bims-kracam 2021-09-26 papers

on K-Ras in cancer metabolism

Issue of 2021–09–26
forty papers selected by
Yasmin Elkabani, Egyptian Foundation for Research and Community Development

Contemporary Perspectives on the Warburg Effect Inhibition in Cancer Therapy.
Glucose Metabolism and Glucose Transporters in Breast Cancer.
Moonlighting functions of metabolic enzymes and metabolites in cancer.
Warburg and pasteur phenotypes modulate cancer behavior and therapy.
Implications of reactive oxygen species on cancer formation and its treatment.
Dual blockade of macropinocytosis and asparagine bioavailability shows synergistic anti-tumor effects on KRAS-mutant colorectal cancer.
SnapShot: Cancer metabolism.
Targeting MYC-enhanced glycolysis for the treatment of small cell lung cancer.
The Mechanism of Warburg Effect-Induced Chemoresistance in Cancer.
Targeting Reactive Oxygen Species Capacity of Tumor Cells with Repurposed Drug as an Anticancer Therapy.
A glutamine 'tug-of-war': targets to manipulate glutamine metabolism for cancer immunotherapy.
Targeting of cancer cell death mechanisms by resveratrol: a review.
Methionine restriction exposes a targetable redox vulnerability of triple-negative breast cancer cells by inducing thioredoxin reductase.
Piperine for treating breast cancer: A review of molecular mechanisms, combination with anticancer drugs, and nanosystems.
Significance of glutathione peroxidase 4 and intracellular iron level in ovarian cancer cells-"utilization" of ferroptosis mechanism.
Breast cancer suppression by curcumin-naringenin-magnetic-nano-particles: In vitro and in vivo studies.
The review of alpha-linolenic acid: Sources, metabolism, and pharmacology.
Targeting steroid hormone receptors for anti-cancer therapy-A review on small molecules and nanotherapeutic approaches.
Photothermal nanozyme-ignited Fenton reaction-independent ferroptosis for breast cancer therapy.
Nanoencapsulation of Polyphenols as Drugs and Supplements for Enhancing Therapeutic Profile - A Review.
Dependence receptors: new targets for cancer therapy.
Oncogenic Ras expression increases cellular formate production.
NIR-activated self-sensitized polymeric micelles for enhanced cancer chemo-photothermal therapy.
ARe we there yet? Understanding androgen receptor signaling in breast cancer.
Combination therapy of vanillic acid and oxaliplatin co-loaded in polysaccharide based functionalized polymeric micelles could offer effective treatment for colon cancer: A hypothesis.
Activated Pancreatic Stellate Cells Enhance the Warburg Effect to Cause the Malignant Development in Chronic Pancreatitis.
Carboxymethyl dextran-based nanocomposites for enhanced chemo-sonodynamic therapy of cancer.
Heme sequestration as an effective strategy for the suppression of tumor growth and progression.
Resveratrol-Based Nanoformulations as an Emerging Therapeutic Strategy for Cancer.
Natural products inducing nucleolar stress: implications in cancer therapy.
Natural substances derived from herbs or plants are promising sources of anticancer agents against colorectal cancer via triggering apoptosis.
Supply and demand: Cellular nutrient uptake and exchange in cancer.
THIOL-BASED ANTIOXIDANTS AND THE EPITHELIAL-MESENCHYMAL TRANSITION IN CANCER.
Is Curcumin at the Threshold of Therapeutic Effectiveness on Patients with Colon Cancer?-A Systematic Review.
Reactive oxygen species (ROS) in cancer pathogenesis and therapy: An update on the role of ROS in anticancer action of benzophenanthridine alkaloids.
ATF3 promotes the serine synthesis pathway and tumor growth under dietary serine restriction.
A flowerlike FePt/MnO2/GOx-based cascade nanoreactor with sustainable O2 supply for synergistic starvation-chemodynamic anticancer therapy.
Glycolysis-related gene expression profiling serves as a novel prognosis risk predictor for human hepatocellular carcinoma.
Cancer as a homeostatic challenge: the role of the hypothalamus.
Heat-Confined Tumor-Docking Reversible Thermogel Potentiates Systemic Antitumor Immune Response During Near-Infrared Photothermal Ablation in Triple-Negative Breast Cancer.

Cancer Control. 2021 Jan-Dec;28:28 10732748211041243

Contemporary Perspectives on the Warburg Effect Inhibition in Cancer Therapy.

Karolina Kozal, Paweł Jóźwiak, Anna Krześlak.

  In the 1920s, Otto Warburg observed the phenomenon of altered glucose metabolism in cancer cells. Although the initial hypothesis suggested that the alteration resulted from mitochondrial damage, multiple studies of the subject revealed a precise, multistage process rather than a random pattern. The phenomenon of aerobic glycolysis emerges not only from mitochondrial abnormalities common in cancer cells, but also results from metabolic reprogramming beneficial for their sustenance. The Warburg effect enables metabolic adaptation of cancer cells to grow and proliferate, simultaneously enabling their survival in hypoxic conditions. Altered glucose metabolism of cancer cells includes, inter alia, qualitative and quantitative changes within glucose transporters, enzymes of the glycolytic pathway, such as hexokinases and pyruvate kinase, hypoxia-inducible factor, monocarboxylate transporters, and lactate dehydrogenase. This review summarizes the current state of knowledge regarding inhibitors of cancer glucose metabolism with a focus on their clinical potential. The altered metabolic phenotype of cancer cells allows for targeting of specific mechanisms, which might improve conventional methods in anti-cancer therapy. However, several problems such as drug bioavailability, specificity, toxicity, the plasticity of cancer cells, and heterogeneity of cells in tumors have to be overcome when designing therapies based on compounds targeted in cancer cell energy metabolism.

Keywords:  aerobic glycolysis; anti-cancer therapy; glucose transporters; hypoxia-inducible factor; inhibitors; lactate dehydrogenase; monocarboxylate transporters; pyruvate kinase

DOI:  https://doi.org/10.1177/10732748211041243
Front Cell Dev Biol. 2021 ;9 728759

Glucose Metabolism and Glucose Transporters in Breast Cancer.

Eunah Shin, Ja Seung Koo.

  Breast cancer is the most common malignancy in women worldwide and is associated with high mortality rates despite the continuously advancing treatment strategies. Glucose is essential for cancer cell metabolism owing to the Warburg effect. During the process of glucose metabolism, various glycolytic metabolites, such as serine and glycine metabolites, are produced and other metabolic pathways, such as the pentose phosphate pathway (PPP), are associated with the process. Glucose is transported into the cell by glucose transporters, such as GLUT. Breast cancer shows high expressions of glucose metabolism-related enzymes and GLUT, which are also related to breast cancer prognosis. Triple negative breast cancer (TNBC), which is a high-grade breast cancer, is especially dependent on glucose metabolism. Breast cancer also harbors various stromal cells such as cancer-associated fibroblasts and immune cells as tumor microenvironment, and there exists a metabolic interaction between these stromal cells and breast cancer cells as explained by the reverse Warburg effect. Breast cancer is heterogeneous, and, consequently, its metabolic status is also diverse, which is especially affected by the molecular subtype, progression stage, and metastatic site. In this review, we will focus on glucose metabolism and glucose transporters in breast cancer, and we will additionally discuss their potential applications as cancer imaging tracers and treatment targets.

Keywords:  breast cancer; glucose metabolism; glucose transporter; pentose phosphate pathway; serine/glycine pathway

DOI:  https://doi.org/10.3389/fcell.2021.728759
Mol Cell. 2021 Sep 16. pii: S1097-2765(21)00698-5. [Epub ahead of print]81(18): 3760-3774

Moonlighting functions of metabolic enzymes and metabolites in cancer.

Chaoyun Pan, Bo Li, M Celeste Simon.

The growing field of tumor metabolism has greatly expanded our knowledge of metabolic reprogramming in cancer. Apart from their established roles, various metabolic enzymes and metabolites harbor non-canonical ("moonlighting") functions to support malignant transformation. In this article, we intend to review the current understanding of moonlighting functions of metabolic enzymes and related metabolites broadly existing in cancer cells by dissecting each major metabolic pathway and its regulation of cellular behaviors. Understanding these non-canonical functions may broaden the horizon of the cancer metabolism field and uncover novel therapeutic vulnerabilities in cancer.

DOI: https://doi.org/10.1016/j.molcel.2021.08.031
Anticancer Drugs. 2021 Sep 17.

Warburg and pasteur phenotypes modulate cancer behavior and therapy.

Caner Karaca, Atilla Tokatli, Anja Tokatli, Aslihan Karadag, Gizem Calibasi-Kocal.

Energetic pathways combine in the heart of metabolism. These essential routes supply energy for biochemical processes through glycolysis and oxidative phosphorylation. Moreover, they support the synthesis of various biomolecules employed in growth and survival over branching pathways. Yet, cellular energetics are often misguided in cancers as a result of the mutations and altered signaling. As nontransformed and Pasteur-like cells metabolize glucose through oxidative respiration when only oxygen is sufficient, some cancer cells bypass this metabolic switch and run glycolysis at higher rates even in the presence of oxygen. The phenomenon is called aerobic glycolysis or the Warburg effect. An increasing number of studies indicate that both Warburg and Pasteur phenotypes are recognized in the cancer microenvironment and take vital roles in the regulation of drug resistance mechanisms such as redox homeostasis, apoptosis and autophagy. Therefore, the different phenotypes call for different therapeutic approaches. Combined therapies targeting energy metabolism grant new opportunities to overcome the challenges. Nevertheless, new biomarkers emerge to classify the energetic subtypes, thereby the cancer therapy, as our knowledge in coupling energy metabolism with cancer behavior grows.

DOI: https://doi.org/10.1097/CAD.0000000000001236
Semin Oncol. 2021 Aug 04. pii: S0093-7754(21)00051-8. [Epub ahead of print]

Implications of reactive oxygen species on cancer formation and its treatment.

Manish A Shah, Harry A Rogoff.

  Elevated levels of reactive oxygen species (ROS) are a hallmark of cancer. Although increased ROS concentrations play important roles in cancer formation and progression, levels above a cytotoxic threshold cause cancer cell death. Cancer cells adapt to high concentrations of ROS via antioxidant production and reprogrammed cellular metabolism (eg, the Warburg effect). Because some widely used anticancer therapies such as radiation therapy and chemotherapy rely on ROS accumulation as a mechanism to induce cancer cell death, a cancer cell's ability to control ROS levels is a driver of treatment resistance and a critical consideration for successful cancer treatment. The necessity for cancer cells to adapt to elevated levels of ROS to survive may represent an Achilles heel for some malignancies, as therapies designed to interfere with this adaptation would be expected to kill cancer cells. In this review, we provide an overview of the implications of ROS on cancer formation and anticancer treatment strategies, with a focus on treatment-resistant disease.

Keywords:  cancer; drug resistance; reactive oxygen species; reduction-oxidation balance; treatment

DOI:  https://doi.org/10.1053/j.seminoncol.2021.05.002
Cancer Lett. 2021 Sep 20. pii: S0304-3835(21)00471-7. [Epub ahead of print]522 129-141

Dual blockade of macropinocytosis and asparagine bioavailability shows synergistic anti-tumor effects on KRAS-mutant colorectal cancer.

Keita Hanada, Kenji Kawada, Gen Nishikawa, Kosuke Toda, Hisatsugu Maekawa, Yasuyo Nishikawa, Hideyuki Masui, Wataru Hirata, Michio Okamoto, Yoshiyuki Kiyasu, Shusaku Honma, Ryotaro Ogawa, Rei Mizuno, Yoshiro Itatani, Hiroyuki Miyoshi, Takehiko Sasazuki, Senji Shirasawa, M Mark Taketo, Kazutaka Obama, Yoshiharu Sakai.

  Mutations of KRAS gene are found in various types of cancer, including colorectal cancer (CRC). Despite intense efforts, no pharmacological approaches are expected to be effective against KRAS-mutant cancers. Macropinocytosis is an evolutionarily conserved actin-dependent endocytic process that internalizes extracellular fluids into large vesicles called macropinosomes. Recent studies have revealed macropinocytosis's important role in metabolic adaptation to nutrient stress in cancer cells harboring KRAS mutations. Here we showed that KRAS-mutant CRC cells enhanced macropinocytosis for tumor growth under nutrient-depleted conditions. We also demonstrated that activation of Rac1 and phosphoinositide 3-kinase were involved in macropinocytosis of KRAS-mutant CRC cells. Furthermore, we found that macropinocytosis was closely correlated with asparagine metabolism. In KRAS-mutant CRC cells engineered with knockdown of asparagine synthetase, macropinocytosis was accelerated under glutamine-depleted condition, and albumin addition could restore the glutamine depletion-induced growth suppression by recovering the intracellular asparagine level. Finally, we discovered that the combination of macropinocytosis inhibition and asparagine depletion dramatically suppressed the tumor growth of KRAS-mutant CRC cells in vivo. These results indicate that dual blockade of macropinocytosis and asparagine bioavailability could be a novel therapeutic strategy for KRAS-mutant cancers.

Keywords:  Asparagine synthetase; KRAS mutation; Macropinocytosis; l-asparaginase

DOI:  https://doi.org/10.1016/j.canlet.2021.09.023
Mol Cell. 2021 Sep 16. pii: S1097-2765(21)00501-3. [Epub ahead of print]81(18): 3878-3878.e1

SnapShot: Cancer metabolism.

Julia S Brunner, Lydia W S Finley.

Metabolic networks support cancer cell survival, proliferation, and malignant progression. Cancer cells take up large amounts of nutrients such as glucose and glutamine whose metabolism provides the energy, reducing equivalents, and biosynthetic precursors required to meet the biosynthetic demands of proliferation. Intermediates of glycolysis and the tricarboxylic acid (TCA) cycle provide critical building blocks for synthesis of non-essential amino acids, nucleotides, and fatty acids. To view this SnapShot, open or download the PDF.

DOI: https://doi.org/10.1016/j.molcel.2021.06.021
Cancer Metab. 2021 Sep 23. 9(1): 33

Targeting MYC-enhanced glycolysis for the treatment of small cell lung cancer.

Kasey R Cargill, C Allison Stewart, Elizabeth M Park, Kavya Ramkumar, Carl M Gay, Robert J Cardnell, Qi Wang, Lixia Diao, Li Shen, You-Hong Fan, Wai Kin Chan, Philip L Lorenzi, Trudy G Oliver, Jing Wang, Lauren A Byers.

   INTRODUCTION: The transcription factor MYC is overexpressed in 30% of small cell lung cancer (SCLC) tumors and is known to modulate the balance between two major pathways of metabolism: glycolysis and mitochondrial respiration. This duality of MYC underscores the importance of further investigation into its role in SCLC metabolism and could lead to insights into metabolic targeting approaches.
METHODS: We investigated differences in metabolic pathways in transcriptional and metabolomics datasets based on cMYC expression in patient and cell line samples. Metabolic pathway utilization was evaluated by flow cytometry and Seahorse extracellular flux methodology. Glycolysis inhibition was evaluated in vitro and in vivo using PFK158, a small molecular inhibitor of PFKFB3.
RESULTS: MYC-overexpressing SCLC patient samples and cell lines exhibited increased glycolysis gene expression directly mediated by MYC. Further, MYC-overexpressing cell lines displayed enhanced glycolysis consistent with the Warburg effect, while cell lines with low MYC expression appeared more reliant on oxidative metabolism. Inhibition of glycolysis with PFK158 preferentially attenuated glucose uptake, ATP production, and lactate in MYC-overexpressing cell lines. Treatment with PFK158 in xenografts delayed tumor growth and decreased glycolysis gene expression.
CONCLUSIONS: Our study highlights an in-depth characterization of SCLC metabolic programming and presents glycolysis as a targetable mechanism downstream of MYC that could offer therapeutic benefit in a subset of SCLC patients.

Keywords:  Glycolysis; MYC; Metabolism; PFK158; Small cell lung cancer

DOI:  https://doi.org/10.1186/s40170-021-00270-9
Front Oncol. 2021 ;11 698023

The Mechanism of Warburg Effect-Induced Chemoresistance in Cancer.

Chang Liu, Ying Jin, Zhimin Fan.

  Although chemotherapy can improve the overall survival and prognosis of cancer patients, chemoresistance remains an obstacle due to the diversity, heterogeneity, and adaptability to environmental alters in clinic. To determine more possibilities for cancer therapy, recent studies have begun to explore changes in the metabolism, especially glycolysis. The Warburg effect is a hallmark of cancer that refers to the preference of cancer cells to metabolize glucose anaerobically rather than aerobically, even under normoxia, which contributes to chemoresistance. However, the association between glycolysis and chemoresistance and molecular mechanisms of glycolysis-induced chemoresistance remains unclear. This review describes the mechanism of glycolysis-induced chemoresistance from the aspects of glycolysis process, signaling pathways, tumor microenvironment, and their interactions. The understanding of how glycolysis induces chemoresistance may provide new molecular targets and concepts for cancer therapy.

Keywords:  Warburg effect; chemoresistance; signaling pathway; transporters and key enzymes of glycolysis; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2021.698023
Oxid Med Cell Longev. 2021 ;2021 8532940

Targeting Reactive Oxygen Species Capacity of Tumor Cells with Repurposed Drug as an Anticancer Therapy.

Jiabing Wang, Dongsheng Sun, Lili Huang, Shijian Wang, Yong Jin.

Accumulating evidence shows that elevated levels of reactive oxygen species (ROS) are associated with cancer initiation, growth, and response to therapies. As concentrations increase, ROS influence cancer development in a paradoxical way, either triggering tumorigenesis and supporting the proliferation of cancer cells at moderate levels of ROS or causing cancer cell death at high levels of ROS. Thus, ROS can be considered an attractive target for therapy of cancer and two apparently contradictory but virtually complementary therapeutic strategies for the regulation of ROS to treat cancer. Despite tremendous resources being invested in prevention and treatment for cancer, cancer remains a leading cause of human deaths and brings a heavy burden to humans worldwide. Chemotherapy remains the key treatment for cancer therapy, but it produces harmful side effects. Meanwhile, the process of de novo development of new anticancer drugs generally needs increasing cost, long development cycle, and high risk of failure. The use of ROS-based repurposed drugs may be one of the promising ways to overcome current cancer treatment challenges. In this review, we briefly introduce the source and regulation of ROS and then focus on the status of repurposed drugs based on ROS regulation for cancer therapy and propose the challenges and direction of ROS-mediated cancer treatment.

DOI: https://doi.org/10.1155/2021/8532940
Immunother Adv. 2021 Jan;1(1): ltab010

A glutamine 'tug-of-war': targets to manipulate glutamine metabolism for cancer immunotherapy.

Laura J Pallett, Sarah Dimeloe, Linda V Sinclair, Adam J Byrne, Anna Schurich.

  Within the tumour microenvironment (TME), there is a cellular 'tug-of-war' for glutamine, the most abundant amino acid in the body. This competition is most evident when considering the balance between a successful anti-tumour immune response and the uncontrolled growth of tumour cells that are addicted to glutamine. The differential effects of manipulating glutamine abundance in individual cell types is an area of intense research and debate. Here, we discuss some of the current strategies in development altering local glutamine availability focusing on inhibition of enzymes involved in the utilisation of glutamine and its uptake by cells in the TME. Further studies are urgently needed to complete our understanding of glutamine metabolism, to provide critical insights into the pathways that represent promising targets and for the development of novel therapeutic strategies for the treatment of advanced or drug resistant cancers.

Keywords:  T cells; cancer immunotherapy; glutamine

DOI:  https://doi.org/10.1093/immadv/ltab010
Apoptosis. 2021 Sep 25.

Targeting of cancer cell death mechanisms by resveratrol: a review.

Xiao Fu, Mu Li, Cuilian Tang, Zezhi Huang, Masoud Najafi.

  Cancer cell death is the utmost aim in cancer therapy. Anti-cancer agents can induce apoptosis, mitotic catastrophe, senescence, or autophagy through the production of free radicals and induction of DNA damage. However, cancer cells can acquire some new properties to adapt to anti-cancer agents. An increase in the incidence of apoptosis, mitotic catastrophe, senescence, and necrosis is in favor of overcoming tumor resistance to therapy. Although an increase in the autophagy process may help the survival of cancer cells, some studies indicated that stimulation of autophagy cell death may be useful for cancer therapy. Using some low toxic agents to amplify cancer cell death is interesting for the eradication of clonogenic cancer cells. Resveratrol (a polyphenol agent) may affect various signaling pathways related to cell death. It can induce death signals and also downregulate the expression of anti-apoptotic genes. Resveratrol has also been shown to modulate autophagy and induce mitotic catastrophe and senescence in some cancer cells. This review focuses on the important targets and mechanisms for the modulation of cancer cell death by resveratrol.

Keywords:  Apoptosis; Autophagy; Cancer cell death; Cancer resistance; Mitotic catastrophe; Resveratrol

DOI:  https://doi.org/10.1007/s10495-021-01689-7
Breast Cancer Res Treat. 2021 Sep 22.

Methionine restriction exposes a targetable redox vulnerability of triple-negative breast cancer cells by inducing thioredoxin reductase.

Dmitry Malin, Yoonkyu Lee, Olga Chepikova, Elena Strekalova, Alexis Carlson, Vincent L Cryns.

   PURPOSE: Tumor cells are dependent on the glutathione and thioredoxin antioxidant pathways to survive oxidative stress. Since the essential amino acid methionine is converted to glutathione, we hypothesized that methionine restriction (MR) would deplete glutathione and render tumors dependent on the thioredoxin pathway and its rate-limiting enzyme thioredoxin reductase (TXNRD).
METHODS: Triple (ER/PR/HER2)-negative breast cancer (TNBC) cells were treated with control or MR media and the effects on reactive oxygen species (ROS) and antioxidant signaling were examined. To determine the role of TXNRD in MR-induced cell death, TXNRD1 was inhibited by RNAi or the pan-TXNRD inhibitor auranofin, an antirheumatic agent. Metastatic and PDX TNBC mouse models were utilized to evaluate in vivo antitumor activity.
RESULTS: MR rapidly and transiently increased ROS, depleted glutathione, and decreased the ratio of reduced glutathione/oxidized glutathione in TNBC cells. TXNRD1 mRNA and protein levels were induced by MR via a ROS-dependent mechanism mediated by the transcriptional regulators NRF2 and ATF4. MR dramatically sensitized TNBC cells to TXNRD1 silencing and the TXNRD inhibitor auranofin, as determined by crystal violet staining and caspase activity; these effects were suppressed by the antioxidant N-acetylcysteine. H-Ras-transformed MCF-10A cells, but not untransformed MCF-10A cells, were highly sensitive to the combination of auranofin and MR. Furthermore, dietary MR induced TXNRD1 expression in mammary tumors and enhanced the antitumor effects of auranofin in metastatic and PDX TNBC murine models.
CONCLUSION: MR exposes a vulnerability of TNBC cells to the TXNRD inhibitor auranofin by increasing expression of its molecular target and creating a dependency on the thioredoxin pathway.

Keywords:  Auranofin; Cancer; Glutathione; Methionine; Nutrition; Oxidative stress; Thioredoxin

DOI:  https://doi.org/10.1007/s10549-021-06398-y
Phytother Res. 2021 Sep 24.

Piperine for treating breast cancer: A review of molecular mechanisms, combination with anticancer drugs, and nanosystems.

Christian Rafael Quijia, Marlus Chorilli.

  Piperine (PIP) is an alkaloid found primarily in Piper longum, and this natural compound has been shown to exert effects on proliferation and survival against various types of cancer. In particular, PIP has potent inhibitory effects on breast cancer (BC), the most prevalent type of cancer in women worldwide. PIP targets numerous signaling pathways associated with the therapy of BC cells through the following mechanisms: (a) induction of arrest of the cell cycle and apoptosis; (b) alteration of the signaling protein expression; (c) reduction in transcription factors; and (d) inhibition of tumor growth. BC cells have the ability to resist conventional drugs, so one of the strategies is the combination of PIP with other phytochemicals such as paclitaxel, thymoquinone, hesperidin, bee venom, tamoxifen, mitoxantrone, piperlongumin, and curcumin. Nanotechnology-based drug encapsulation systems are currently used to enhance the release of PIP. This includes polymer nanoparticles, carbon nanotubes, and liposomes. In the present review, the chemistry and bioavailability of PIP, its molecular targets in BC, and nanotechnological strategies are discussed. Future research directions are also discussed to further understand this promising natural product.

Keywords:  chemotherapeutic drug; drug delivery; molecular mechanism

DOI:  https://doi.org/10.1002/ptr.7291
Inflamm Res. 2021 Sep 19.

Significance of glutathione peroxidase 4 and intracellular iron level in ovarian cancer cells-"utilization" of ferroptosis mechanism.

Dingxi Li, Mengli Zhang, Hongtu Chao.

   OBJECTIVE AND DESIGN: Ovarian cancer is the major cause of death in gynecologic diseases worldwide. Ferroptosis, a nonapoptotic form of cell death, is featured by accumulation of iron-based lipid peroxidation. The elevated iron level and malondialdehyde (MDA) in ovarian cancer cells suggest more vulnerable to ferroptosis, nevertheless, ferroptosis is not observed in ovarian cancer cells. Glutathione peroxidase 4 (GPX4) is a critical regulator of ferroptosis.
METHODS: We determined whether GPX4 knockdown could induce ferroptosis to prevent cell proliferation in ovarian cancer. Human ovarian cancer cells and normal human ovarian epithelial cell line IOSE-80 were cultured and administrated with deferoxamine (DFO) or ferric ammonium citrate (FAC). GPX4 knockdown was established for investigating the functions of GPX4 in ovarian cancer cells and in tumor xenograft mice.
RESULTS: A positively correlation was showed among the levels of GPX4, iron and cell proliferation. Chelation of intracellular iron by DFO disrupted intracellular iron level and was detrimental to ovarian cancer cell survival. FAC-induced elevation of intracellular iron inhibited proliferation, aggravated apoptosis, boosted inflammation and suppressed lipid peroxide reducibility in ovarian cancer cells. Knockdown of GPX4 had similar effects with FAC in ovarian cancer cells. Inhibition of GPX4 suppressed tumor growth, induced ferroptosis, accelerated cell apoptosis, reduced Fe3+ accumulation and suppressed lipid peroxide reducibility in tumor bearing mice.
CONCLUSION: We demonstrate the significance of GPX4 and intracellular iron level in ovarian cancer cells. Importantly, inhibition of GPX4 interferes with both intracellular iron homeostasis and lipid peroxide reducibility, inducing ferroptosis and exerting anti-cancer effect, which can be a potential effective strategy for ovarian cancer therapy.

Keywords:  Ferroptosis; Glutathione peroxidase 4; Iron; Malondialdehyde; Ovarian cancer

DOI:  https://doi.org/10.1007/s00011-021-01495-6
Tumour Biol. 2021 ;43(1): 225-247

Breast cancer suppression by curcumin-naringenin-magnetic-nano-particles: In vitro and in vivo studies.

Mostafa A Askar, Omama E El Shawi, Omayma A R Abou Zaid, Nahla A Mansour, Amal M Hanafy.

   BACKGROUND: The limitations of surgery, radiotherapy, and chemotherapy in cancer treatment and the increase in the application of nanomaterials in the field of biomedicine have promoted the use of nanomaterials in combination with radiotherapy for cancer treatment.
OBJECTIVE: To improve the efficiency of cancer treatment, curcumin-naringenin loaded dextran-coated magnetic nanoparticles (CUR-NAR-D-MNPs) were used as chemotherapy and in combination with radiotherapy to verify their effectiveness in treating tumors.
METHODS: CUR-NAR-D-MNPs were prepared and studied by several characterization methods. Median inhibitory concentration (IC50) and cellular toxicity were evaluated by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay. The cell death and radiosensitization were studied by acridine orange/ethidium bromide dual staining of MCF-7 human breast cancer cells.
RESULTS: CUR-NAR-D-MNPs induce apoptosis and inhibited cell proliferation through reactive oxygen species (ROS) generation. CUR-NAR-D-MNPs used alone had a certain therapeutic effect on tumors. CUR-NAR-D-MNPs plus radiotherapy significantly reduced the tumor volume and led to cell cycle arrest and induction of apoptosis through modulation of P53high, P21high, TNF-αlow, CD44low, and ROShigh signalingCONCLUSIONS:CUR-NAR-D-MNPs are effective in the treatment of tumors when combined with radiotherapy, and show radiosensitization effects against cancer proliferation in vitro and in vivo.

Keywords:  Curcumin-narenginin; antitumor; in-vitro; in-vivo studies; magnetite-nanoparticles; radiosensitization

DOI:  https://doi.org/10.3233/TUB-211506
Phytother Res. 2021 Sep 22.

The review of alpha-linolenic acid: Sources, metabolism, and pharmacology.

Qianghua Yuan, Fan Xie, Wei Huang, Mei Hu, Qilu Yan, Zemou Chen, Yan Zheng, Li Liu.

  α-linolenic acid (ALA, 18:3n-3) is a carboxylic acid composed of 18 carbon atoms and three cis double bonds, and is an essential fatty acid indispensable to the human body. This study aims to systematically review related studies on the dietary sources, metabolism, and pharmacological effects of ALA. Information on ALA was collected from the internet database PubMed, Elsevier, ResearchGate, Web of Science, Wiley Online Library, and Europe PMC using a combination of keywords including "pharmacology," "metabolism," "sources." The following findings are mainly contained. (a) ALA can only be ingested from food and then converted into eicosapentaenoic acid and docosahexaenoic acid in the body. (b) This conversion process is relatively limited and affected by many factors such as dose, gender, and disease. (c) Pharmacological research shows that ALA has the anti-metabolic syndrome, anticancer, antiinflammatory, anti-oxidant, anti-obesity, neuroprotection, and regulation of the intestinal flora properties. (d) There are the most studies that prove ALA has anti-metabolic syndrome effects, including experimental studies and clinical trials. (e) The therapeutic effect of ALA will be affected by the dosage. In short, ALA is expected to treat many diseases, but further high quality studies are needed to firmly establish the clinical efficacy of ALA.

Keywords:  dietary sources; metabolism; pharmacology; toxicology; α-linolenic acid

DOI:  https://doi.org/10.1002/ptr.7295
Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2021 Sep 19. e1755

Targeting steroid hormone receptors for anti-cancer therapy-A review on small molecules and nanotherapeutic approaches.

Namita Mahadik, Dwaipayan Bhattacharya, Akshaya Padmanabhan, Kalyani Sakhare, Kumar Pranav Narayan, Rajkumar Banerjee.

  The steroid hormone receptors (SHRs) among nuclear hormone receptors (NHRs) are steroid ligand-dependent transcription factors that play important roles in the regulation of transcription of genes promoted via hormone responsive elements in our genome. Aberrant expression patterns and context-specific regulation of these receptors in cancer, have been routinely reported by multiple research groups. These gave an window of opportunity to target those receptors in the context of developing novel, targeted anticancer therapeutics. Besides the development of a plethora of SHR-targeting synthetic ligands and the availability of their natural, hormonal ligands, development of many SHR-targeted, anticancer nano-delivery systems and theranostics, especially based on small molecules, have been reported. It is intriguing to realize that these cytoplasmic receptors have become a hot target for cancer selective delivery. This is in spite of the fact that these receptors do not fall in the category of conventional, targetable cell surface bound or transmembrane receptors that enjoy over-expression status. Glucocorticoid receptor (GR) is one such exciting SHR that in spite of it being expressed ubiquitously in all cells, we discovered it to behave differently in cancer cells, thus making it a truly druggable target for treating cancer. This review selectively accumulates the knowledge generated in the field of SHR-targeting as a major focus for cancer treatment with various anticancer small molecules and nanotherapeutics on progesterone receptor, mineralocorticoid receptor, and androgen receptor while selectively emphasizing on GR and estrogen receptor. This review also briefly highlights lipid-modification strategy to convert ligands into SHR-targeted cancer nanotherapeutics. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Biology-Inspired Nanomaterials > Lipid-Based Structures Therapeutic Approaches and Drug Discovery > Emerging Technologies.

Keywords:  androgen receptor; estrogen receptor; glucocorticoid receptor; mineralocorticoid receptor; progesterone receptor; steroid hormone receptors; targeted cancer therapy

DOI:  https://doi.org/10.1002/wnan.1755
J Control Release. 2021 Sep 20. pii: S0168-3659(21)00498-3. [Epub ahead of print]339 14-26

Photothermal nanozyme-ignited Fenton reaction-independent ferroptosis for breast cancer therapy.

Lei Xing, Xiao-Ying Liu, Tian-Jiao Zhou, Xing Wan, Yi Wang, Hu-Lin Jiang.

  Ferroptosis is a type of programmed cell death caused by the iron-dependent lipid hydroperoxide pathway and has attracted significant interest. However, Fenton reaction-dependent ferroptosis has shown unsatisfactory therapeutic effects in tumor therapy, mainly due to inadequate reaction conditions in the tumor microenvironment. Here, we report a new strategy for Fenton-independent pathway by employing photothermal nanozyme to overcome limitations of the low efficiency of Fenton reaction. Specifically, we used iron redox pair (Fe2+/Fe3+)-containing hollow mesoporous Prussian blue (HMPB) nanocubes as the iron sources to fabricate iron-loaded liposome (HMPB@Lip). HMPB@Lip not only exerts the photothermal therapy, but also functions as nanozyme catalyzing lipid peroxidation for ferroptosis therapy. Importantly, Fenton reaction-independent ferroptosis triggered by photothermal nanozyme achieved effective tumor ablation. Therefore, HMPB@Lip can be used as a potential multifunctional nanozyme for effective Fenton reaction-independent ferroptosis therapy.

Keywords:  Fenton reaction; Ferroptosis; Nanozyme; Photothermal therapy; Prussian blue

DOI:  https://doi.org/10.1016/j.jconrel.2021.09.019
Curr Mol Pharmacol. 2021 Sep 22.

Nanoencapsulation of Polyphenols as Drugs and Supplements for Enhancing Therapeutic Profile - A Review.

Saima Khatoon, Nida Kalam, Mohd Farooq Shaikh, M Saquib Hasnain, Aurangzeb Khurram Hafiz, Mohammed Tahir Ansari.

  Polyphenolic phytoconstituents have been widely in use worldwide since ages and are categorised as secondary metabolites of plants. The application of polyphenols such as quercetin, resveratrol. curcumin as nutritional supplement has been researched widely. The use of polyphenols, and specifically quercetin for improving the memory and mental endurance have shown significant effects among rats. Even though similar results has not been resonated among human but encouraging preclinical results have encouraged researchers to explore other polyphenols to study the effects as supplements among athletes. The phytopharmacological research has elucidated the use of natural polyphenols to prevent and treat various physiological and metabolic disorders owing to its free radical scavenging properties, anti-inflammatory, anti-cancer and immunomodulatory effects. In spite of the tremendous pharmacological profile, one of the most dominant problem regarding the use of polyphenolic compounds is their low bioavailability. Nanonization is considered as one of the most prominent approaches among many. This article aims to review and discuss the molecular mechanisms of recently developed nanocarrier-based drug delivery systems for polyphenols and its application as drugs and supplements. Nanoformulations of natural polyphenols are bioactive agents, such as quercetin, kaempferol, fisetin, rutin, hesperetin, and naringenin epigalloccatechin-3-gallate, genistein, ellagic acid, gallic acid, chlorogenic acid, ferulic acid, curcuminoids and stilbenes is expected to have better efficacy. These delivery systems are expected to provide higher penetrability of polyphenols at cellular levels and exhibit a controlled release of the drugs. It is widely accepted that natural polyphenols do demonstrate significant therapeutic effect. However, the hindrances in their absorption, specificity and bioavailability can be overcome using nanotechnology.

Keywords:  Athletes; Bioavailability; Drug Delivery; Metabolites. ; Nanocarriers; Polyphenols; Supplements

DOI:  https://doi.org/10.2174/1874467214666210922120924
EMBO Mol Med. 2021 Sep 20. e14495

Dependence receptors: new targets for cancer therapy.

Morgan Brisset, Mélodie Grandin, Agnès Bernet, Patrick Mehlen, Frédéric Hollande.

  Dependence receptors are known to promote survival and positive signaling such as proliferation, migration, and differentiation when activated, but to actively trigger apoptosis when unbound to their ligand. Their abnormal regulation was shown to be an important feature of tumorigenesis, allowing cancer cells to escape apoptosis triggered by these receptors while promoting in parallel major aspects of tumorigenesis such as proliferation, angiogenesis, invasiveness, and chemoresistance. This involvement in multiple cancer hallmarks has raised interest in dependence receptors as targets for cancer therapy. Although additional studies remain necessary to fully understand the complexity of signaling pathways activated by these receptors and to target them efficiently, it is now clear that dependence receptors represent very exciting targets for future cancer treatment. This manuscript reviews current knowledge on the contribution of dependence receptors to cancer and highlights the potential for therapies that activate pro-apoptotic functions of these proteins.

Keywords:  apoptosis; cancer hallmarks; treatment resistance; tumor progression

DOI:  https://doi.org/10.15252/emmm.202114495
Amino Acids. 2021 Sep 22.

Oncogenic Ras expression increases cellular formate production.

T Pongnopparat, G Tingley, Y Gao, J T Brosnan, M E Brosnan, S L Christian.

  One-carbon units, critical intermediates for cell growth, may be produced by a variety of means, one of which is via the production of formate. Excessive formate accumulation, known as formate overflow and a characteristic of oxidative cancer, has been observed in cancer cells. However, the basis for this high rate of formate production is unknown. We examined the effect of elevated expression of oncogenic Ras (RasV12), on formate production in NIH-3T3 cells (mouse fibroblasts) cultured with either labelled 13C-serine or 13C-glycine. Formate accumulation by the fibroblasts transformed by RasV12 was increased two-threefold over those by vector control (Babe) cells. The production of formate exceeded the rate of utilization in both cell types. 13C-formate was produced almost exclusively from the #3 carbon of 13C-serine. Virtually no labelled formate was produced from either the #2 carbon of serine or the #2 carbon of glycine. The increased formate production by RasV12 cells was associated with increased mRNA abundances for enzymes of formate production in both the mitochondria and the cytosol. Thus, we find the oncogenic RasV12 significantly increases formate overflow and may be one way for tumor cells to produce one-carbon units required for enhanced proliferation of these cells and/or for other processes which have not been identified.

Keywords:  Cytosol; Folate; Glycine; Methylenetetrahydrofolate; Mitochondria; Serine

DOI:  https://doi.org/10.1007/s00726-021-03078-5
J Control Release. 2021 Sep 15. pii: S0168-3659(21)00496-X. [Epub ahead of print]

NIR-activated self-sensitized polymeric micelles for enhanced cancer chemo-photothermal therapy.

Lijun Yang, Xiaoxue Hou, Yumin Zhang, Dianyu Wang, Jinjian Liu, Fan Huang, Jianfeng Liu.

  NIR-activated therapies based on light-responsive drug delivery systems are emerging as a remote-controlled method for cancer precise therapy. In this work, fluorescent dye indocyanine green (ICG)-conjugated and bioactive compound gambogic acid (GA)-loaded polymeric micelles (GA@PEG-TK-ICG PMs) were smoothly fabricated via the self-assembly of the reactive oxygen species (ROS)-responsive thioketal (TK)-linked amphiphilic polymer poly(ethyleneglycol)-thioketal-(indocyanine green) (PEG-TK-ICG). The resultant micelles demonstrated increased resistance to photobleaching, enhanced photothermal conversion efficiency, NIR-controlled drug release behavior, preferable biocompatibility, and excellent tumor accumulation performance. Moreover, upon an 808 nm laser irradiation, the micellar photoactive chromophore ICG converted the absorbed optical energy to both hyperthermia for photothermal therapy (PTT) and ROS as the feedback trigger to the micelles for the tumor-specific release of GA, which could serve as not only a chemotherapeutic drug to directly kill tumor cells but also a heat shock protein 90 (HSP90) inhibitor to realize the photothermal sensitization. As a result, an extremely high tumor inhibition rate (97.9%) of mouse 4 T1 breast cancer models was achieved with negligible side effects after the chemo-photothermal synergistic therapy. This NIR-activated nanosystem with photothermal self-sensitization function may provide a feasible option for the effective treatment of aggressive breast cancers.

Keywords:  Chemo-photothermal therapy; Gambogic acid; Heat shock protein; NIR-activated nanosystem; Self-sensitization

DOI:  https://doi.org/10.1016/j.jconrel.2021.09.017
NPJ Breast Cancer. 2020 Sep 25. 6(1): 47

ARe we there yet? Understanding androgen receptor signaling in breast cancer.

Anna R Michmerhuizen, Daniel E Spratt, Lori J Pierce, Corey W Speers.

The role of androgen receptor (AR) activation and expression is well understood in prostate cancer. In breast cancer, expression and activation of AR is increasingly recognized for its role in cancer development and its importance in promoting cell growth in the presence or absence of estrogen. As both prostate and breast cancers often share a reliance on nuclear hormone signaling, there is increasing appreciation of the overlap between activated cellular pathways in these cancers in response to androgen signaling. Targeting of the androgen receptor as a monotherapy or in combination with other conventional therapies has proven to be an effective clinical strategy for the treatment of patients with prostate cancer, and these therapeutic strategies are increasingly being investigated in breast cancer. This overlap suggests that targeting androgens and AR signaling in other cancer types may also be effective. This manuscript will review the role of AR in various cellular processes that promote tumorigenesis and metastasis, first in prostate cancer and then in breast cancer, as well as discuss ongoing efforts to target AR for the more effective treatment and prevention of cancer, especially breast cancer.

DOI: https://doi.org/10.1038/s41523-020-00190-9
Med Hypotheses. 2021 Sep 14. pii: S0306-9877(21)00198-5. [Epub ahead of print]156 110679

Combination therapy of vanillic acid and oxaliplatin co-loaded in polysaccharide based functionalized polymeric micelles could offer effective treatment for colon cancer: A hypothesis.

Jaskiran Kaur, Monica Gulati, K Gowthamarajan, Sukriti Vishwas, Dinesh Kumar Chellappan, Gaurav Gupta, Kamal Dua, Narendra Kumar Pandey, Bimlesh Kumar, Sachin Kumar Singh.

  Colon cancer is characterised by the persistent change in bowel habits due to the formation of polyps (cancerous) in the inner lining of the colon. Clinically, there are several anticancer drugs available to treat colon cancer. Oxaliplatin (third generation platinum drug) is widely prescribed anticancer drug due to its broad range anticancer properties and low toxicities over cisplatin and carboplatin. Currently, use of oxaliplatin as adjuvant chemotherapy represents a standard care for the treatment of advanced colon cancer. Despite this, its rapid degradation in systemic circulations upon administration, lack of tumor specificity, and low bioavailability limits its anticancer potential. On the other hand, vanillic acid (VA) has shown anticancer potential in colon cancer by targeting mTOR/Ras pathway, HIF-1α inhibition, NF-ĸB, and Nrf2 that regulate cell growth, cell survival, proliferation and adaptation to cancer microenvironment. Normal oral delivery of these two drugs offers non-specific drug release in gastrointestinal tract that leads to unwanted toxicity and very less amount of drug become available for colonic site. Therefore, loading of these two drugs in polysaccharide based functionalized polymeric micelles (FPMs) can offer selective targeting at colonic site and could offer better therapeutic efficacy at much lesser doses of drugs. Therefore, a new hypothesis has been proposed that the combination of vanillic acid with oxaliplatin co-loaded in FPMs could provide colon targeting ability with enhanced potency and safety profile by targeting multiple pathways than current adjuvant chemotherapies available in the market for the treatment of colon cancer.

Keywords:  Colon cancer; Colon targeted delivery; Functionalized polymeric micelles; Oxaliplatin; Vanillic acid

DOI:  https://doi.org/10.1016/j.mehy.2021.110679
Front Oncol. 2021 ;11 714598

Activated Pancreatic Stellate Cells Enhance the Warburg Effect to Cause the Malignant Development in Chronic Pancreatitis.

Ye Tao, Feng Shao, Ming Cai, Zhen Liu, Yao Peng, Qiang Huang, Futao Meng.

  Chronic pancreatitis (CP) is a precancerous condition associated with pancreatic ductal adenocarcinoma (PDAC), but its evolutionary mechanism is unclear. Pancreatic stellate cells (PSCs) are closely related to the occurrence and development of CP and PDAC, but it is not clear whether PSCs play a key role in this "inflammation-cancer transition". Our research found that co-culture with activated PSCs promoted the proliferation, migration and invasion of normal pancreatic duct epithelial cells and pancreatic cancer cells. At the same time, activated PSCs had a significant effect on the expression of the glycolysis markers (pyruvate kinase M2, lactate dehydrogenase A, glucose transporter 1, hexokinase-II and monocarboxylate transporter 4; PKM2, LDHA, GLUT1, HK2 and MCT4) in normal pancreatic duct epithelial cells and pancreatic cancer cells and increased lactic acid production and glucose consumption in these two cells. In vivo experiments showed that the expression of the glycolysis markers in pancreatic duct epithelial cells and the marker protein (α-SMA) of activated PSCs in the pancreatic duct peripancreatic interstitium were higher in pancreatic cancer tissues and chronic pancreatitis tissues than in normal pancreatic tissues in both animals and humans. In addition, analysis of human tissue specimens showed that there is a correlation between the expression of glycolysis markers and α-SMA. These findings indicate that activated PSCs play an important role in the development and progression of chronic pancreatitis into pancreatic cancer by regulating and promoting aerobic glycolysis. Our research provides a new theoretical basis for further understanding the mechanism of CP malignancy and the selection of targets for reversing CP malignancy.

Keywords:  activated pancreatic stellate cells; co-culture; malignant development in chronic pancreatitis; pancreatic ductal adenocarcinoma; the Warburg effect

DOI:  https://doi.org/10.3389/fonc.2021.714598
Carbohydr Polym. 2021 Dec 01. pii: S0144-8617(21)00875-4. [Epub ahead of print]273 118488

Carboxymethyl dextran-based nanocomposites for enhanced chemo-sonodynamic therapy of cancer.

Wooram Um, Pramod Kumar E K, Yeari Song, Jeongjin Lee, Jae Yoon An, Hyeyeon Joo, Dong Gil You, Jae Hyung Park.

  Glutathione (GSH), a tripeptide abundant in the cancer cells, inhibits the cytotoxic effect of reactive oxygen species (ROS) and is associated with anti-apoptosis, thus facilitating tumor growth. Here, we report GSH-depleting carboxymethyl dextran nanocomposites for chemo-sonodynamic therapy for cancer. The nanocomposite is composed of the TiO2-based core as the sonosensitizer, MnO2 coat as the GSH-consuming chemosensitizer, and carboxymethyl dextran as the hydrophilic shell. The in vitro cell experiments demonstrated that, when taken up by the cancer cells, the nanocomposites can deplete intracellular GSH by reducing MnO2 to Mn2+ which induces intracellular ROS production. Upon exposure to ultrasound, the nanocomposites effectively generated cytotoxic singlet oxygen at the intracellular level, remarkably enhancing the cytotoxicity to cancer cells. Notably, chemo-sonodynamic activity of the nanocomposites induced apoptosis as well as necrosis of cancer cells, implying their high potential as the anticancer therapeutics.

Keywords:  Cancer therapy; Carboxymethyl dextran; Glutathione; Nanoparticles; Sonodynamic therapy

DOI:  https://doi.org/10.1016/j.carbpol.2021.118488
Mol Cancer Ther. 2021 Sep 22. pii: molcanther.0033.2021. [Epub ahead of print]

Heme sequestration as an effective strategy for the suppression of tumor growth and progression.

Tianyuan Wang, Adnin Ashrafi, Purna Chaitanya Konduri, Poorva Ghosh, Sanchareeka Dey, Parsa Modareszadeh, Narges Salamat, Parinaz Sadat Alemi, Eranda Berisha, Li Zhang.

Heme is an essential nutritional, metabolic, and signaling molecule in living organisms. Pathogenic microbes extract heme from hosts to obtain metallonutrient, while heme fuels mitochondrial respiration and ATP generation in lung tumor cells. Here, we generated small heme-sequestering proteins (HeSPs) based on bacterial hemophores. These HeSPs contain neutral mutations in the heme-binding pocket and hybrid sequences from hemophores of different bacteria. We showed that HeSPs bound to heme and effectively extracted heme from hemoglobin. They strongly inhibited heme uptake and cell proliferation and induced apoptosis in non-small lung cancer (NSCLC) cells, while their effects on non-tumorigenic cell lines representing normal lung cells were not significant. HeSPs strongly suppressed the growth of human NSCLC tumor xenografts in mice. HeSPs decreased oxygen consumption rates and ATP levels in tumor cells isolated from treated mice, while they did not affect liver and blood cell functions. Immunohistochemistry, along with data from Western blotting and functional assays, revealed that HeSPs reduced the levels of key proteins involved in heme uptake, as well as the consumption of major fuels for tumor cells, glucose and glutamine. Further, we found that HeSPs reduced the levels of angiogenic and vascular markers, as well as vessel density in tumor tissues. Together, these results demonstrate that HeSPs act via multiple mechanisms, including the inhibition of oxidative phosphorylation, to suppress tumor growth and progression. Evidently, heme sequestration can be a powerful strategy for suppressing lung tumors and likely drug-resistant tumors that rely on oxidative phosphorylation for survival.

DOI: https://doi.org/10.1158/1535-7163.MCT-21-0033
Front Mol Biosci. 2021 ;8 649395

Resveratrol-Based Nanoformulations as an Emerging Therapeutic Strategy for Cancer.

Javad Sharifi-Rad, Cristina Quispe, Zhazira Mukazhanova, Ewa Knut, Aknur Turgumbayeva, Aliya Kipchakbayeva, Gulnaz Seitimova, Mohamad Fawzi Mahomoodally, Devina Lobine, Aaron Koay, Jinfan Wang, Helen Sheridan, Gerardo Leyva-Gómez, María L Del Prado-Audelo, Hernán Cortes, Antonio Rescigno, Paolo Zucca, Oksana Sytar, Muhammad Imran, Célia F Rodrigues, Natália Cruz-Martins, Halina Ekiert, Manoj Kumar, Ahmad Faizal Abdull Razis, Usman Sunusi, Ramla Muhammad Kamal, Agnieszka Szopa.

  Resveratrol is a polyphenolic stilbene derivative widely present in grapes and red wine. Broadly known for its antioxidant effects, numerous studies have also indicated that it exerts anti-inflammatory and antiaging abilities and a great potential in cancer therapy. Regrettably, the oral administration of resveratrol has pharmacokinetic and physicochemical limitations such as hampering its effects so that effective administration methods are demanding to ensure its efficiency. Thus, the present review explores the published data on the application of resveratrol nanoformulations in cancer therapy, with the use of different types of nanodelivery systems. Mechanisms of action with a potential use in cancer therapy, negative effects, and the influence of resveratrol nanoformulations in different types of cancer are also highlighted. Finally, the toxicological features of nanoresveratrol are also discussed.

Keywords:  bio-availability; cancer therapy; clinical applications; drug-delivery systems; resveratrol

DOI:  https://doi.org/10.3389/fmolb.2021.649395
Anticancer Drugs. 2021 Sep 22.

Natural products inducing nucleolar stress: implications in cancer therapy.

Mi Wu, Lu Lu, Sisi Chen, Ying Li, Qiuting Zhang, Shujun Fu, Xiyun Deng.

The nucleolus is the site of ribosome biogenesis and is found to play an important role in stress sensing. For over 100 years, the increase in the size and number of nucleoli has been considered as a marker of aggressive tumors. Despite this, the contribution of the nucleolus and the biologic processes mediated by it to cancer pathogenesis has been largely overlooked. This state has been changed over the recent decades with the demonstration that the nucleolus controls numerous cellular functions associated with cancer development. Induction of nucleolar stress has recently been regarded as being superior to conventional cytotoxic/cytostatic strategy in that it is more selective to neoplastic cells while sparing normal cells. Natural products represent an excellent source of bioactive molecules and some of them have been found to be able to induce nucleolar stress. The demonstration of these nucleolar stress-inducing natural products has paved the way for a new therapeutic approach to more delicate tumor cell-killing. This review provides a contemporary summary of the role of the nucleolus as a novel promising target for cancer therapy, with particular emphasis on natural products as an exciting new class of anti-cancer drugs with nucleolar stress-inducing properties.

DOI: https://doi.org/10.1097/CAD.0000000000001146
J Pharm Pharmacol. 2021 Sep 24. pii: rgab130. [Epub ahead of print]

Natural substances derived from herbs or plants are promising sources of anticancer agents against colorectal cancer via triggering apoptosis.

Zi-Bo Liu, Ting Zhang, Xun Ye, Zi-Qi Liu, Xue Sun, Li-Lin Zhang, Chun-Jie Wu.

   OBJECTIVES: Nowadays, one of the most common gastrointestinal cancers is colorectal cancer (CRC). Chemotherapy is still one of the main methods to treat cancer. However, the currently available synthetic chemotherapy drugs often cause serious adverse reactions. Apoptosis is generally considered as an ideal way for induction the death of tumour cells without the body's inflammatory response, and it is reported that lots of natural agents could trigger various cancer cells to apoptosis. The overarching aim of this project was to elucidate the specific mechanisms by which natural substances induce apoptosis in CRC cells and to be used as an alternative therapeutic option in the future.
KEY FINDINGS: The mechanisms for the pro-apoptotic effects of natural substances derived from herbs or plants include death receptor pathway, mitochondrial pathway, endoplasmic reticulum stress pathway, related signal transduction pathways (PI3K/Akt, MAPK, p53 signalling), and so on.
SUMMARY: This paper updated this information regarding the anti-tumour effects of natural agents via induction of apoptosis against CRC, which would be beneficial for future new drug research regarding natural products from herbs or plants.

Keywords:  apoptosis; colorectal cancer; molecular mechanism; natural substances; signalling pathways

DOI:  https://doi.org/10.1093/jpp/rgab130
Mol Cell. 2021 Sep 16. pii: S1097-2765(21)00693-6. [Epub ahead of print]81(18): 3731-3748

Supply and demand: Cellular nutrient uptake and exchange in cancer.

Vasileios Papalazarou, Oliver D K Maddocks.

  Nutrient supply and demand delineate cell behavior in health and disease. Mammalian cells have developed multiple strategies to secure the necessary nutrients that fuel their metabolic needs. This is more evident upon disruption of homeostasis in conditions such as cancer, when cells display high proliferation rates in energetically challenging conditions where nutritional sources may be scarce. Here, we summarize the main routes of nutrient acquisition that fuel mammalian cells and their implications in tumorigenesis. We argue that the molecular mechanisms of nutrient acquisition not only tip the balance between nutrient supply and demand but also determine cell behavior upon nutrient limitation and energetic stress and contribute to nutrient partitioning and metabolic coordination between different cell types in inflamed or tumorigenic environments.

Keywords:  SLC proteins; amino acid; cancer; nutrient scavenging; nutrient transport; nutrient transporters

DOI:  https://doi.org/10.1016/j.molcel.2021.08.026
Antioxid Redox Signal. 2021 Sep 20.

THIOL-BASED ANTIOXIDANTS AND THE EPITHELIAL-MESENCHYMAL TRANSITION IN CANCER.

Fernando T Ogata, Alex Yuri Simoes Sato, Lucia Coppo, Roberto J Arai, Arnold I Stern, Hugo P Monteiro.

   SIGNIFICANCE: The epithelial-mesenchymal transition (EMT) is commonly associated with tumor metastasis. Oxidative and nitrosative stress are maintained in cancer cells and are involved in the EMT. Cancer cells are endowed with high levels of enzymatic and non-enzymatic antioxidants which counteract the effects of oxidative and nitrosative stress. Thiol-based antioxidant systems such as the Thioredoxin/Thioredoxin reductase (Trx/TrxR) and Glutathione/Glutaredoxin (GSH/Grx) are continually active in cancer cells, while the Thioredoxin-interacting protein (Txnip), the negative regulator of the Trx/TrxR system, is down regulated. Recent Advances: Trx/TrxR and GSH/Grx systems play a major role in maintaining EMT signaling and cancer cell progression.
CRITICAL ISSUES: Enhanced stress conditions stimulated in cancer cells inhibit EMT signal-ing. The elevated expression levels of the Trx/TrxR and GSH/Grx systems in these cells provide the antioxidant protection necessary to guarantee the occurrence of the EMT.
FUTURE DIRECTIONS: Elevation of the intracellular ROS and NO concentrations in cancer cells has been viewed as a promising strategy for elimination of these cells. The devel-opment of inhibitors of GSH synthesis and of the Trx/TrxR system together with genet-ic-based strategies to enhance Txnip levels may provide the necessary means to achieve this goal.

Keywords:  Epithelial-mesenchymal transition; oxidative stress; nitrosative stress; Thioredoxin; Thioredoxin reductase; Thioredoxin-interacting protein; Glutaredoxin.

DOI:  https://doi.org/10.1089/ars.2021.0199
Front Pharmacol. 2021 ;12 707231

Is Curcumin at the Threshold of Therapeutic Effectiveness on Patients with Colon Cancer?-A Systematic Review.

Laila Khaled Ismael Abdelgawad Shafei, Mohamed Izham Mohamed Ibrahim, Nashiru Billa.

  Curcumin, obtained from curcuma longa, has been the subject of decades of scientific investigation on its therapeutic usefulness. It is reported to possess several therapeutic properties, of which anti-colon cancer is of interest in this review. Clinically however, curcumin has yet to firm up its place among established anti-colon cancer therapeutic contenders. We aimed to systematically review prevailing clinical evidence on the role of curcumin in colon cancer treatment. The review drawing from literature on clinical studies indicates fairly long term tolerability. No regression of tumor was reported when curcumin was the sole intervention. Increase in p53 level expression was reported in a placebo controlled study but no reduction in PGE2 or 5HETE. Pharmacokinetic data on healthy humans indicate that formulated curcumin delivery systems present significantly higher systemic bioavailability. It appears therefore that the clinical use of curcumin can potentially be realized only through appropriate formulation interventions. Systematic Review Registration: [website], identifier [registration number].

Keywords:  cancer; clinical trial; colon; curcumin; formulation; nanoparticle delivery; outcome measures; systematic review

DOI:  https://doi.org/10.3389/fphar.2021.707231
Biomed Pharmacother. 2021 Sep 15. pii: S0753-3322(21)00926-4. [Epub ahead of print]143 112142

Reactive oxygen species (ROS) in cancer pathogenesis and therapy: An update on the role of ROS in anticancer action of benzophenanthridine alkaloids.

Abdul Q Khan, Khalid Rashid, Abdulhadi A AlAmodi, Maha Victor Agha, Sabah Akhtar, Ishrat Hakeem, Syed Shadab Raza, Shahab Uddin.

  Reactive oxygen species play crucial role in biological homeostasis and pathogenesis of human diseases including cancer. In this line, now it has become evident that ROS level/concentration is a major factor in the growth, progression and stemness of cancer cells. Moreover, cancer cells maintain a delicate balance between ROS and antioxidants to promote pathogenesis and clinical challenges via targeting a battery of signaling pathways converging to cancer hallmarks. Recent findings also entail the therapeutic importance of ROS for the better clinical outcomes in cancer patients as they induce apoptosis and autophagy. Moreover, poor clinical outcomes associated with cancer therapies are the major challenge and use of natural products have been vital in attenuation of these challenges due to their multitargeting potential with less adverse effects. In fact, most available drugs are derived from natural resources, either directly or indirectly and available evidence show the clinical importance of natural products in the management of various diseases, including cancer. ROS play a critical role in the anticancer actions of natural products, particularly phytochemicals. Benzophenanthridine alkaloids of the benzyl isoquinoline family of alkaloids, such as sanguinarine, possess several pharmacological properties and are thus being studied for the treatment of different human diseases, including cancer. In this article, we review recent findings, on how benzophenanthridine alkaloid-induced ROS play a critical role in the attenuation of pathological changes and stemness features associated with human cancers. In addition, we highlight the role of ROS in benzophenanthridine alkaloid-mediated activation of the signaling pathway associated with cancer cell apoptosis and autophagy.

Keywords:  Benzophenanthridine alkaloids; Cancer; Cancer stemness; Natural products; Oxidative stress; ROS

DOI:  https://doi.org/10.1016/j.biopha.2021.112142
Cell Rep. 2021 Sep 21. pii: S2211-1247(21)01153-0. [Epub ahead of print]36(12): 109706

ATF3 promotes the serine synthesis pathway and tumor growth under dietary serine restriction.

Xingyao Li, Daniel Gracilla, Lun Cai, Mingyi Zhang, Xiaolin Yu, Xiaoguang Chen, Junran Zhang, Xiaochun Long, Han-Fei Ding, Chunhong Yan.

  The serine synthesis pathway (SSP) involving metabolic enzymes phosphoglycerate dehydrogenase (PHGDH), phosphoserine aminotransferase 1 (PSAT1), and phosphoserine phosphatase (PSPH) drives intracellular serine biosynthesis and is indispensable for cancer cells to grow in serine-limiting environments. However, how SSP is regulated is not well understood. Here, we report that activating transcription factor 3 (ATF3) is crucial for transcriptional activation of SSP upon serine deprivation. ATF3 is rapidly induced by serine deprivation via a mechanism dependent on ATF4, which in turn binds to ATF4 and increases the stability of this master regulator of SSP. ATF3 also binds to the enhancers/promoters of PHGDH, PSAT1, and PSPH and recruits p300 to promote expression of these SSP genes. As a result, loss of ATF3 expression impairs serine biosynthesis and the growth of cancer cells in the serine-deprived medium or in mice fed with a serine/glycine-free diet. Interestingly, ATF3 expression positively correlates with PHGDH expression in a subset of TCGA cancer samples.

Keywords:  ATF3; ATF4; PHGDH; PSAT1; PSPH; p300; serine biosynthesis; serine deprivation; serine metabolism; serine synthesis pathway

DOI:  https://doi.org/10.1016/j.celrep.2021.109706
J Mater Chem B. 2021 Sep 23.

A flowerlike FePt/MnO2/GOx-based cascade nanoreactor with sustainable O2 supply for synergistic starvation-chemodynamic anticancer therapy.

Yunkai Kou, Zhichao Dai, Ping Cui, Zunfu Hu, Lu Tian, Feifei Zhang, Haiqiang Duan, Qiying Xia, Qingyun Liu, Xiuwen Zheng.

The development of versatile nanotheranostic agents has received increasing interest in cancer treatment. Herein, in this study, we rationally designed and prepared a novel flowerlike multifunctional cascade nanoreactor, BSA-GOx@MnO2@FePt (BGMFP), by integrating glucose oxidase (GOx), manganese dioxide (MnO2) and FePt for synergetic cancer treatment with satisfying therapeutic efficiency. In an acidic environment, intratumoral H2O2 could be decomposed to O2 to accelerate the consumption of glucose catalyzed by GOx to induce cancer starvation. Moreover, the accumulation of gluconic acid and H2O2 generated along with the consumption of glucose would in turn promote the catalytic efficiency of MnO2 and boost O2 evolution, which could enhance the efficiency of starvation therapy. Moreover, FePt as an excellent Fenton agent could simultaneously convert H2O2 to the toxic hydroxyl radical (˙OH), subsequently resulting in amplified intracellular oxidative stress and cell apoptosis. Therefore, BGMFP could catalyze a cascade of intracellular biochemical reactions and optimize the unique properties of MnO2, GOx and FePt via mutual promotion of each other to realize O2 supply, chemodynamic therapy (CDT) and starvation therapy. The anticancer results in vitro and in vivo demonstrated that BGMFP possessed remarkable tumor inhibition capacity through enhancing the starvation therapy and CDT. It is appreciated that BGMFP could be a promising platform for synergetic cancer treatment.

DOI: https://doi.org/10.1039/d1tb01539g
Sci Rep. 2021 Sep 23. 11(1): 18875

Glycolysis-related gene expression profiling serves as a novel prognosis risk predictor for human hepatocellular carcinoma.

Lingyu Zhang, Yu Li, Yibei Dai, Danhua Wang, Xuchu Wang, Ying Cao, Weiwei Liu, Zhihua Tao.

Metabolic pattern reconstruction is an important factor in tumor progression. Metabolism of tumor cells is characterized by abnormal increase in anaerobic glycolysis, regardless of high oxygen concentration, resulting in a significant accumulation of energy from glucose sources. These changes promotes rapid cell proliferation and tumor growth, which is further referenced a process known as the Warburg effect. The current study reconstructed the metabolic pattern in progression of cancer to identify genetic changes specific in cancer cells. A total of 12 common types of solid tumors were included in the current study. Gene set enrichment analysis (GSEA) was performed to analyze 9 glycolysis-related gene sets, which are implicated in the glycolysis process. Univariate and multivariate analyses were used to identify independent prognostic variables for construction of a nomogram based on clinicopathological characteristics and a glycolysis-related gene prognostic index (GRGPI). The prognostic model based on glycolysis genes showed high area under the curve (AUC) in LIHC (Liver hepatocellular carcinoma). The findings of the current study showed that 8 genes (AURKA, CDK1, CENPA, DEPDC1, HMMR, KIF20A, PFKFB4, STMN1) were correlated with overall survival (OS) and recurrence-free survival (RFS). Further analysis showed that the prediction model accurately distinguished between high- and low-risk cancer patients among patients in different clusters in LIHC. A nomogram with a well-fitted calibration curve based on gene expression profiles and clinical characteristics showed good discrimination based on internal and external cohorts. These findings indicate that changes in expression level of metabolic genes implicated in glycolysis can contribute to reconstruction of tumor-related microenvironment.

DOI: https://doi.org/10.1038/s41598-021-98381-2
Trends Neurosci. 2021 Sep 21. pii: S0166-2236(21)00167-3. [Epub ahead of print]

Cancer as a homeostatic challenge: the role of the hypothalamus.

Nikita Francis, Jeremy C Borniger.

  The initiation, progression, and metastatic spread of cancer elicits diverse changes in systemic physiology. In this way, cancer represents a novel homeostatic challenge to the host system. Here, we discuss how the hypothalamus, a critical brain region involved in homeostasis senses, integrates and responds to cancer-induced changes in physiology. Through this lens, cancer-associated changes in behavior (e.g., sleep disruption) and physiology (e.g., glucocorticoid dysregulation) can be viewed as the result of an inability to re-establish homeostasis. We provide examples at each level (receptor sensing, integration of systemic signals, and efferent regulatory pathways) of how homeostatic organization becomes disrupted across different cancers. Finally, we lay out predictions of this hypothesis and highlight outstanding questions that aim to guide further work in this area.

Keywords:  cytokines; feedback loops; hypothalamus; interoception; metabolism; sleep

DOI:  https://doi.org/10.1016/j.tins.2021.08.008
Adv Healthc Mater. 2021 Sep 20. e2100907

Heat-Confined Tumor-Docking Reversible Thermogel Potentiates Systemic Antitumor Immune Response During Near-Infrared Photothermal Ablation in Triple-Negative Breast Cancer.

Vishnu Revuri, Santhosh Kalash Rajendrakumar, Myong-Suk Park, Adityanarayan Mohapatra, Saji Uthaman, Jagannath Mondal, Woo Kyun Bae, In-Kyu Park, Yong-Kyu Lee.

  Triple-negative breast cancer (TNBC) features immunologically "cold" tumor microenvironments with limited cytotoxic T lymphocyte (CTL) infiltration. Although ablation therapies have demonstrated modulation of "cold" TNBC tumors to inflamed "hot" tumors, recruitment of myeloid derived suppressor cells (MDSCs) at the tumors post ablation therapies prevents the infiltration of CTLs and challenge the antitumor potentials of T-cell therapies. Here, a thermal ablation immunotherapy strategy is developed to prevent the immune suppressive effects of MDSCs during photothermal ablation and induce a durable systemic antitumor immunity to eradicate TNBC tumors. An injectable pluronic F127/hyaluronic acid (HA)-based hydrogel embedded with manganese dioxide (BM) nanoparticles and TLR7 agonist resiquimod (R848) (BAGEL-R848), is synthesized to induce in situ laser-assisted gelation of the hydrogel and achieve desired ablation temperatures at a low laser-exposure time. Upon 808-nm laser irradiation, a significant reduction in the tumor burden is observed in BAGEL-R848-injected 4T1 tumor-bearing mice. The ablation induced immunogenic cell death and sustained release of R848 from BAGEL-R848 promotes dendritic cell maturation and reduced MDSCs localization in tumors. In addition, inflammatory M1 macrophages and CD8+IFN+ CTL are enriched in distant tumors in bilateral 4T1 tumor model, preventing metastatic tumor growth and signifying the potential of BAGEL-R848 to treat TNBC.

Keywords:  Resiquimod; breast cancer; myeloid-derived suppressor cells; photothermal immunotherapy

DOI:  https://doi.org/10.1002/adhm.202100907