective strategy to improve metabolic health in mice with obesity and TNBC and reduce angiogenesis in tumors, but may have a negative interaction when used as a concurrent complementary therapy. Caution should be taken when considering the consumption of moringa seed extracts while receiving chemotherapy for breast cancer treatment. Further investigations of alternative timings of moringa therapy are warranted.

Keywords:  chemotherapy; herbal supplement; moringa oleifera; obesity; triple negative breast cancer

DOI:  https://doi.org/10.3390/nu13092923
Life (Basel). 2021 Sep 14. pii: 963. [Epub ahead of print]11(9):

Calcitriol Suppresses Warburg Effect and Cell Growth in Human Colorectal Cancer Cells.

Chun-Yin Huang, Yu-Ting Weng, Po-Chen Li, Nien-Tsu Hsieh, Chun-I Li, Hsiao-Sheng Liu, Ming-Fen Lee.

  Increasing lines of evidence indicate that the biologically active form of vitamin D, calcitriol (1,25-dihydroxyvitamin D3), prevents cancer progression by reducing cell proliferation, increasing cell differentiation, and inhibiting angiogenesis, among other potential roles. Cancer cells in solid tumors preferably undergo the "Warburg effect" to support cell growth by upregulating glycolysis, and the glycolytic intermediates further serve as building blocks to generate biomass. The objective of the current study is to investigate whether calcitriol affects glucose metabolism and cell growth in human colorectal cancer cells. Calcitriol reduced the expression of cyclin D1 and c-Myc. In addition, calcitriol reduced the expression of glucose transporter 1 (GLUT1) and key glycolytic enzymes and decreased extracellular acidification rate but increased oxygen consumption rate in human colorectal cancer cells. In a subcutaneous HT29 xenograft NOD/SCID mouse model, the volume and weight of the tumors were smaller in the calcitriol groups as compared with the control group, and the expression levels of GLUT1 and glycolytic enzymes, hexokinase 2 and lactate dehydrogenase A, were also lower in the calcitriol groups in a dose-responsive manner. Our data indicate that calcitriol suppresses glycolysis and cell growth in human colorectal cancer cells, suggesting an inhibitory role of the biologically active form of vitamin D in colorectal cancer progression.

Keywords:  Warburg effect; calcitriol; cell growth; colorectal cancer; vitamin D

DOI:  https://doi.org/10.3390/life11090963
Nutrients. 2021 Sep 10. pii: 3162. [Epub ahead of print]13(9):

An Updated Comprehensive Review on Vitamin A and Carotenoids in Breast Cancer: Mechanisms, Genetics, Assessment, Current Evidence, and Future Clinical Implications.

Jee Ah Kim, Ja-Hyun Jang, Soo-Youn Lee.

  Vitamin A and carotenoids are fat-soluble micronutrients that play important role as powerful antioxidants modulating oxidative stress and cancer development. Breast cancer is the most common malignancy in women. As the risk of breast cancer is dependent on various lifestyle factors such as dietary modifications, there is increasing interest surrounding the anti-cancerous properties of vitamin A and carotenoids. Despite the suggested protective roles of vitamin A and carotenoids in breast cancer development, their clinical application for the prevention and treatment of breast cancer is limited. In this narrative review, we discuss the roles of vitamin A and carotenoids along with the evaluation method of vitamin A status. We also exhibit the association of genetic variations involved in metabolism of vitamin A and carotenoids with cancers and other diseases. We demonstrate the epidemiological evidence for the relationship of vitamin A and carotenoids with breast cancer risk, their effects on cancer mechanism, and the recent updates in clinical practice of vitamin A or carotenoids as a potential therapeutic agent against breast cancer. This review provides insight into the preventive and therapeutic roles of vitamin A and carotenoids in breast cancer development and progression.

Keywords:  breast cancer; cancer risk; cancer signaling; carotenoids; novel targets; prevention; retinoids; treatment; vitamin A

DOI:  https://doi.org/10.3390/nu13093162
Cancers (Basel). 2021 Sep 10. pii: 4544. [Epub ahead of print]13(18):

Multi-Omic Approaches to Breast Cancer Metabolic Phenotyping: Applications in Diagnosis, Prognosis, and the Development of Novel Treatments.

Nuria Gómez-Cebrián, Inés Domingo-Ortí, José Luis Poveda, María J Vicent, Leonor Puchades-Carrasco, Antonio Pineda-Lucena.

  Breast cancer (BC) is characterized by high disease heterogeneity and represents the most frequently diagnosed cancer among women worldwide. Complex and subtype-specific gene expression alterations participate in disease development and progression, with BC cells known to rewire their cellular metabolism to survive, proliferate, and invade. Hence, as an emerging cancer hallmark, metabolic reprogramming holds great promise for cancer diagnosis, prognosis, and treatment. Multi-omics approaches (the combined analysis of various types of omics data) offer opportunities to advance our understanding of the molecular changes underlying metabolic rewiring in complex diseases such as BC. Recent studies focusing on the combined analysis of genomics, epigenomics, transcriptomics, proteomics, and/or metabolomics in different BC subtypes have provided novel insights into the specificities of metabolic rewiring and the vulnerabilities that may guide therapeutic development and improve patient outcomes. This review summarizes the findings of multi-omics studies focused on the characterization of the specific metabolic phenotypes of BC and discusses how they may improve clinical BC diagnosis, subtyping, and treatment.

Keywords:  biomarkers; breast cancer; early diagnosis; metabolism; multi-omics; prognosis; subtyping; treatment

DOI:  https://doi.org/10.3390/cancers13184544
Cells. 2021 Sep 17. pii: 2462. [Epub ahead of print]10(9):

Ferroptosis Meets Cell-Cell Contacts.

Cornelia Dietrich, Thomas G Hofmann.

  Ferroptosis is a regulated form of cell death characterized by iron dependency and increased lipid peroxidation. Initially assumed to be selectively induced in tumour cells, there is increasing evidence that ferroptosis plays an important role in pathophysiology and numerous cell types and tissues. Deregulated ferroptosis has been linked to human diseases, such as neurodegenerative diseases, cardiovascular disorders, and cancer. Along these lines, ferroptosis is a promising pathway to overcoming therapy resistance of cancer cells. It is therefore of utmost importance to understand the cellular signalling pathways and the molecular mechanisms underlying ferroptosis regulation, including context-specific effects mediated by the neighbouring cells through cell-cell contacts. Here, we give an overview on the molecular events and machinery linked to ferroptosis induction and commitment. We further summarize and discuss current knowledge about the role of cell-cell contacts, which differ in ferroptosis regulation between normal somatic cells and cancer cells. We present emerging concepts on the underlying mechanisms, address open questions, and discuss the possible impact of cell-cell contacts on exploiting ferroptosis in cancer therapy.

Keywords:  cancer therapy; cell–cell contacts; epithelial–mesenchymal transition; ferroptosis

DOI:  https://doi.org/10.3390/cells10092462
Front Cell Dev Biol. 2021 ;9 736935

Targeting Histone Modifications in Breast Cancer: A Precise Weapon on the Way.

Wei Li, Hao Wu, Shiyao Sui, Qin Wang, Shouping Xu, Da Pang.

  Histone modifications (HMs) contribute to maintaining genomic stability, transcription, DNA repair, and modulating chromatin in cancer cells. Furthermore, HMs are dynamic and reversible processes that involve interactions between numerous enzymes and molecular components. Aberrant HMs are strongly associated with tumorigenesis and progression of breast cancer (BC), although the specific mechanisms are not completely understood. Moreover, there is no comprehensive overview of abnormal HMs in BC, and BC therapies that target HMs are still in their infancy. Therefore, this review summarizes the existing evidence regarding HMs that are involved in BC and the potential mechanisms that are related to aberrant HMs. Moreover, this review examines the currently available agents and approved drugs that have been tested in pre-clinical and clinical studies to evaluate their effects on HMs. Finally, this review covers the barriers to the clinical application of therapies that target HMs, and possible strategies that could help overcome these barriers and accelerate the use of these therapies to cure patients.

Keywords:  acetylation; breast cancer; epi-drugs; histone modification; methylation

DOI:  https://doi.org/10.3389/fcell.2021.736935
Int J Mol Sci. 2021 Sep 10. pii: 9819. [Epub ahead of print]22(18):

Anti-Cancer Activity of Phytochemicals Targeting Hypoxia-Inducible Factor-1 Alpha.

Ba Da Yun, Seung Wan Son, Soo Young Choi, Hyo Jeong Kuh, Tae-Jin Oh, Jong Kook Park.

  Hypoxia-inducible factor-1 alpha (HIF-1α) is overexpressed in cancer, leading to a poor prognosis in patients. Diverse cellular factors are able to regulate HIF-1α expression in hypoxia and even in non-hypoxic conditions, affecting its progression and malignant characteristics by regulating the expression of the HIF-1α target genes that are involved in cell survival, angiogenesis, metabolism, therapeutic resistance, et cetera. Numerous studies have exhibited the anti-cancer effect of HIF-1α inhibition itself and the augmentation of anti-cancer treatment efficacy by interfering with HIF-1α-mediated signaling. The anti-cancer effect of plant-derived phytochemicals has been evaluated, and they have been found to possess significant therapeutic potentials against numerous cancer types. A better understanding of phytochemicals is indispensable for establishing advanced strategies for cancer therapy. This article reviews the anti-cancer effect of phytochemicals in connection with HIF-1α regulation.

Keywords:  HIF; cancer; hypoxia; naturally derived compounds; normoxia; phytochemical

DOI:  https://doi.org/10.3390/ijms22189819
Cancers (Basel). 2021 Sep 07. pii: 4499. [Epub ahead of print]13(18):

Dietary Polyphenols: Promising Adjuvants for Colorectal Cancer Therapies.

Laura Bracci, Alessia Fabbri, Manuela Del Cornò, Lucia Conti.

  Colorectal cancer (CRC) is a major cancer type and a leading cause of death worldwide. Despite advances in therapeutic management, the current medical treatments are not sufficient to control metastatic disease. Treatment-related adverse effects and drug resistance strongly contribute to therapy failure and tumor recurrence. Combination therapy, involving cytotoxic treatments and non-toxic natural compounds, is arousing great interest as a promising more effective and safer alternative. Polyphenols, a heterogeneous group of bioactive dietary compounds mainly found in fruit and vegetables, have received great attention for their capacity to modulate various molecular pathways active in cancer cells and to affect host anticancer response. This review provides a summary of the most recent (i.e., since 2016) preclinical and clinical studies using polyphenols as adjuvants for CRC therapies. These studies highlight the beneficial effects of dietary polyphenols in combination with cytotoxic drugs or irradiation on both therapy outcome and drug resistance. Despite substantial preclinical evidence, data from a few pilot clinical trials are available to date with promising but still inconclusive results. Larger randomized controlled studies and polyphenol formulations with improved bioavailability are needed to translate the research progress into clinical applications and definitively prove the added value of these molecules in CRC management.

Keywords:  anticancer drug; clinical study; colorectal cancer; combination therapy; polyphenols; preclinical study

DOI:  https://doi.org/10.3390/cancers13184499
Pharmaceutics. 2021 Aug 27. pii: 1345. [Epub ahead of print]13(9):

Liposome Photosensitizer Formulations for Effective Cancer Photodynamic Therapy.

Sherif Ashraf Fahmy, Hassan Mohamed El-Said Azzazy, Jens Schaefer.

  Photodynamic therapy (PDT) is a promising non-invasive strategy in the fight against that which circumvents the systemic toxic effects of chemotherapeutics. It relies on photosensitizers (PSs), which are photoactivated by light irradiation and interaction with molecular oxygen. This generates highly reactive oxygen species (such as 1O2, H2O2, O2, ·OH), which kill cancer cells by necrosis or apoptosis. Despite the promising effects of PDT in cancer treatment, it still suffers from several shortcomings, such as poor biodistribution of hydrophobic PSs, low cellular uptake, and low efficacy in treating bulky or deep tumors. Hence, various nanoplatforms have been developed to increase PDT treatment effectiveness and minimize off-target adverse effects. Liposomes showed great potential in accommodating different PSs, chemotherapeutic drugs, and other therapeutically active molecules. Here, we review the state-of-the-art in encapsulating PSs alone or combined with other chemotherapeutic drugs into liposomes for effective tumor PDT.

Keywords:  cancer; liposomes; photodynamic therapy; photosensitizers; stealth liposomes; tetraether lipids; thermosensitive liposomes

DOI:  https://doi.org/10.3390/pharmaceutics13091345
Genes (Basel). 2021 Sep 11. pii: 1402. [Epub ahead of print]12(9):

Wild-Type KRAS Allele Effects on Druggable Targets in KRAS Mutant Lung Adenocarcinomas.

Elisa Baldelli, Emna El Gazzah, John Conor Moran, Kimberley A Hodge, Zarko Manojlovic, Rania Bassiouni, John D Carpten, Vienna Ludovini, Sara Baglivo, Lucio Crinò, Fortunato Bianconi, Ting Dong, Jeremy Loffredo, Emanuel F Petricoin, Mariaelena Pierobon.

  KRAS mutations are one of the most common oncogenic drivers in non-small cell lung cancer (NSCLC) and in lung adenocarcinomas in particular. Development of therapeutics targeting KRAS has been incredibly challenging, prompting indirect inhibition of downstream targets such as MEK and ERK. Such inhibitors, unfortunately, come with limited clinical efficacy, and therefore the demand for developing novel therapeutic strategies remains an urgent need for these patients. Exploring the influence of wild-type (WT) KRAS on druggable targets can uncover new vulnerabilities for the treatment of KRAS mutant lung adenocarcinomas. Using commercially available KRAS mutant lung adenocarcinoma cell lines, we explored the influence of WT KRAS on signaling networks and druggable targets. Expression and/or activation of 183 signaling proteins, most of which are targets of FDA-approved drugs, were captured by reverse-phase protein microarray (RPPA). Selected findings were validated on a cohort of 23 surgical biospecimens using the RPPA. Kinase-driven signatures associated with the presence of the KRAS WT allele were detected along the MAPK and AKT/mTOR signaling pathway and alterations of cell cycle regulators. FoxM1 emerged as a potential vulnerability of tumors retaining the KRAS WT allele both in cell lines and in the clinical samples. Our findings suggest that loss of WT KRAS impacts on signaling events and druggable targets in KRAS mutant lung adenocarcinomas.

Keywords:  KRAS; drug target; non-small cell lung cancer; reverse-phase protein microarray; zygosity

DOI:  https://doi.org/10.3390/genes12091402
Biomedicines. 2021 Sep 04. pii: 1159. [Epub ahead of print]9(9):

Galectins in Cancer and the Microenvironment: Functional Roles, Therapeutic Developments, and Perspectives.

Chien-Hsiu Li, Yu-Chan Chang, Ming-Hsien Chan, Yi-Fang Yang, Shu-Mei Liang, Michael Hsiao.

  Changes in cell growth and metabolism are affected by the surrounding environmental factors to adapt to the cell's most appropriate growth model. However, abnormal cell metabolism is correlated with the occurrence of many diseases and is accompanied by changes in galectin (Gal) performance. Gals were found to be some of the master regulators of cell-cell interactions that reconstruct the microenvironment, and disordered expression of Gals is associated with multiple human metabolic-related diseases including cancer development. Cancer cells can interact with surrounding cells through Gals to create more suitable conditions that promote cancer cell aggressiveness. In this review, we organize the current understanding of Gals in a systematic way to dissect Gals' effect on human disease, including how Gals' dysregulated expression affects the tumor microenvironment's metabolism and elucidating the mechanisms involved in Gal-mediated diseases. This information may shed light on a more precise understanding of how Gals regulate cell biology and facilitate the development of more effective therapeutic strategies for cancer treatment by targeting the Gal family.

Keywords:  cancer; galectin; metabolism; tumor microenvironment

DOI:  https://doi.org/10.3390/biomedicines9091159
Biomolecules. 2021 Sep 09. pii: 1336. [Epub ahead of print]11(9):

Mediterranean Diet Food Components as Possible Adjuvant Therapies to Counteract Breast and Prostate Cancer Progression to Bone Metastasis.

Paola Maroni, Paola Bendinelli, Alessandro Fulgenzi, Anita Ferraretto.

  Bone metastasis is a serious and often lethal complication of particularly frequent carcinomas, such as breast and prostate cancers, which not only reduces survival but also worsens the patients' quality of life. Therefore, it is important to find new and/or additional therapeutic possibilities that can counteract the colonization of bone tissue. High adherence to the Mediterranean diet (MD) is effective in the prevention of cancer and improves cancer patients' health, thus, here, we considered its impact on bone metastasis. We highlighted some molecular events relevant for the development of a metastatic phenotype in cancer cells and the alterations of physiological bone remodeling, which occur during skeleton colonization. We then considered those natural compounds present in MD foods with a recognized role to inhibit or reverse the metastatic process both in in vivo and in vitro systems, and we reported the identified mechanisms of action. The knowledge of this bioactivity by the dietary components of the MD, together with its wide access to all people, could help not only to maintain healthy status but also to improve the quality of life of patients with bone metastases.

Keywords:  Mediterranean diet; bone metastasis; breast cancer; epithelial-mesenchymal transition; nutrients; osteoblastic bone metastasis; osteolytic bone metastasis; prostate cancer

DOI:  https://doi.org/10.3390/biom11091336
Eur J Med Chem. 2021 Sep 04. pii: S0223-5234(21)00674-7. [Epub ahead of print]226 113825

Combining histone deacetylase inhibitors (HDACis) with other therapies for cancer therapy.

Mengjiao Zhou, Minjian Yuan, Meng Zhang, Chenyi Lei, Omer Aras, Xiaohong Zhang, Feifei An.

  Histone deacetylases (HDACs) play an important role in regulating the expression of genes involved in tumorigenesis and tumor maintenance, and hence they have been considered as key targets in cancer therapy. As a novel category of antitumor agents, histone deacetylase inhibitors (HDACis) can induce cell cycle arrest, apoptosis, and differentiation in cancer cells, ultimately combating cancer. Although in the United States, the use of HDACis for the treatment of certain cancers has been approved, the therapeutic efficacy of HDACis as a single therapeutic agent in solid tumorshas been unsatisfactory and drug resistance may yet occur. To enhance therapeutic efficacy and limit drug resistance, numerous combination therapies involving HDACis in synergy with other antitumor therapies have been studied. In this review, we describe the classification of HDACs. Moreover, we summarize the antitumor mechanism of the HDACis for targeting key cellular processes of cancers (cell cycle, apoptosis, angiogenesis, DNA repair, and immune response). In addition, we outline the major developments of other antitumor therapies in combination with HDACis, including chemotherapy, radiotherapy, phototherapy, targeted therapy, and immunotherapy. Finally, we discuss the current state and challenges of HDACis-drugs combinations in future clinical studies, with the aim of optimizing the antitumor effect of such combinations.

Keywords:  Cancer; Combination therapies; Histone deacetylases inhibitors; Histone deacetylations

DOI:  https://doi.org/10.1016/j.ejmech.2021.113825
Biochim Biophys Acta Gen Subj. 2021 Sep 28. pii: S0304-4165(21)00180-X. [Epub ahead of print] 130021

Regulatory role of acetylation on enzyme activity and fluxes of energy metabolism pathways.

Rafael Moreno-Sánchez, Juan Carlos Gallardo-Pérez, Silvia Cecilia Pacheco-Velazquez, Diana Xochiquetzal Robledo-Cadena, Sara Rodríguez-Enríquez, Rusely Encalada, Emma Saavedra, Álvaro Marín-Hernández.

  BACKGROUND: Most of the enzymes involved in the central carbon metabolism are acetylated in Lys residues. It has been claimed that this covalent modification represents a novel regulatory mechanism by which both enzyme/transporter activities and pathway fluxes can be modulated.METHODS: To establish which enzymes are regulated by acetylation, a systematic experimental analysis of activities and acetylation profile for several energy metabolism enzymes and pathway fluxes was undertaken in cells and mitochondria.
RESULTS: The majority of the glycolytic and neighbor enzymes as well as mitochondrial enzymes indeed showed Lys-acetylation, with GLUT1, HPI, CS, ATP synthase displaying comparatively lower acetylation patterns. The incubation of cytosolic and mitochondrial fractions with recombinant Sirt-3 produced lower acetylation signals, whereas incubation with acetyl-CoA promoted protein acetylation. Significant changes in acetylation levels of MDH and IDH-2 from rat liver mitochondria revealed no change in their activities. Similar observations were attained for the cytosolic enzymes from AS-30D and HeLa cells. A minor but significant (23%) increase in the AAT-MDH complex activity induced by acetylation was observed. To examine this question further, AS-30D and HeLa cells were treated with nicotinamide and valproic acid. These compounds promoted changes in the acetylation patterns of glycolytic proteins, although their activities and the glycolytic flux (as well as the OxPhos flux) revealed no clear correlation with acetylation.
CONCLUSION: Acetylation seems to play no predominant role in the control of energy metabolism enzyme activities and pathway fluxes.
GENERAL SIGNIFICANCE: The physiological function of protein acetylation on energy metabolism pathways remains to be elucidated.

Keywords:  Acetyl-CoA; Cancer cells; Glycolysis; Nicotinamide; Sirt3; Valproic acid

DOI:  https://doi.org/10.1016/j.bbagen.2021.130021
Pharmaceutics. 2021 Sep 02. pii: 1391. [Epub ahead of print]13(9):

Delivery of Various Cargos into Cancer Cells and Tissues via Cell-Penetrating Peptides: A Review of the Last Decade.

Alireza Shoari, Raheleh Tooyserkani, Mehdi Tahmasebi, Dennis W P M Löwik.

  Cell-penetrating peptides (CPPs), also known as protein transduction domains, are a class of diverse amino acid sequences with the ability to cross cellular membranes. CPPs can deliver several bioactive cargos, including proteins, peptides, nucleic acids and chemotherapeutics, into cells. Ever since their discovery, synthetic and natural CPPs have been utilized in therapeutics delivery, gene editing and cell imaging in fundamental research and clinical experiments. Over the years, CPPs have gained significant attention due to their low cytotoxicity and high transduction efficacy. In the last decade, multiple investigations demonstrated the potential of CPPs as carriers for the delivery of therapeutics to treat various types of cancer. Besides their remarkable efficacy owing to fast and efficient delivery, a crucial benefit of CPP-based cancer treatments is delivering anticancer agents selectively, rather than mediating toxicities toward normal tissues. To obtain a higher therapeutic index and to improve cell and tissue selectivity, CPP-cargo constructions can also be complexed with other agents such as nanocarriers and liposomes to obtain encouraging outcomes. This review summarizes various types of CPPs conjugated to anticancer cargos. Furthermore, we present a brief history of CPP utilization as delivery systems for anticancer agents in the last decade and evaluate several reports on the applications of CPPs in basic research and preclinical studies.

Keywords:  cancer; cargos; cell-penetrating peptides; drug delivery; therapeutic molecules

DOI:  https://doi.org/10.3390/pharmaceutics13091391
Crit Rev Ther Drug Carrier Syst. 2021 ;38(6): 1-48

Understanding Nanotechnology in the Treatment of Oral Cancer: A Comprehensive Review.

Neeraj Taneja, Aftab Alam, Ranjana S Patnaik, Tannu Taneja, Sonia Gupta, Sunil M K.

Oral cancer is the 11th most common cancer in the world with a high morbidity rate. Various conventional therapies have been used for the treatment of oral cancer such as surgery, radiotherapy, and chemotherapy used either alone or in combination but these have many limitations, making them unsuitable for treating oral cancer. Nanotechnology has been emerged out as an innovative tool in the field of oral cancer which has proved to provide effective results overcoming the limitations of conventional drug therapies. This system involves a nanoparticle drug delivery system based on a targeted therapy in which therapeutic drugs or agents act on the targeted cells without affecting normal healthy cells. Literature has shown that several nanoparticles, organic and inorganic nanoparticles, have been used as the drug delivery system in different types of oral cancers such as oral squamous cell carcinoma, cancer of the tongue, head, and neck cancers. Drugs like cisplatin, 5-fluorouracil, methotrexate, doxorubicin, etc., when coated with nano-polymers have shown better results compared with conventional drugs in oral cancer. Other nanoparticles such as liposomes, hydrogels, nanodiamonds, carbon rods, etc. have also been used with minimal side effects. This paper aims to review and discuss various nanotechnology systems in the field of oral cancer and to evaluate the efficacy of these systems in treating oral cancer compared with conventional drug delivery methods.

DOI: https://doi.org/10.1615/CritRevTherDrugCarrierSyst.2021036437
Pharmaceutics. 2021 Aug 31. pii: 1375. [Epub ahead of print]13(9):

Targeted Photodynamic Therapy Using Alloyed Nanoparticle-Conjugated 5-Aminolevulinic Acid for Breast Cancer.

Hanieh Montaseri, Cherie Ann Kruger, Heidi Abrahamse.

  Photodynamic therapy (PDT) has been investigated as an effective, non-invasive, and alternative tumor-ablative therapy that uses photosensitizers (PSs) and safe irradiation light in the presence of oxygen to generate reactive oxygen species (ROS) to kill malignant cancer cells. However, the off-target activation of the PSs can hinder effective PDT. Therefore, an advanced drug delivery system is required to selectively deliver the PS to the therapeutic region only and reduce off-target side effects in cancer treatment. The integration of laser-initiated PDT with nanotechnology has provided new opportunities in cancer therapy. In this study, plasmonic bimetallic nanoparticles (NPs) were prepared for the targeted PDT (TPDT) of in vitro cultured MCF-7 breast cancer cells. The NPs were functionalized with PEG through Au-thiol linkage to enhance their biocompatibility and subsequently attached to the PS precursor 5-aminolevulinic acid via electrostatic interactions. In order to enhance specific targeting, anti-HER-2 antibodies (Ab) were decorated onto the surface of the nanoconjugate (NC) to fabricate a 5-ALA/Au-Ag-PEG-Ab NC. In vitro studies showed that the synthesized NC can enter MCF-7 cells and localize in the cytoplasm to metabolize 5-ALA to protoporphyrin IX (PpIX). Upon light irradiation, PpIX can efficiently produce ROS for the PDT treatment of MCF-7. Cellular viability studies showed a decrease from 49.8% ± 5.6 ** to 13.8% ± 2.0 *** for free 5-ALA versus the NC, respectively, under equivalent concentrations of the PS (0.5 mM, IC50). These results suggest that the active targeted NC platform has an improved PDT effect on MCF-7 breast cancer cells.

Keywords:  5-aminolevulinic acid; MCF-7 breast cancer treatment; alloyed bimetallic nanoparticles; targeted photodynamic therapy

DOI:  https://doi.org/10.3390/pharmaceutics13091375
Pharmaceutics. 2021 Aug 25. pii: 1332. [Epub ahead of print]13(9):

Photodynamic Therapy Review: Principles, Photosensitizers, Applications, and Future Directions.

José H Correia, José A Rodrigues, Sara Pimenta, Tao Dong, Zhaochu Yang.

  Photodynamic therapy (PDT) is a minimally invasive therapeutic modality that has gained great attention in the past years as a new therapy for cancer treatment. PDT uses photosensitizers that, after being excited by light at a specific wavelength, react with the molecular oxygen to create reactive oxygen species in the target tissue, resulting in cell death. Compared to conventional therapeutic modalities, PDT presents greater selectivity against tumor cells, due to the use of photosensitizers that are preferably localized in tumor lesions, and the precise light irradiation of these lesions. This paper presents a review of the principles, mechanisms, photosensitizers, and current applications of PDT. Moreover, the future path on the research of new photosensitizers with enhanced tumor selectivity, featuring the improvement of PDT effectiveness, has also been addressed. Finally, new applications of PDT have been covered.

Keywords:  PDT in medical devices; PDT mechanisms; PDT tumor treatment; antimicrobial PDT; new photosensitizers; non-oncologic applications of PDT

DOI:  https://doi.org/10.3390/pharmaceutics13091332
J Biochem Mol Toxicol. 2021 Sep 29. e22928

Synergistic effect of anethole and doxorubicin alleviates cell proliferation, cell cycle arrest, and ER stress and promotes ROS-mediated apoptosis in triple-negative breast cancer cells.

Poornima Arumugam, Banupriya Sampathkumar, Haribalan Perumalsamy, Sri Renukadevi Balusamy, Vignesh Ramesh, Sumathi Sundaravadevel.

  The heterogeneity and poor prognosis of triple-negative breast cancer (TNBC) have limited the treatment options and made clinical management challenging. This has nurtured a major effort to discover druggable molecular targets. Currently, chemotherapy is the primary treatment strategy for this disease. Doxorubicin is the most frequently used chemotherapeutic drug for TNBC and due to the fact that chemotherapeutic drugs have a lot of side effects, we evaluated the synergistic effect of the phytocompound anethole and doxorubicin. The cytotoxic effect of anethole in combination with doxorubicin on MDA-MB-231 cells was evaluated by various parameters, including apoptosis, cell cycle analysis, DNA damage, and cell proliferation. Furthermore, mitochondrial membranepotential (MMP), endoplasmic reticulum (ER) stress, and reactive oxygen species (ROS) levels were also evaluated in the cells treated with/without anethole and doxorubicin. Expression of the apoptotic proteins was evaluated by Western blot analysis. Initial evaluation of cytotoxicity of anethole on MDA-MB-231 cells demonstrated preferential suppression of cell proliferation and when treated along with doxorubicin it showed enhanced cytotoxicity with a synergistic effect. Cell cycle analysis revealed arrest at different stages of the cell cycle, such as sub G0-G1, G0-G1, S, and G2M in various treatment groups and apoptotic cell death was subsequently evident with propidium iodide (PI) staining. The synergistic action of anethole and doxorubicin effectively induced mitochondrial membrane potential loss, which, in turn, led to a burst of ROS production, which eventually produced unfolded protein response by damaging the ER. Synergistic anticancer effect was observed on exposure of MDA-MB-231 cells to anethole and doxorubicin in inducing cell death.

Keywords:  anethole; doxorubicin; reactive oxygen species and apoptosis; triple-negative breast cancer

DOI:  https://doi.org/10.1002/jbt.22928
Proc Natl Acad Sci U S A. 2021 Oct 05. pii: e2110387118. [Epub ahead of print]118(40):

A genetic model of methionine restriction extends Drosophila health- and lifespan.

Andrey A Parkhitko, Lin Wang, Elizabeth Filine, Patrick Jouandin, Dmitry Leshchiner, Richard Binari, John M Asara, Joshua D Rabinowitz, Norbert Perrimon.

  Loss of metabolic homeostasis is a hallmark of aging and is characterized by dramatic metabolic reprogramming. To analyze how the fate of labeled methionine is altered during aging, we applied 13C5-Methionine labeling to Drosophila and demonstrated significant changes in the activity of different branches of the methionine metabolism as flies age. We further tested whether targeted degradation of methionine metabolism components would "reset" methionine metabolism flux and extend the fly lifespan. Specifically, we created transgenic flies with inducible expression of Methioninase, a bacterial enzyme capable of degrading methionine and revealed methionine requirements for normal maintenance of lifespan. We also demonstrated that microbiota-derived methionine is an alternative and important source in addition to food-derived methionine. In this genetic model of methionine restriction (MetR), we also demonstrate that either whole-body or tissue-specific Methioninase expression can dramatically extend Drosophila health- and lifespan and exerts physiological effects associated with MetR. Interestingly, while previous dietary MetR extended lifespan in flies only in low amino acid conditions, MetR from Methioninase expression extends lifespan independently of amino acid levels in the food. Finally, because impairment of the methionine metabolism has been previously associated with the development of Alzheimer's disease, we compared methionine metabolism reprogramming between aging flies and a Drosophila model relevant to Alzheimer's disease, and found that overexpression of human Tau caused methionine metabolism flux reprogramming similar to the changes found in aged flies. Altogether, our study highlights Methioninase as a potential agent for health- and lifespan extension.

Keywords:  13C-Methionine labeling; Alzheimer’s disease; Methioninase; aging; methionine restriction

DOI:  https://doi.org/10.1073/pnas.2110387118
Cancer J. 2021 Sep-Oct 01;27(5):27(5): 386-394

Clinical Targeting of Altered Metabolism in High-Grade Glioma.

Andrew J Scott, Costas A Lyssiotis, Daniel R Wahl.

ABSTRACT: High-grade gliomas are among the deadliest of all cancers despite standard treatments, and new therapeutic strategies are needed to improve patient outcome. Targeting the altered metabolic state of tumors with traditional chemotherapeutic agents has a history of success, and our increased understanding of cellular metabolism in the past 2 decades has reinvigorated the concept of novel metabolic therapies in brain tumors. Here we highlight metabolic alterations in advanced gliomas and their translation into clinical trials using both novel agents and already established drugs repurposed for cancer treatment in an effort to improve outcome for these deadly diseases.

DOI: https://doi.org/10.1097/PPO.0000000000000550
Pharmaceuticals (Basel). 2021 Aug 26. pii: 854. [Epub ahead of print]14(9):

Retinoids Delivery Systems in Cancer: Liposomal Fenretinide for Neuroectodermal-Derived Tumors.

Veronica Bensa, Enzo Calarco, Elena Giusto, Patrizia Perri, Maria Valeria Corrias, Mirco Ponzoni, Chiara Brignole, Fabio Pastorino.

  Retinoids are a class of natural and synthetic compounds derived from vitamin A. They are involved in several biological processes like embryogenesis, reproduction, vision, growth, inflammation, differentiation, proliferation, and apoptosis. In light of their important functions, retinoids have been widely investigated for their therapeutic applications. Thus far, their use for the treatment of several types of cancer and skin disorders has been reported. However, these therapeutic agents present several limitations for their widespread clinical translatability, i.e., poor solubility and chemical instability in water, sensitivity to light, heat, and oxygen, and low bioavailability. These characteristics result in internalization into target cells and tissues only at low concentration and, consequently, at an unsatisfactory therapeutic dose. Furthermore, the administration of retinoids causes severe side-effects. Thus, in order to improve their pharmacological properties and circulating half-life, while minimizing their off-target uptake, various retinoids delivery systems have been recently developed. This review intends to provide examples of retinoids-loaded nano-delivery systems for cancer treatment. In particular, the use and the therapeutic results obtained by using fenretinide-loaded liposomes against neuroectodermal-derived tumors, such as melanoma, in adults, and neuroblastoma, the most common extra-cranial solid tumor of childhood, will be discussed.

Keywords:  fenretinide (4-HPR); liposomes; nanotechnology; retinoids

DOI:  https://doi.org/10.3390/ph14090854
Mar Drugs. 2021 Aug 27. pii: 488. [Epub ahead of print]19(9):

Marine Power on Cancer: Drugs, Lead Compounds, and Mechanisms.

Lichuan Wu, Ke Ye, Sheng Jiang, Guangbiao Zhou.

  Worldwide, 19.3 million new cancer cases and almost 10.0 million cancer deaths occur each year. Recently, much attention has been paid to the ocean, the largest biosphere of the earth that harbors a great many different organisms and natural products, to identify novel drugs and drug candidates to fight against malignant neoplasms. The marine compounds show potent anticancer activity in vitro and in vivo, and relatively few drugs have been approved by the U.S. Food and Drug Administration for the treatment of metastatic malignant lymphoma, breast cancer, or Hodgkin's disease. This review provides a summary of the anticancer effects and mechanisms of action of selected marine compounds, including cytarabine, eribulin, marizomib, plitidepsin, trabectedin, zalypsis, adcetris, and OKI-179. The future development of anticancer marine drugs requires innovative biochemical biology approaches and introduction of novel therapeutic targets, as well as efficient isolation and synthesis of marine-derived natural compounds and derivatives.

Keywords:  anticancer; marine environment drug; mechanisms of action; natural compounds

DOI:  https://doi.org/10.3390/md19090488
Antioxidants (Basel). 2021 Sep 05. pii: 1419. [Epub ahead of print]10(9):

Antioxidant Role of Kaempferol in Prevention of Hepatocellular Carcinoma.

Nidhi Sharma, Subhrajit Biswas, Noura Al-Dayan, Alaa Saud Alhegaili, Maryam Sarwat.

  Reactive oxygen species (ROS) are noxious to cells because their increased level interacts with the body's defense mechanism. These species also cause mutations and uncontrolled cell division, resulting in oxidative stress (OS). Prolonged oxidative stress is responsible for incorrect protein folding in the endoplasmic reticulum (ER), causing a stressful condition, ER stress. These cellular stresses (oxidative stress and ER stress) are well-recognized biological factors that play a prominent role in the progression of hepatocellular carcinoma (HCC). HCC is a critical global health problem and the third leading cause of cancer-related mortality. The application of anti-oxidants from herbal sources significantly reduces oxidative stress. Kaempferol (KP) is a naturally occurring, aglycone dietary flavonoid that is present in various plants (Crocus sativus, Coccinia grandis, Euphorbia pekinensis, varieties of Aloe vera, etc.) It is capable of interacting with pleiotropic proteins of the human body. Efforts are in progress to develop KP as a potential candidate to prevent HCC with no adverse effects. This review emphasizes the molecular mechanism of KP for treating HCC, targeting oxidative stress.

Keywords:  ER stress; HCC; anti-oxidants; free radicals; kaempferol; oxidative stress

DOI:  https://doi.org/10.3390/antiox10091419
Biosensors (Basel). 2021 Sep 18. pii: 344. [Epub ahead of print]11(9):

Applications of Aptamer-Bound Nanomaterials in Cancer Therapy.

Liangxi Zhu, Jingzhou Zhao, Zhukang Guo, Yuan Liu, Hui Chen, Zhu Chen, Nongyue He.

  Cancer is still a major disease that threatens human life. Although traditional cancer treatment methods are widely used, they still have many disadvantages. Aptamers, owing to their small size, low toxicity, good specificity, and excellent biocompatibility, have been widely applied in biomedical areas. Therefore, the combination of nanomaterials with aptamers offers a new method for cancer treatment. First, we briefly introduce the situation of cancer treatment and aptamers. Then, we discuss the application of aptamers in breast cancer treatment, lung cancer treatment, and other cancer treatment methods. Finally, perspectives on challenges and future applications of aptamers in cancer therapy are discussed.

Keywords:  aptamers; cancer; nanomaterials; targeting; treatment

DOI:  https://doi.org/10.3390/bios11090344
PLoS One. 2021 ;16(9): e0257403

Metformin and sodium dichloroacetate effects on proliferation, apoptosis, and metabolic activity tested alone and in combination in a canine prostate and a bladder cancer cell line.

Katharina Klose, Eva-Maria Packeiser, Petra Müller, José Luis Granados-Soler, Jan Torben Schille, Sandra Goericke-Pesch, Manfred Kietzmann, Hugo Murua Escobar, Ingo Nolte.

An important approach in tumor therapy is combining substances with different action mechanisms aiming to enhance the antineoplastic effect, decrease the therapeutic dosage, and avoid resistance mechanisms. Moreover, evaluating compounds already approved for the treatment of non-neoplastic diseases is promising for new antineoplastic therapies. Sodium dichloroacetate (DCA) reactivates oxidative phosphorylation in the cancer cell mitochondria, reducing apoptosis resistance in cancer cells. Furthermore, metformin inhibits the proliferation of tumor cells and CD133+ cancer -stem-like cells. In the present study, we evaluated the independent and synergistic effect of metformin and DCA on the metabolic activity, cell proliferation, and apoptosis of a canine prostate adenocarcinoma (Adcarc1258) and a transitional cell carcinoma cell line (TCC1506) in comparison to a primary canine fibroblast culture. Determining metformin uptake in tumor cells was performed by quantitative HPLC. Depending on the dosage, metformin as a single agent inhibited the metabolic activity and cell proliferation of the tumor cells, showing only minor effects on the fibroblasts. Furthermore, 1 mM metformin increased apoptosis over 96 h in the tumor cell lines but not in fibroblasts. Additionally, metformin uptake into the tumor cells in vitro was measurable by quantitative HPLC. Synergistic effects for the combination therapy were observed in both neoplastic cell lines as well as in the fibroblasts. Based on these results, metformin might be a promising therapeutic agent for canine urogenital tumors. Further studies on kinetics, toxicology, bioavailability, and application of metformin in dogs are necessary.

DOI: https://doi.org/10.1371/journal.pone.0257403
Int J Mol Sci. 2021 Sep 17. pii: 10027. [Epub ahead of print]22(18):

Metformin and Dichloroacetate Suppress Proliferation of Liver Cancer Cells by Inhibiting mTOR Complex 1.

Tae Suk Kim, Minjong Lee, Minji Park, Sae Yun Kim, Min Suk Shim, Chea Yeon Lee, Dae Hee Choi, Yuri Cho.

  The Warburg effect is important for cancer cell proliferation. This phenomenon can be flexible by interaction between glycolysis and mitochondrial oxidation for energy production. We aimed to investigate the anticancer effects of the pyruvate dehydrogenase kinase inhibitor, dichloroacetate (DCA) and the mitochondrial respiratory complex I inhibitor metformin in liver cancer cells. The anticancer effect of DCA and/or metformin on HepG2, PLC/PRF5 human liver cancer cell lines, MH-134 murine hepatoma cell lines, and primary normal hepatocytes using MTT assay. Inhibition of lactate/ATP production and intracellular reactive oxygen species generation by DCA and metformin was investigated. Inhibition of PI3K/Akt/mTOR complex I was evaluated to see whether it occurred through AMPK signaling. Anticancer effects of a combination treatment of DCA and metformin were evaluated in HCC murine model. The results showed that metformin and DCA effectively induced apoptosis in liver cancer cells. A combination treatment of metformin and DCA did not affect viability of primary normal hepatocytes. Metformin upregulated glycolysis in liver cancer cells, thereby increasing sensitivity to the DCA treatment. Metformin and DCA inhibited mTOR complex I signaling through upregulated AMPK-independent REDD1. In addition, metformin and DCA increased reactive oxygen species levels in liver cancer cells, which induced apoptosis. A combination treatment of metformin and DCA significantly suppressed the tumor growth of liver cancer cells using in vivo xenograft model. Taken together, the combined treatment of metformin and DCA suppressed the growth of liver cancer cells. This strategy may be effective for patients with advanced liver cancer.

Keywords:  REDD1; Warburg effect; liver cancer; mTOR complex I

DOI:  https://doi.org/10.3390/ijms221810027
Genes Dev. 2021 Oct 01. 35(19-20): 1325-1326

Anticipating resistance to KRAS inhibition: a novel role for USP21 in macropinocytosis regulation.

Howard C Crawford.

  Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers. Virtually all PDAC harbors an oncogenic mutation in the KRAS gene, making it the prime target for therapy. Most previous attempts to inhibit KRAS directly have been disappointing, but recent success in targeting some KRAS mutants presages a new era in PDAC therapy. Models of PDAC have predicted that identifying KRAS inhibitor resistance mechanisms will be critical. In this issue of Genes & Development, Hou and colleagues (pp. 1327-1332) identify one such mechanism in which the deubiquitinase USP21 up-regulates the nutrient-scavenging process of macropinocytosis, rescuing PDAC cells from Kras extinction.

Keywords:  KRAS; MARK3; USP21; macropinocytosis; targeted therapy resistance

DOI:  https://doi.org/10.1101/gad.348971.121
Int J Mol Sci. 2021 Sep 07. pii: 9667. [Epub ahead of print]22(18):

Oncogenes, Proto-Oncogenes, and Lineage Restriction of Cancer Stem Cells.

Geoffrey Brown.

  In principle, an oncogene is a cellular gene (proto-oncogene) that is dysfunctional, due to mutation and fusion with another gene or overexpression. Generally, oncogenes are viewed as deregulating cell proliferation or suppressing apoptosis in driving cancer. The cancer stem cell theory states that most, if not all, cancers are a hierarchy of cells that arises from a transformed tissue-specific stem cell. These normal counterparts generate various cell types of a tissue, which adds a new dimension to how oncogenes might lead to the anarchic behavior of cancer cells. It is that stem cells, such as hematopoietic stem cells, replenish mature cell types to meet the demands of an organism. Some oncogenes appear to deregulate this homeostatic process by restricting leukemia stem cells to a single cell lineage. This review examines whether cancer is a legacy of stem cells that lose their inherent versatility, the extent that proto-oncogenes play a role in cell lineage determination, and the role that epigenetic events play in regulating cell fate and tumorigenesis.

Keywords:  epigenetics; lineage determination; oncogenes; proto-oncogenes; stem cells

DOI:  https://doi.org/10.3390/ijms22189667
Int J Mol Sci. 2021 Sep 08. pii: 9707. [Epub ahead of print]22(18):

Recent Advances in Phenolic Metabolites and Skin Cancer.

Teodora Daria Pop, Zorita Diaconeasa.

  Skin cancer represents any tumor development from the cutaneous structures within the epidermis, dermis or subcutaneous tissue, and is considered to be the most prevalent type of cancer. Compared to other types of cancer, skin cancer is proven to have a positive growth rate of prevalence and mortality. There are available various treatments, including chemotherapy, immunotherapy, radiotherapy and targeted therapy, but because of the multidrug resistance development, a low success has been registered. By this, the importance of studying naturally occurring compounds that are both safe and effective in the chemoprevention of skin cancer is emphasized. This review focuses on melanoma because it is the deadliest form of skin cancer, with a significantly increasing incidence in the last decades. As chemopreventive agents, we present polyphenols and their antioxidant activity, anti-inflammatory effect, their ability to balance the cell cycle and to induce apoptosis and their various other effects on skin melanoma. Besides chemoprevention, studies suggest that polyphenols can have treating abilities in some conditions. The limitations of using polyphenols are also pointed out, which are related to their poor bioavailability and stability, but as the technology is well developed, it is possible to augment the efficacy of polyphenols in the case of melanoma.

Keywords:  chemoprevention; melanoma; polyphenols; skin cancer

DOI:  https://doi.org/10.3390/ijms22189707
Int J Mol Sci. 2021 Sep 10. pii: 9807. [Epub ahead of print]22(18):

Targeting Autophagy with Natural Products as a Potential Therapeutic Approach for Cancer.

Md Abdul Alim Al-Bari, Yuko Ito, Samrein Ahmed, Nada Radwan, Hend S Ahmed, Nabil Eid.

  Macro-autophagy (autophagy) is a highly conserved eukaryotic intracellular process of self-digestion caused by lysosomes on demand, which is upregulated as a survival strategy upon exposure to various stressors, such as metabolic insults, cytotoxic drugs, and alcohol abuse. Paradoxically, autophagy dysfunction also contributes to cancer and aging. It is well known that regulating autophagy by targeting specific regulatory molecules in its machinery can modulate multiple disease processes. Therefore, autophagy represents a significant pharmacological target for drug development and therapeutic interventions in various diseases, including cancers. According to the framework of autophagy, the suppression or induction of autophagy can exert therapeutic properties through the promotion of cell death or cell survival, which are the two main events targeted by cancer therapies. Remarkably, natural products have attracted attention in the anticancer drug discovery field, because they are biologically friendly and have potential therapeutic effects. In this review, we summarize the up-to-date knowledge regarding natural products that can modulate autophagy in various cancers. These findings will provide a new position to exploit more natural compounds as potential novel anticancer drugs and will lead to a better understanding of molecular pathways by targeting the various autophagy stages of upcoming cancer therapeutics.

Keywords:  anticancer drugs; autophagy; autophagy modulators; mTOR signaling; natural products; resveratrol; ω-3 PUFAs

DOI:  https://doi.org/10.3390/ijms22189807
Cancer Control. 2021 Jan-Dec;28:28 10732748211038735

Cancer Biology, Epidemiology, and Treatment in the 21st Century: Current Status and Future Challenges From a Biomedical Perspective.

Patricia Piña-Sánchez, Antonieta Chávez-González, Martha Ruiz-Tachiquín, Eduardo Vadillo, Alberto Monroy-García, Juan José Montesinos, Rocío Grajales, Marcos Gutiérrez de la Barrera, Hector Mayani.

  Since the second half of the 20th century, our knowledge about the biology of cancer has made extraordinary progress. Today, we understand cancer at the genomic and epigenomic levels, and we have identified the cell that starts neoplastic transformation and characterized the mechanisms for the invasion of other tissues. This knowledge has allowed novel drugs to be designed that act on specific molecular targets, the immune system to be trained and manipulated to increase its efficiency, and ever more effective therapeutic strategies to be developed. Nevertheless, we are still far from winning the war against cancer, and thus biomedical research in oncology must continue to be a global priority. Likewise, there is a need to reduce unequal access to medical services and improve prevention programs, especially in countries with a low human development index.

Keywords:  cancer; cell therapy; epidemiology; epigenomics; genomics; immunotherapy; metastasis; stem cells; targeted therapy

DOI:  https://doi.org/10.1177/10732748211038735
J Control Release. 2021 Sep 22. pii: S0168-3659(21)00503-4. [Epub ahead of print]339 75-90

Photodynamic cancer therapy using liposomes as an advanced vesicular photosensitizer delivery system.

Saeid Moghassemi, Arezoo Dadashzadeh, Ricardo Bentes Azevedo, Olivier Feron, Christiani A Amorim.

  The multidisciplinary field of photodynamic therapy (PDT) is a combination of photochemistry and photophysics sciences, which has shown tremendous potential for cancer therapy application. PDT employs a photosensitizing agent (PS) and light to form cytotoxic reactive oxygen species and subsequently oxidize light-exposed tissue. Despite numerous advantages of PDT and enormous progress in this field, common PSs are still far from ideal treatment because of their poor permeability, non-specific phototoxicity, side effects, hydrophobicity, weak bioavailability, and tendency to self-aggregation. To circumvent these limitations, PS can be encapsulated in liposomes, an advanced drug delivery system that has demonstrated the ability to enhance drug permeability into biological membranes and loading both hydrophobic and lipophilic agents. Moreover, liposomes can also be coated by targeting agents to improve delivery efficiency. The present review aims to summarize the principles of PDT, various PS generations, PS-loaded nanoparticles, liposomes, and their impact on PDT, then discuss recent photodynamic cancer therapy strategies using liposomes as PS-loaded vectors, and highlight future possibilities and perspectives.

Keywords:  Drug delivery systems; Liposome; Nanomedicine; Nanoparticle; Photodynamic therapy

DOI:  https://doi.org/10.1016/j.jconrel.2021.09.024
Cancers (Basel). 2021 Sep 13. pii: 4587. [Epub ahead of print]13(18):

Intermittent and Periodic Fasting, Hormones, and Cancer Prevention.

Giulia Salvadori, Mario Giuseppe Mirisola, Valter D Longo.

  The restriction of proteins, amino acids or sugars can have profound effects on the levels of hormones and factors including growth hormone, IGF-1 and insulin. In turn, these can regulate intracellular signaling pathways as well as cellular damage and aging, but also multisystem regeneration. Both intermittent (IF) and periodic fasting (PF) have been shown to have both acute and long-term effects on these hormones. Here, we review the effects of nutrients and fasting on hormones and genes established to affect aging and cancer. We describe the link between dietary interventions and genetic pathways affecting the levels of these hormones and focus on the mechanisms responsible for the cancer preventive effects. We propose that IF and PF can reduce tumor incidence both by delaying aging and preventing DNA damage and immunosenescence and also by killing damaged, pre-cancerous and cancer cells.

Keywords:  DNA damage; aging; cancer prevention; fasting; growth hormones

DOI:  https://doi.org/10.3390/cancers13184587
Pharmaceutics. 2021 Sep 09. pii: 1433. [Epub ahead of print]13(9):

Peptide-Conjugated Nano Delivery Systems for Therapy and Diagnosis of Cancer.

Isha Gaurav, Xuehan Wang, Abhimanyu Thakur, Ashok Iyaswamy, Sudha Thakur, Xiaoyu Chen, Gaurav Kumar, Min Li, Zhijun Yang.

  Peptides are strings of approximately 2-50 amino acids, which have gained huge attention for theranostic applications in cancer research due to their various advantages including better biosafety, customizability, convenient process of synthesis, targeting ability via recognizing biological receptors on cancer cells, and better ability to penetrate cell membranes. The conjugation of peptides to the various nano delivery systems (NDS) has been found to provide an added benefit toward targeted delivery for cancer therapy. Moreover, the simultaneous delivery of peptide-conjugated NDS and nano probes has shown potential for the diagnosis of the malignant progression of cancer. In this review, various barriers hindering the targeting capacity of NDS are addressed, and various approaches for conjugating peptides and NDS have been discussed. Moreover, major peptide-based functionalized NDS targeting cancer-specific receptors have been considered, including the conjugation of peptides with extracellular vesicles, which are biological nanovesicles with promising ability for therapy and the diagnosis of cancer.

Keywords:  cancer; extracellular vesicles; peptide; targeted nano delivery; theranostic

DOI:  https://doi.org/10.3390/pharmaceutics13091433
Pharmaceutics. 2021 Aug 25. pii: 1327. [Epub ahead of print]13(9):

Targeting Tumor Cells with Nanoparticles for Enhanced Co-Drug Delivery in Cancer Treatment.

Wen-Ying Huang, Chih-Ho Lai, Shin-Lei Peng, Che-Yu Hsu, Po-Hung Hsu, Pei-Yi Chu, Chun-Lung Feng, Yu-Hsin Lin.

  Gastric cancer (GC) is a fatal malignant tumor, and effective therapies to attenuate its progression are lacking. Nanoparticle (NP)-based solutions may enable the design of novel treatments to eliminate GC. Refined, receptor-targetable NPs can selectively target cancer cells and improve the cellular uptake of drugs. To overcome the current limitations and enhance the therapeutic effects, epigallocatechin-3-gallate (EGCG) and low-concentration doxorubicin (DX) were encapsulated in fucoidan and d-alpha-tocopherylpoly (ethylene glycol) succinate-conjugated hyaluronic acid-based NPs for targeting P-selectin-and cluster of differentiation (CD)44-expressing gastric tumors. The EGCG/DX-loaded NPs bound to GC cells and released bioactive combination drugs, demonstrating better anti-cancer effects than the EGCG/DX combination solution. In vivo assays in an orthotopic gastric tumor mouse model showed that the EGCG/DX-loaded NPs significantly increased the activity of gastric tumors without inducing organ injury. Overall, our EGCG/DX-NP system exerted a beneficial effect on GC treatment and may facilitate the development of nanomedicine-based combination chemotherapy against GC in the future.

Keywords:  combination chemotherapy; d-alpha-tocopherylpoly (ethylene glycol) succinate; fucoidan; gastric cancer; nanoparticle

DOI:  https://doi.org/10.3390/pharmaceutics13091327
ACS Chem Biol. 2021 Oct 01.

Bioactive Compounds of Arthrospira spp. (Spirulina) with Potential Anticancer Activities: A Systematic Review.

Maria Rafaele O B da Silva, Gisele M da Silva, Amannda L F da Silva, Luiza R A de Lima, Raquel P Bezerra, Daniela de A V Marques.

Arthrospira, a genus of blue-green cyanobacteria, is known for its great biological activity due to the presence of a large number of substances that are potentially active against tumor cells. This review aimed to evaluate the potential of Arthrospira spp. for the treatment or reduction of several types of cancer, in addition to elucidating the mechanism of action by which their compounds act on tumor cells. A systematic review was carried out in PubMed, Science Direct, LILACS, and SciELO databases, including original studies from 2009 to 2020. A total of 1306 articles were independently assessed according to the eligibility criteria, of which 20 articles were selected and assessed for the risk of bias using seven criteria developed by the authors. Arthrospira spp. of cyanobacteria have been evaluated against eight different types of cancer, mainly colon cancer. Among all the compounds, phycocyanin was the most used, followed by peptides and photosensitizers. In general, compounds from Arthrospira spp. act as anticancer agents by inhibiting the proliferation of tumor cells, triggering cell cycle arrest, and inducing apoptosis via different signaling pathways. In addition, these compounds also exhibited antioxidant, antiangiogenic, and antimetastatic activities. Phycocyanin demonstrated better efficacy against several types of cancer via different activities and therapeutic targets. Furthermore, it was the only molecule that functioned in synergy with other drugs that are already well established for the treatment of cancer.

DOI: https://doi.org/10.1021/acschembio.1c00568
Nutrients. 2021 Aug 30. pii: 3043. [Epub ahead of print]13(9):

The Pro-Health Benefits of Morusin Administration-An Update Review.

Anita Panek-Krzyśko, Monika Stompor-Gorący.

  Prenylflavonoids are widespread in nature. Plants are valuable sources of natural polyphenolic compounds with isoprenyl groups, which include flavones, flavanones, chalcones and aurones. They can be found in flowers, bark and stems. One of the most important compounds found in the bark of white mulberry (Morus alba) is morusin, a prenylated flavone with interesting pro-health properties. The research carried out so far revealed that morusin has antioxidant, antitumor, anti-inflammatory and anti-allergic activity. Moreover, its neuroprotective and antihyperglycemic properties have also been confirmed. Morusin suppresses the growth of different types of tumors, including breast cancer, glioblastoma, pancreatic cancer, hepatocarcinoma, prostate cancer, and gastric cancer. It also inhibits the inflammatory response by suppressing COX activity and iNOS expression. Moreover, an antimicrobial effect against Gram-positive bacteria was observed after treatment with morusin. The objective of this review is to summarize the current knowledge about the positive effects of morusin on human health in order to facilitate future study on the development of plant polyphenolic drugs and nutraceutics in the group of prenylflavones.

Keywords:  morusin; nutraceuticals; pharmafood; prenylated polyphenols; pro-health effect

DOI:  https://doi.org/10.3390/nu13093043
Cancers (Basel). 2021 Sep 07. pii: 4502. [Epub ahead of print]13(18):

Potential of Bioactive Food Components against Gastric Cancer: Insights into Molecular Mechanism and Therapeutic Targets.

Seog Young Kang, Dongwon Hwang, Soyoung Shin, Jinju Park, Myoungchan Kim, M D Hasanur Rahman, Md Ataur Rahman, Seong-Gyu Ko, Bonglee Kim.

  Gastric cancer, also known as stomach cancer, is a cancer that develops from the lining of the stomach. Accumulated evidence and epidemiological studies have indicated that bioactive food components from natural products play an important role in gastric cancer prevention and treatment, although its mechanism of action has not yet been elucidated. Particularly, experimental studies have shown that natural bioactive food products display a protective effect against gastric cancer via numerous molecular mechanisms, such as suppression of cell metastasis, anti-angiogenesis, inhibition of cell proliferation, induction of apoptosis, and modulation of autophagy. Chemotherapy remains the standard treatment for advanced gastric cancer along with surgery, radiation therapy, hormone therapy, as well as immunotherapy, and its adverse side effects including neutropenia, stomatitis, mucositis, diarrhea, nausea, and emesis are well documented. However, administration of naturally occurring bioactive phytochemical food components could increase the efficacy of gastric chemotherapy and other chemotherapeutic resistance. Additionally, several studies have suggested that bioactive food components with structural stability, potential bioavailability, and powerful bioactivity are important to develop novel treatment strategies for gastric cancer management, which may minimize the adverse effects. Therefore, the purpose of this review is to summarize the potential therapeutic effects of natural bioactive food products on the prevention and treatment of gastric cancer with intensive molecular mechanisms of action, bioavailability, and safety efficacy.

Keywords:  angiogenesis; apoptosis; autophagy; bioactive food components; chemo-resistance; gastric cancer; metastasis

DOI:  https://doi.org/10.3390/cancers13184502