bims-rehoca 2021-10-17 papers

bims-rehoca

Biomed News

on Redox homeostasis in cancer

Issue of 2021‒10‒17
twenty-five papers selected by
Vittoria Raimondi
Veneto Institute of Oncology

Podophyllotoxin Induces ROS-Mediated Apoptosis and Cell Cycle Arrest in Human Colorectal Cancer Cells via p38 MAPK Signaling.
EF24 exerts cytotoxicity against NSCLC via inducing ROS accumulation.
Endogenous Copper for Nanocatalytic Oxidative Damage and Self-Protection Pathway Breakage of Cancer.
Thymoquinone induces oxidative stress-mediated apoptosis through downregulation of Jak2/STAT3 signaling pathway in human melanoma cells.
RORα Suppresses Cancer-Associated Inflammation by Repressing Respiratory Complex I-Dependent ROS Generation.
Macrophage peroxiredoxin 5 deficiency promotes lung cancer progression via ROS-dependent M2-like polarization.
Quercetin-3-Glucoside Extracted from Apple Pomace Induces Cell Cycle Arrest and Apoptosis by Increasing Intracellular ROS Levels.
Photo-Sonodynamic Combination Activity of Cationic Morpholino-Phthalocyanines Conjugated to Nitrogen and Nitrogen-Sulfur Doped Graphene Quantum Dots against MCF-7 Breast Cancer Cell Line In Vitro.
Emerging Roles of Energy Metabolism in Ferroptosis Regulation of Tumor Cells.
Melatonin increases 5-flurouracil-mediated apoptosis of colorectal cancer cells through enhancing oxidative stress and downregulating survivin and XIAP.
Metformin Affects Olaparib Sensitivity through Induction of Apoptosis in Epithelial Ovarian Cancer Cell Lines.
The E3 Ubiquitin Ligase NEDD4-1 Mediates Temozolomide-Resistant Glioblastoma through PTEN Attenuation and Redox Imbalance in Nrf2-HO-1 Axis.
Antidiabetic DPP-4 Inhibitors Reprogram Tumor Microenvironment That Facilitates Murine Breast Cancer Metastasis Through Interaction With Cancer Cells via a ROS-NF-кB-NLRP3 Axis.
Mitochondrial Ca2+-overloading by oxygen/glutathione depletion-boosted photodynamic therapy based on a CaCO3 nanoplatform for tumor synergistic therapy.
Curcumin and Its New Derivatives: Correlation between Cytotoxicity against Breast Cancer Cell Lines, Degradation of PTP1B Phosphatase and ROS Generation.
Redox Regulation in Cancer Cells during Metastasis.
Assessment of cytotoxic effects of new derivatives of pyrazino[1,2-a] benzimidazole on isolated human glioblastoma cells and mitochondria.
Metabolic reprogramming in epithelial ovarian cancer.
Mitochondrial Breast Cancer Resistant Protein Sustains the Proliferation and Survival of Drug-Resistant Breast Cancer Cells by Regulating Intracellular Reactive Oxygen Species.
Biodegradable mesoporous manganese carbonate nanocomposites for LED light-driven cancer therapy via enhancing photodynamic therapy and attenuating survivin expression.
Incomptine A Induces Apoptosis, ROS Production and a Differential Protein Expression on Non-Hodgkin's Lymphoma Cells.
Effects of imidacloprid on viability and increase of reactive oxygen and nitrogen species in HepG2 cell line.
Utilization of Pharmacological Ascorbate to Enhance Hydrogen Peroxide-Mediated Radiosensitivity in Cancer Therapy.
Ruthenium Half-Sandwich Type Complexes with Bidentate Monosaccharide Ligands Show Antineoplastic Activity in Ovarian Cancer Cell Models through Reactive Oxygen Species Production.
A Versatile Calcium Phosphate Nanogenerator for Tumor Microenvironment-activated Cancer Synergistic Therapy.

Biomol Ther (Seoul). 2021 Oct 13.

Podophyllotoxin Induces ROS-Mediated Apoptosis and Cell Cycle Arrest in Human Colorectal Cancer Cells via p38 MAPK Signaling.

Seung-On Lee, Sang Hoon Joo, Ah-Won Kwak, Mee-Hyun Lee, Ji-Hye Seo, Seung-Sik Cho, Goo Yoon, Jung-Il Chae, Jung-Hyun Shim.

  Podophyllotoxin (PT), a lignan compound from the roots and rhizomes of Podophyllum peltatum, has diverse pharmacological activities including anticancer effect in several types of cancer. The molecular mechanism of the anticancer effects of PT on colorectal cancer cells has not been reported yet. In this study, we sought to evaluate the anticancer effect of PT on human colorectal cancer HCT116 cells and identify the detailed molecular mechanism. PT inhibited the growth of cells and colony formation in a concentration-dependent manner and induced apoptosis as determined by the annexin V/7-aminoactinomycin D double staining assay. PT-induced apoptosis was accompanied by cell cycle arrest in the G2/M phase and an increase in the generation of reactive oxygen species (ROS). The effects of PT on the induction of ROS and apoptosis were prevented by pretreatment with N-acetyl-L-cysteine (NAC), indicating that an increase in ROS generation mediates the apoptosis of HCT116 cells induced by PT. Furthermore, Western blot analysis showed that PT upregulated the level of phospho (p)-p38 mitogen-activated protein kinase (MAPK). The treatment of SB203580, a p38 inhibitor, strongly prevented the apoptosis induced by PT, suggesting that PT-induced apoptosis involved the p38 MAPK signaling pathway. In addition, PT induced the loss of mitochondrial membrane potential and multi-caspase activation. The results suggested that PT induced cell cycle arrest in the G2/M phase and apoptosis through the p38 MAPK signaling pathway by upregulating ROS in HCT116 cells.

Keywords:  Apoptosis; Cell cycle arrest; Colon cancer; Podophyllotoxin; Reactive oxygen species; p38

DOI:  https://doi.org/10.4062/biomolther.2021.143
Cancer Cell Int. 2021 Oct 12. 21(1): 531

EF24 exerts cytotoxicity against NSCLC via inducing ROS accumulation.

Minghui Chang, Ming Shang, Fang Yuan, Wei Guo, Cuijuan Wang.

  BACKGROUND: The role of Diphenyldifluoroketone (EF24), a synthetic analogue of curcumin with noteworthy antitumor potential, remains unclear in non-small cell lung cancer (NSCLC). Herein, the inhibitory effect of EF24 on NSCLC and its mechanism were studied.METHODS: Cytotoxicity was measured by MTT assay, colony formation assay and xenograft model. Cell apoptosis and reactive oxygen species (ROS) level were quantified by flow cytometer. Protein level was detected by western blot assay. Mitochondria and autophagosomes were observed using transmission electron microscope and confocal microscopy.
RESULTS: In-vitro, EF24 significantly induced proliferation inhibition, apoptosis, mitochondrial fission and autophagy of NSCLC cell lines. These cytotoxic effects were significantly attenuated by two reactive oxygen species (ROS) scavengers, indicating its anti-cancer effects largely depend on ROS accumulation. In-vivo, EF24 inhibited tumor growth in a dose-dependent manner. Moreover, no pathological changes of heart, lung, spleen, kidney and liver of mice were observed. Collectively, EF24 induced ROS accumulation, in turn activates cell apoptosis, and then exerts its cytotoxicity on NSCLC cells.
CONCLUSIONS: The results showed that EF24 exerted cytotoxicity against NSCLC via ROS accumulation. Thus, EF24 might serve as a potential anti-cancer agent for the treatment of NSCLC.

Keywords:  EF24; Non-small cell lung cancer; Reactive oxygen species

DOI:  https://doi.org/10.1186/s12935-021-02240-z
ACS Nano. 2021 Oct 15.

Endogenous Copper for Nanocatalytic Oxidative Damage and Self-Protection Pathway Breakage of Cancer.

Yuedong Guo, Yingying Xu, Qunqun Bao, Chao Shen, Dalong Ni, Ping Hu, Jianlin Shi.

  Nanocatalytic medicine is one of the most recent advances in the development of nanomedicine, which catalyzes intratumoral chemical reactions to produce toxins such as reactive oxygen species in situ for cancer specific treatment by using exogenous-delivered catalysts such as Fenton agents. However, the overexpression of reductive glutathione and Cu-Zn superoxide dismutase in cancer cells will significantly counteract the therapeutic efficacy by reactive oxygen species-mediated oxidative damages. Additionally, the direct delivery of iron-based Fenton agents may arouse undesired detrimental effects such as anaphylactic reactions. In this study, instead of exogenously delivering Fenton agents, the endogenous copper ions from intracellular Cu-Zn superoxide dismutase have been employed as the source of Fenton-like agents by chelating the Cu ions from the superoxide dismutase using a common metal ion chelator, N,N,N',N'-tetrakis(2-pyridinylmethyl)-1,2-ethanediamine (TPEN), followed by the TPEN-Cu(II) chelate reduction to TPEN-Cu(I) by reductive glutathione. Briefly, TPEN was loaded in a disulfide bond-containing link poly(acrylic acid) shell-coated hybrid mesoporous silica/organosilicate (MSN@MON) nanocomposite as a reductive glutathione-responsive nanoplatform, which features inter-related triple functions: intratumoral reductive glutathione-responsive link poly(acrylic acid) disruption and TPEN release; the accompanying reductive glutathione consumption and Cu-Zn superoxide dismutase deactivation by TPEN chelating Cu ions from this superoxide dismutase; and the Fenton reaction catalyzed by TPEN-Cu(I) chelate as a Fenton-like agent generated from TPEN-Cu(II) reduction by the remaining reductive glutathione in cancer cells, thereby cutting off the self-protection pathway of cancer cells under severe oxidation stress and ensuring cancer cell apoptosis by reactive oxygen species produced by the catalytic Fenton-like reactions. Such a nanocatalyst demonstrates excellent biosafety and augmented therapeutic efficacy by simultaneous nanocatalytic oxidative damage and intrinsic protection pathway breakage of cancer cells.

Keywords:  GSH response; SOD; TPEN; mesoporous silicon oxide; nanocatalytic medicine

DOI:  https://doi.org/10.1021/acsnano.1c05451
Food Chem Toxicol. 2021 Oct 07. pii: S0278-6915(21)00637-2. [Epub ahead of print]157 112604

Thymoquinone induces oxidative stress-mediated apoptosis through downregulation of Jak2/STAT3 signaling pathway in human melanoma cells.

Pawan Kumar Raut, Hui Seong Lee, Sang Hoon Joo, Kyung-Soo Chun.

  Melanoma is a highly aggressive and treatment-resistant cancer, and the incidence and mortality rates are increasing worldwide. Thymoquinone (TQ) is the active component of Nigella sativa seed extracts and exerts anticancer effects in various cancer cells. However, the anticancer effects of TQ on melanoma and the underlying molecular mechanisms remain elusive. In this study, TQ treatment induced apoptosis in SK-MEL-28 cells. Interestingly, constitutive phosphorylation of Janus kinase 2 (Jak2) and signal transducer and activator of transcription 3 (STAT3) was markedly decreased following TQ treatment. Furthermore, TQ treatment downregulated STAT3-dependent genes including cyclin D1, D2, and D3 and survivin. Moreover, inhibition of Jak2/STAT3 using AG490, an inhibitor of Jak2 or genetic ablation of STAT3, abrogated the expression of target genes. TQ increased the levels of reactive oxygen species (ROS), whereas pretreatment with N-acetyl cysteine (NAC), a ROS scavenger, prevented the suppressive effect of TQ on Jak2/STAT3 activation and protected SK-MEL-28 cells from TQ-induced apoptosis. TQ administration further attenuated the growth of SK-MEL-28 tumor xenografts. Taken together, TQ induced apoptosis of SK-MEL-28 by hindering the Jak2/STAT3 signaling pathway through ROS generation. Our results support further development of TQ as a potential anticancer therapeutic agent for treating melanoma.

Keywords:  Apoptosis; Jak2/STAT3 signaling; Melanoma; Reactive oxygen species; Thymoquinone

DOI:  https://doi.org/10.1016/j.fct.2021.112604
Int J Mol Sci. 2021 Oct 01. pii: 10665. [Epub ahead of print]22(19):

RORα Suppresses Cancer-Associated Inflammation by Repressing Respiratory Complex I-Dependent ROS Generation.

Wei Mao, Gaofeng Xiong, Yuanyuan Wu, Chi Wang, Daret St Clair, Jia-Da Li, Ren Xu.

  Breast cancer development is associated with macrophage infiltration and differentiation in the tumor microenvironment. Our previous study highlights the crucial function of reactive oxygen species (ROS) in enhancing macrophage infiltration during the disruption of mammary tissue polarity. However, the regulation of ROS and ROS-associated macrophage infiltration in breast cancer has not been fully determined. Previous studies identified retinoid orphan nuclear receptor alpha (RORα) as a potential tumor suppressor in human breast cancer. In the present study, we showed that retinoid orphan nuclear receptor alpha (RORα) significantly decreased ROS levels and inhibited ROS-mediated cytokine expression in breast cancer cells. RORα expression in mammary epithelial cells inhibited macrophage infiltration by repressing ROS generation in the co-culture assay. Using gene co-expression and chromatin immunoprecipitation (ChIP) analyses, we identified complex I subunits NDUFS6 and NDUFA11 as RORα targets that mediated its function in suppressing superoxide generation in mitochondria. Notably, the expression of RORα in 4T1 cells significantly inhibited cancer metastasis, reduced macrophage accumulation, and enhanced M1-like macrophage differentiation in tumor tissue. In addition, reduced RORα expression in breast cancer tissue was associated with an increased incidence of cancer metastasis. These results provide additional insights into cancer-associated inflammation, and identify RORα as a potential target to suppress ROS-induced mammary tumor progression.

Keywords:  breast cancer; complex I; macrophage; orphan nuclear receptor; reactive oxygen species; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms221910665
Free Radic Biol Med. 2021 Oct 09. pii: S0891-5849(21)00758-9. [Epub ahead of print]

Macrophage peroxiredoxin 5 deficiency promotes lung cancer progression via ROS-dependent M2-like polarization.

Jung Bae Seong, Bokyung Kim, Soyoon Kim, Mi Hye Kim, Young-Ho Park, Youngjeon Lee, Hong Jun Lee, Chang-Won Hong, Dong-Seok Lee.

  Strategies for cancer treatment have traditionally focused on suppressing cancer cell behavior, but many recent studies have demonstrated that regulating the tumor microenvironment (TME) can also inhibit disease progression. Macrophages are major TME components, and the direction of phenotype polarization is known to regulate tumor behavior, with M2-like polarization promoting progression. It is also known that reactive oxygen species (ROS) in macrophages drive M2 polarization, and M2 polarization promote lung cancer progression. Lung cancer patients with lower expression of the antioxidant enzyme peroxiredoxin 5 (Prx5) demonstrate poorer survival. This study revealed that Prx5 deficiency in macrophages induced M2 macrophage polarization by lung cancer. We report that injection of lung cancer cells produced larger tumors in Prx5-deficit mice than wild-type mice independent of cancer cell Prx5 expression. Through co-culture with lung cancer cell lines, Prx5-deficient macrophages exhibited M2 polarization, and reduced expression levels of the M1-associated inflammatory factors iNOS, TNFα, and Il-1β. Moreover, these Prx5-deficient macrophages promoted the proliferation and migration of co-cultured lung cancer cells. Conversely, suppression of ROS generation by N-acetyl cysteine (NAC) inhibited the M2-like polarization of Prx5-deficient macrophages, increased expression levels of inflammatory factors, inhibited the proliferation and migration of co-cultured lung cancer cells, and suppressed tumor growth in mice. These findings suggest that blocking the M2 polarization of macrophages may promote lung cancer regression.

Keywords:  Lung cancer; Macrophage polarization; Peroxiredoxin 5; ROS; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.10.010
Int J Mol Sci. 2021 Oct 04. pii: 10749. [Epub ahead of print]22(19):

Quercetin-3-Glucoside Extracted from Apple Pomace Induces Cell Cycle Arrest and Apoptosis by Increasing Intracellular ROS Levels.

Arti Nile, Shivraj Hariram Nile, Juhyun Shin, Gyunseok Park, Jae-Wook Oh.

  Cervical cancer is a life-threatening disease and the fourth most common cancer among women worldwide. Apple pomace is a multifunctional phenolic compound possessing effective biological activity against cervical cancer cells. This study aimed to investigate the anticancer effects of quercetin-3-glucoside (Q3G) extracted from apple pomace in HeLa cell lines and analyze its molecular mechanisms. High-performance liquid chromatography revealed that Q3G, coumaric acid, phloridzin, quercetin, and phloretin are the major polyphenolic compounds constituting apple pomace. Among them, Q3G possessed the greatest antioxidant and anti-inflammatory effects in vitro and exhibited significant cytotoxic effects in HeLa cells in a dose-and time-dependent manner. Flow cytometric analysis indicated that Q3G induced cell cycle arrest at the S phase in a time-dependent manner by altering cyclin-dependent kinase 2. Moreover, it induced apoptosis via chromosomal DNA degradation and increased reactive oxygen species generation. Furthermore, Q3G treatment altered the apoptosis-associated protein expression in the cells by activating caspase-9/-3, downregulating anti-apoptosis protein B-cell lymphoma (Bcl)-2 expressions and up regulating the pro-apoptotic Bcl-2-associated X protein. BH3-interacting domain death agonist cleavage occurred prior to the degradation of an anti-apoptotic Mu-2-related death-inducing gene involved in cell death signaling. Consequently, apple pomace Q3G holds promise as an anti-inflammatory and anticancer agent for treating cervical cancer.

Keywords:  ROS generation; anticancer; apoptosis; apple pomace; cell cycle progression; quercetin-3-glucoside

DOI:  https://doi.org/10.3390/ijms221910749
Photodiagnosis Photodyn Ther. 2021 Oct 07. pii: S1572-1000(21)00396-3. [Epub ahead of print] 102573

Photo-Sonodynamic Combination Activity of Cationic Morpholino-Phthalocyanines Conjugated to Nitrogen and Nitrogen-Sulfur Doped Graphene Quantum Dots against MCF-7 Breast Cancer Cell Line In Vitro.

Lindokuhle Cindy Nene, Tebello Nyokong.

  In this work, we explore the reactive oxygen species (ROS) generation abilities of cationic morpholino-substituted-phthalocyanine (Pc) conjugated to nitrogen (NGQDs) and nitrogen-sulfur (NSGQDs) doped-graphene quantum dots upon irradiation with light for photodynamic therapy (PDT), ultrasound for sonodynamic therapy (SDT) and the combination of both in photo-sonodynamic therapy (PSDT). The in vitro cytotoxicity studies were conducted using the Michigan Cancer Foundation-7 breast cancer cell lines (MCF-7 cells). For PDT treatments, only the 1O2 was detected for all the sensitizers, whereas both the 1O2 and •OH radicals were evident after SDT and PSDT treatments. An increase in the 1O2 generation was observed for the conjugates compared to the GQDs and the Pc alone. However, the •OH radicals were reduced in the conjugates compared to the GQDs and the Pc alone. The NGQDs generally showed better ROS generation efficacy compared to the NSGQDs, alone and in the conjugates. The combination therapy also shows improved efficacy compared to the monotherapies for the Pcs and Pc-GQDs conjugates.

Keywords:  Cancer; Graphene quantum dots; Hydroxyl radicals; Photodynamic therapy; Phthalocyanines; Singlet oxygen; Sonodynamic therapy

DOI:  https://doi.org/10.1016/j.pdpdt.2021.102573
Adv Sci (Weinh). 2021 Oct 10. e2100997

Emerging Roles of Energy Metabolism in Ferroptosis Regulation of Tumor Cells.

Xuemei Yao, Wei Li, De Fang, Chuyu Xiao, Xiao Wu, Menghuan Li, Zhong Luo.

  Ferroptosis is a new form of regulated cell death, which is characterized by the iron-dependent accumulation of lethal lipid peroxides and involved in many critical diseases. Recent reports revealed that cellular energy metabolism activities such as glycolysis, pentose phosphate pathway (PPP), and tricarboxylic acid cycle are involved in the regulation of key ferroptosis markers such as reduced nicotinamide adenine dinucleotide phosphate (NADPH), glutathione (GSH), and reactive oxygen species (ROS), therefore imposing potential regulatory roles in ferroptosis. Remarkably, tumor cells can activate adaptive metabolic responses to inhibit ferroptosis for self-preservation such as the upregulation of glycolysis and PPP. Due to the rapid proliferation of tumor cells and the intensified metabolic rate, tumor energy metabolism has become a target for disrupting the redox homeostasis and induce ferroptosis. Based on these emerging insights, regulatory impact of those-tumor specific metabolic aberrations is systematically characterized, such as rewired glucose metabolism and metabolic compensation through glutamine utilization on ferroptosis and analyzed the underlying molecular mechanisms. Additionally, those ferroptosis-based therapeutic strategies are also discussed by exploiting those metabolic vulnerabilities, which may open up new avenues for tumor treatment in a clinical context.

Keywords:  cellular energy metabolism; ferroptosis; glucose; glutamine

DOI:  https://doi.org/10.1002/advs.202100997
Bioimpacts. 2021 ;11(4): 253-261

Melatonin increases 5-flurouracil-mediated apoptosis of colorectal cancer cells through enhancing oxidative stress and downregulating survivin and XIAP.

Ainaz Mihanfar, Bahman Yousefi, Saber Ghazizadeh Darband, Shirin Sadighparvar, Mojtaba Kaviani, Maryam Majidinia.

  Introduction: Colorectal cancer (CRC) is one of the most lethal human malignancies with a global alarming rate of incidence. The development of resistance against common chemotherapeutics such as 5-fluorouracil (5-FU) remains a big burden for CRC therapy. Therefore, we investigated the effects of melatonin on the increasing 5-FU- mediated apoptosis and its underlying mechanism in SW-480 CRC cell line. Methods: The effects of melatonin and 5- FU, alone or in combination, on cell proliferation were evaluated using an MTT assay. Further, Annexin-V Flow cytometry was used for determining the effects of melatonin and 5-FU on the apoptosis of SW-480 cell lines. The expression levels of Bax, Bcl-2, pro-caspase-3/activated caspase 3, X-linked inhibitor of apoptosis proteins (XIAP), and survivin were measured after 48 hours incubation with drugs. Cellular levels of reactive oxygen species (ROS), catalase, superoxide dismutase and glutathione peroxidase were also evaluated. Results: Melatonin and 5-FU significantly decreased the cell proliferation of SW-480 cells. Combination of 5-FU with melatonin significantly decreased the IC50 value of 5-FU from 100 μM to 50 μM. Moreover, combination therapy increased intracellular levels of ROS and suppressed antioxidant enzymatic activities (P < 0.05). Treatment with either melatonin or 5-FU resulted in the induction of apoptosis in comparison to control (P > 0.05). XIAP and survivin expression levels potently decreased after combination treatment with melatonin and 5-FU (P < 0.05). Conclusion: We demonstrated that melatonin exerts a reversing effect on the resistance to apoptosis by targeting oxidative stress, XIAP and survivin in CRC cells. Therefore, more studies need for better understanding of underlying mechanisms for beneficial effects of combination of melatonin and 5-FU.

Keywords:  5-FU; Colorectal cancer; Melatonin; Oxidative stress; Survivin; XIAP

DOI:  https://doi.org/10.34172/bi.2021.36
Int J Mol Sci. 2021 Sep 29. pii: 10557. [Epub ahead of print]22(19):

Metformin Affects Olaparib Sensitivity through Induction of Apoptosis in Epithelial Ovarian Cancer Cell Lines.

Patrycja Gralewska, Arkadiusz Gajek, Agnieszka Marczak, Aneta Rogalska.

  This study examined the effect of combination treatment with the poly (ADP-ribose) polymerase inhibitor olaparib and metformin on homologous recombination (HR)-proficient epithelial ovarian cancer (EOC). Ovarian cancer cell lines (OV-90 and SKOV-3) were treated with olaparib, metformin, or a combination of both. Cell viability was assessed by MTT and colony formation assays. The production of reactive oxygen species (ROS) and changes in mitochondrial membrane potential were examined using the specific fluorescence probes, DCFH2-DA (2',7'-dichloro-dihydrofluorescein diacetate) and JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolcarbocyanine). Apoptotic and necrotic changes were measured by double staining with Hoechst 33258 and propidium iodide, orange acridine and ethidium bromide staining, phosphatidylserine externalization, TUNEL assay, caspase 3/7 activity, and cytochrome c and p53 expression. Compared with single-drug treatment, the combination of olaparib and metformin significantly inhibited cell proliferation and colony formation in HR-proficient ovarian cancer cells. ROS production preceded a decrease in mitochondrial membrane potential. The changes in ROS levels suggested their involvement in inducing apoptosis in response to combination treatment. The present results indicate a shift towards synergism in cells with mutant or null p53, treated with olaparib combined with metformin, providing a new approach to the treatment of gynecologic cancers. Taken together, the results support the use of metformin to sensitize EOC to olaparib therapy.

Keywords:  PARP inhibitor; combination therapy; metformin; olaparib; ovarian cancer; replication stress

DOI:  https://doi.org/10.3390/ijms221910557
Int J Mol Sci. 2021 Sep 23. pii: 10247. [Epub ahead of print]22(19):

The E3 Ubiquitin Ligase NEDD4-1 Mediates Temozolomide-Resistant Glioblastoma through PTEN Attenuation and Redox Imbalance in Nrf2-HO-1 Axis.

Hao-Yu Chuang, Li-Yun Hsu, Chih-Ming Pan, Narpati Wesa Pikatan, Vijesh Kumar Yadav, Iat-Hang Fong, Chao-Hsuan Chen, Chi-Tai Yeh, Shao-Chih Chiu.

  BACKGROUND: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. It is highly resistant to chemotherapy, and tumor recurrence is common. Neuronal precursor cell-expressed developmentally downregulated 4-1 (NEDD4-1) is an E3 ligase that controls embryonic development and animal growth. NEDD4-1 regulates the tumor suppressor phosphatase and tensin homolog (PTEN), one of the major regulators of the PI3K/AKT/mTOR signaling axis, as well as the response to oxidative stress.METHODS: The expression levels of NEDD4-1 in GBM tissues and different cell lines were determined by quantitative real-time polymerase chain reaction and immunohistochemistry. In vitro and in vivo assays were performed to explore the biological effects of NEDD4-1 on GBM cells. Temozolomide (TMZ)-resistant U87MG and U251 cell lines were specifically established to determine NEDD4-1 upregulation and its effects on the tumorigenicity of GBM cells. Subsequently, miRNA expression in TMZ-resistant cell lines was investigated to determine the dysregulated miRNA underlying the overexpression of NEDD4-1. Indole-3-carbinol (I3C) was used to inhibit NEDD4-1 activity, and its effect on chemoresistance to TMZ was verified.
RESULTS: NEDD4-1 was significantly overexpressed in the GBM and TMZ-resistant cells and clinical samples. NEDD4-1 was demonstrated to be a key oncoprotein associated with TMZ resistance, inducing oncogenicity and tumorigenesis of TMZ-resistant GBM cells compared with TMZ-responsive cells. Mechanistically, TMZ-resistant cells exhibited dysregulated expression of miR-3129-5p and miR-199b-3p, resulting in the induced NEDD4-1 mRNA-expression level. The upregulation of NEDD4-1 attenuated PTEN expression and promoted the AKT/NRF2/HO-1 oxidative stress signaling axis, which in turn conferred amplified defense against reactive oxygen species (ROS) and eventually higher resistance against TMZ treatment. The combination treatment of I3C, a known inhibitor of NEDD4-1, with TMZ resulted in a synergistic effect and re-sensitized TMZ-resistant tumor cells both in vitro and in vivo.
CONCLUSIONS: These findings demonstrate the critical role of NEDD4-1 in regulating the redox imbalance in TMZ-resistant GBM cells via the degradation of PTEN and the upregulation of the AKT/NRF2/HO-1 signaling pathway. Targeting this regulatory axis may help eliminate TMZ-resistant glioblastoma.

Keywords:  NEDD4-1; TMZ resistance; glioblastoma; indole-3-carbinol; ubiquitin ligase

DOI:  https://doi.org/10.3390/ijms221910247
Front Oncol. 2021 ;11 728047

Antidiabetic DPP-4 Inhibitors Reprogram Tumor Microenvironment That Facilitates Murine Breast Cancer Metastasis Through Interaction With Cancer Cells via a ROS-NF-кB-NLRP3 Axis.

Rui Li, Xin Zeng, Meihua Yang, Jinmei Feng, Xiaohui Xu, Liming Bao, Tingbo Ye, Xin Wang, Bingqian Xue, Yi Huang.

  Improvement of understanding of the safety profile and biological significance of antidiabetic agents in breast cancer (BC) progression may shed new light on minimizing the unexpected side effect of antidiabetic reagents in diabetic patients with BC. Our recent finding showed that Saxagliptin (Sax) and Sitagliptin (Sit), two common antidiabetic dipeptidyl peptidase-4 inhibitors (DPP-4i) compounds, promoted murine BC 4T1 metastasis via a ROS-NRF2-HO-1 axis in nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice. However, the potential role of DPP-4i in BC progression under immune-competent status remains largely unknown. Herein, we extended our investigation and revealed that Sax and Sit also accelerated murine BC 4T1 metastasis in orthotopic, syngeneic, and immune-competent BALB/c mice. Mechanically, we found that DPP-4i not only activated ROS-NRF2-HO-1 axis but also triggered reactive oxygen species (ROS)-dependent nuclear factor kappa B (NF-κB) activation and its downstream metastasis-associated gene levels in vitro and in vivo, while NF-кB inhibition significantly abrogated DPP-4i-driven BC metastasis in vitro. Meanwhile, inhibition of NRF2-HO-1 activation attenuated DPP-4i-driven NF-кB activation, while NRF2 activator ALA enhanced NF-кB activation, indicating an essential role of ROS-NRF2-HO-1 axis in DPP-4i-driven NF-кB activation. Furthermore, we also found that DPP-4i increased tumor-infiltrating CD45, MPO, F4/80, CD4, and Foxp3-positive cells and myeloid-derived suppressor cells (MDSCs), and decreased CD8-positive lymphocytes in metastatic sites, but did not significantly alter cell viability, apoptosis, differentiation, and suppressive activation of 4T1-induced splenic MDSCs. Moreover, we revealed that DPP-4i triggered ROS-NF-κB-dependent NLRP3 inflammasome activation in BC cells, leading to increase in inflammation cytokines such as interleukin (IL)-6, tumor necrosis factor alpha (TNF-α), vascular endothelial growth factor (VEGF), intercellular cell adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), IL-1β and IL-33, and MDSCs inductors granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, and M-CSF, which play a crucial role in the remodeling of tumor immune-suppressive microenvironment. Thus, our findings suggest that antidiabetic DPP-4i reprograms tumor microenvironment that facilitates murine BC metastasis by interaction with BC cells via a ROS-NRF2-HO-1-NF-κB-NLRP3 axis. This finding not only provides a mechanistic insight into the oncogenic ROS-NRF2-HO-1 in DPP-4i-driven BC progression but also offers novel insights relevant for the improvement of tumor microenvironment to alleviate DPP-4i-induced BC metastasis.

Keywords:  DPP-4 inhibitors; NF-кB; NLRP3 inflammasome; breast cancer; metastasis; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2021.728047
Acta Biomater. 2021 Oct 12. pii: S1742-7061(21)00683-8. [Epub ahead of print]

Mitochondrial Ca2+-overloading by oxygen/glutathione depletion-boosted photodynamic therapy based on a CaCO3 nanoplatform for tumor synergistic therapy.

Jiawei Zhu, Aihong Jiao, Qinzhe Li, Xinyi Lv, Xiaorui Wang, Xuejiao Song, Buhong Li, Yewei Zhang, Xiaochen Dong.

  The Ca2+ buffering capacity of mitochondria maintains the balance of cell physiological activities. The exogenous reactive oxygen species (ROS) can be used to break the balance, resulting in mitochondrial dysfunction and irreversible cell apoptosis. Herein, the CaCO3-based tumor microenvironment (TME) responsive nanoplatform (CaNPCAT+BSO@Ce6-PEG) was designed for oxygen/GSH depletion-boosted photodynamic therapy (PDT) and mitochondrial Ca2+-overloading synergistic therapy. In acidic TME, CaCO3 decomposed and released the cargos (catalase (CAT), buthionine sulfoximine (BSO), chlorin e6 (Ce6), and Ca2+). The tumor hypoxia and reductive microenvironment could be significantly reversed by CAT and BSO, which greatly enhanced the PDT efficacy. The generated 1O2 during PDT process not only directly killed cancer cells but also destroyed the Ca2+ buffering capacity, leading to the mitochondrial Ca2+-overloading. The increased Ca2+ concentration promoted the process of oxidative phosphorylation and inhibited the production of adenosine triphosphate (ATP), resulting in the acceleration of cell death. Under the joint action of enhanced PDT and mitochondrial Ca2+-overloading, the CaNPCAT+BSO@Ce6-PEG NPs showed remarkable synergistic effects in tumor inhibition without any side effects. STATEMENT OF SIGNIFICANCE: In the manuscript, a CaCO3-based nano-platform for tumor microenvironment response was designed. With the decomposition of CaNPCAT+BSO@Ce6-PEG NPs in the acidic tumor microenvironment, the released catalase (CAT) and buthionine sulfoximine (BSO) could relieve the tumor hypoxia and inhibit GSH production. Under 660 nm laser irradiation, the photodynamic effect was enhanced and caused apoptosis. Meanwhile, the Ca2+ buffering capacity was destroyed which led to the mitochondrial Ca2+-overloading. The synergistic effect of enhanced PDT and mitochondrial Ca2+-overloading made the CaNPCAT+BSO@Ce6-PEG NPs present remarkable antitumor performance.

Keywords:  Ca(2+)-buffering capacity; Ca(2+)-overloading; Mitochondrial dysfunction; Oxygen/GSH depletion; Photodynamic therapy

DOI:  https://doi.org/10.1016/j.actbio.2021.10.016
Int J Mol Sci. 2021 Sep 26. pii: 10368. [Epub ahead of print]22(19):

Curcumin and Its New Derivatives: Correlation between Cytotoxicity against Breast Cancer Cell Lines, Degradation of PTP1B Phosphatase and ROS Generation.

Tomasz Kostrzewa, Karol Wołosewicz, Marek Jamrozik, Joanna Drzeżdżon, Julia Siemińska, Dagmara Jacewicz, Magdalena Górska-Ponikowska, Marcin Kołaczkowski, Ryszard Łaźny, Alicja Kuban-Jankowska.

  Breast cancer is the most common cancer of women-it affects more than 2 million women worldwide. PTP1B phosphatase can be one of the possible targets for new drugs in breast cancer therapy. In this paper, we present new curcumin derivatives featuring a 4-piperidone ring as PTP1B inhibitors and ROS inducers. We performed cytotoxicity analysis for twelve curcumin derivatives against breast cancer MCF-7 and MDA-MB-231 cell lines and the human keratinocyte HaCaT cell line. Furthermore, because curcumin is a known antioxidant, we assessed antioxidant effects in its derivatives. For the most potent cytotoxic compounds, we determined intracellular ROS and PTP1B phosphatase levels. Moreover, for curcumin and its derivatives, we performed real-time microscopy to observe the photosensitizing effect. Finally, computational analysis was performed for the curcumin derivatives with an inhibitory effect against PTP1B phosphatase to assess the potential binding mode of new inhibitors within the allosteric site of the enzyme. We observed that two tested compounds are better anticancer agents than curcumin. Moreover, we suggest that blocking the -OH group in phenolic compounds causes an increase in the cytotoxicity effect, even at a low concentration. Furthermore, due to this modification, a higher level of ROS is induced, which correlates with a lower level of PTP1B.

Keywords:  PTP1B phosphatase; ROS generation; breast cancer; curcumin derivatives

DOI:  https://doi.org/10.3390/ijms221910368
Cancer Discov. 2021 Oct 14.

Redox Regulation in Cancer Cells during Metastasis.

Alpaslan Tasdogan, Jessalyn M Ubellacker, Sean J Morrison.

Metastasis is an inefficient process in which the vast majority of cancer cells are fated to die, partly because they experience oxidative stress. Metastasizing cancer cells migrate through diverse environments that differ dramatically from their tumor of origin, leading to redox imbalances. The rare metastasizing cells that survive undergo reversible metabolic changes that confer oxidative stress resistance. We review the changes in redox regulation that cancer cells undergo during metastasis. By better understanding these mechanisms, it may be possible to develop pro-oxidant therapies that block disease progression by exacerbating oxidative stress in cancer cells. SIGNIFICANCE: Oxidative stress often limits cancer cell survival during metastasis, raising the possibility of inhibiting cancer progression with pro-oxidant therapies. This is the opposite strategy of treating patients with antioxidants, an approach that worsened outcomes in large clinical trials.

DOI: https://doi.org/10.1158/2159-8290.CD-21-0558
Life Sci. 2021 Oct 06. pii: S0024-3205(21)01009-2. [Epub ahead of print]286 120022

Assessment of cytotoxic effects of new derivatives of pyrazino[1,2-a] benzimidazole on isolated human glioblastoma cells and mitochondria.

Mahban Rahimifard, Hamed Haghi-Aminjan, Mahmoudreza Hadjighassem, Razieh Pourahmad Jaktaji, Zeinab Bagheri, Mahsa Azami Movahed, Afshin Zarghi, Jalal Pourahmad.

  AIMS: Glioblastoma multiforme (GBM) is a highly devastating malignant brain tumor with poor pharmacotherapy. Based on COX-2 inhibitory effects in preventing cancer progression, new pyrazino[1,2-a]benzimidazole derivatives were assessed on isolated human GBM cells.MAIN METHODS: In this study, firstly, primary culture of astrocytes from human GBM samples was prepared and exposed to 2,6-dimethyl pyrazino[1,2-a]benzimidazole (L1) and 3,4,5-trimethoxy pyrazino[1,2-a]benzimidazole (L2) for finding their half-maximal inhibitory concentration (IC50). In the following, in two phases, cell apoptosis pathway and mitochondrial markers were investigated on GBM and also HEK293 cells (as non-cancerous normal cells).
KEY FINDINGS: The MTT results represented a remarkable selective cytotoxic effect of both L1 and L2 on GBM cells, and interestingly not on normal cells. After 48 h, IC50 of L1 and L2 were calculated as 13 μM and 85 μM, respectively. Annexin/PI staining showed that L1 and L2 induce apoptosis in GBM cells, and caspase measurement showed that apoptosis occurs through mitochondrial signaling. In the clonogenic assay, GBM cells formed more paraclones and fewer holoclones after treating with L1 and L2. L1 and L2 also selectively enhanced mitochondrial damaged markers, including reactive oxygen species (ROS) formation, and mitochondrial swelling, decreased mitochondrial membrane potential (MMP) and cytochrome c release in isolated cancerous GBM mitochondria.
SIGNIFICANCE: Our findings on human primary astrocyte cells illustrated that L1 and L2 compounds, with COX-2 inhibitory effect, through the intrinsic pathway of apoptosis concerning mitochondrial damage enhancement have therapeutic potentials on GBM.

Keywords:  Apoptosis; COX-2 inhibitor; Clonogenic potential; Glioblastoma multiforme; Mitochondria; Pyrazino[1,2-a]benzimidazole derivative

DOI:  https://doi.org/10.1016/j.lfs.2021.120022
Am J Transl Res. 2021 ;13(9): 9950-9973

Metabolic reprogramming in epithelial ovarian cancer.

Chalaithorn Nantasupha, Chanisa Thonusin, Kittipat Charoenkwan, Siriporn Chattipakorn, Nipon Chattipakorn.

Cancer cells usually show adaptations to their metabolism that facilitate their growth, invasiveness, and metastasis. Therefore, reprogramming the energy metabolism is one of the current key foci of cancer research and treatment. Although aerobic glycolysis-the Warburg effect-has been thought to be the dominant energy metabolism in cancer, recent data indicate a different possibility, specifically that oxidative phosphorylation (OXPHOS) is the more likely form of energy metabolism in some cancer cells. Due to the heterogeneity of epithelial ovarian cancer, there are different metabolic preferences among cell types, study types (in vivo/in vitro), and invasiveness. Current knowledge acknowledges glycolysis to be the main energy provider in ovarian cancer growth, invasion, migration, and viability, so specific agents targeting the glycolysis or OXPHOS pathways have been used in previous studies to attenuate tumor progression and increase chemosensitization. However, chemoresistant cell lines exert various metabolic preferences. This review comprehensively summarizes the information from existing reports which could together provide an in-depth understanding and insights for the development of a novel targeted therapy which can be used as an adjunctive treatment to standard chemotherapy to decelerate tumor progression and decrease the epithelial ovarian cancer mortality rate.

Keywords: Chemoresistance; chemosensitivity; epithelial ovarian cancer; glycolysis; oxidative phosphorylation
Front Cell Dev Biol. 2021 ;9 719209

Mitochondrial Breast Cancer Resistant Protein Sustains the Proliferation and Survival of Drug-Resistant Breast Cancer Cells by Regulating Intracellular Reactive Oxygen Species.

He Zhang, Xingxing Han, Zhaosong Wang, Zhiyong Wang, Yanfen Cui, Ran Tian, Yuying Zhu, Baoai Han, Hui Liu, Xiaoyan Zuo, Sixin Ren, Jianfei Tian, Ruifang Niu, Fei Zhang.

  ATP-binding cassette (ABC) transporter family are major contributors to the drug resistance establishment of breast cancer cells. Breast cancer resistant protein (BCRP), one of the ABC transporters, has long been recognized as a pump that effluxes the therapeutic drugs against the concentration gradient. However, recent studies suggest that the biological function of BCRP is not limited in its drug pump activity. Herein, the role of BCRP in the proliferation and survival of drug-resistant breast cancer cells was investigated. We found that BCRP is not the major drug pump to efflux epirubicin in the resistant cells that express multiple ABC transporters. Silencing of BCRP significantly impairs cell proliferation and induces apoptosis of the resistant cells in vitro and in vivo. RNA-sequencing and high-throughput proteomics suggest that BCRP is an inhibitory factor of oxidative phosphorylation (OXPHOS). Further research suggests that BCRP is localized in the mitochondria of the resistant cells. Knockdown of BCRP elevated the intracellular reactive oxygen species level and eventually promotes the cell to undergo apoptosis. This study demonstrated that BCRP exerts important onco-promoting functions in the drug-resistant breast cancer cells independent of its well-recognized drug efflux activity, which shed new light on understanding the complex functional role of ABC transporters in drug-resistant cells.

Keywords:  breast cancer resistant protein; drug-resistant breast cancer; proliferation; reactive oxygen species; survival

DOI:  https://doi.org/10.3389/fcell.2021.719209
J Nanobiotechnology. 2021 Oct 09. 19(1): 310

Biodegradable mesoporous manganese carbonate nanocomposites for LED light-driven cancer therapy via enhancing photodynamic therapy and attenuating survivin expression.

Lihua Li, Lingling Chen, Ling Huang, Xiangling Ye, Zefeng Lin, Xiaoming Wei, Xianfeng Yang, Zhongmin Yang.

  Triple-negative breast cancer (TNBC) is one of the most daunting diseases, low toxicity and efficient approaches are in urgent demand. Herein, we developed degradable mesoporous manganese carbonate nanocubes (MnCO3 NCs), incorporated with survivin shRNA-expressing plasmid DNA (iSur-pDNA) and riboflavin (Rf), namely MRp NCs, for synergistic TNBC therapy. The MnCO3, itself, could generate O2 and CO2 under H2O2 and thus relieve the hypoxia and acidic tumor microenvironment (TME). Furthermore, the MnCO3 NCs exhibited high Rf loading capacity and iSur-pDNA delivery ability after polyethyleneimine modification. Specifically, MRp NCs decompose in TME, meanwhile they deprived the endogenous expression of survivin gene and significantly amplified the generation of reactive oxygen species after exposure to LED light, resulting in serious tumor destruction. The multifunctional MRp NCs with LED light-driven characters are able to provide a high efficiency, low toxicity and promising strategy for TNBC therapy.

Keywords:  LED light responsive; Mesoporous MnCO3 nanocubes; O2 and CO2 release; Reactive oxygen species; Triple negative breast cancer

DOI:  https://doi.org/10.1186/s12951-021-01057-2
Int J Mol Sci. 2021 Sep 29. pii: 10516. [Epub ahead of print]22(19):

Incomptine A Induces Apoptosis, ROS Production and a Differential Protein Expression on Non-Hodgkin's Lymphoma Cells.

Emmanuel Pina-Jiménez, Fernando Calzada, Elihú Bautista, Rosa María Ordoñez-Razo, Claudia Velázquez, Elizabeth Barbosa, Normand García-Hernández.

  Sesquiterpene lactones are of pharmaceutical interest due their cytotoxic and antitumor properties, which are commonly found within plants of several genera from the Asteraceae family such as the Decachaeta genus. From Decachaeta incompta four heliangolide, namely incomptines A-D have been isolated. In this study, cytotoxic properties of incomptine A (IA) were evaluated on four lymphoma cancer cell lines: U-937, Farage, SU-DHL-2, and REC-1. The type of cell death induced by IA and its effects on U-937 cells were analyzed based on its capability to induce apoptosis and produce reactive oxygen species (ROS) through flow cytometry with 4',6-diamidino-2-phenylindole staining, dual annexin V/DAPI staining, and dichlorofluorescein 2',7'-diacetate, respectively. A differential protein expression analysis study was carried out by isobaric tags for relative and absolute quantitation (iTRAQ) through UPLC-MS/MS. Results reveal that IA exhibited cytotoxic activity against the cell line U-937 (CC50 of 0.12 ± 0.02 μM) and the incubation of these cells in presence of IA significantly increased apoptotic population and intracellular ROS levels. In the proteomic approach 1548 proteins were differentially expressed, out of which 587 exhibited a fold-change ≥ 1.5 and 961 a fold-change ≤ 0.67. Most of these differentially regulated proteins are involved in apoptosis, oxidative stress, glycolytic metabolism, or cytoskeleton structuration.

Keywords:  Decachaeta incompta; ROS production; apoptosis; cytotoxic activity; iTRAQ; incomptine A; sesquiterpene lactone

DOI:  https://doi.org/10.3390/ijms221910516
Toxicol Mech Methods. 2021 Oct 12. 1-33

Effects of imidacloprid on viability and increase of reactive oxygen and nitrogen species in HepG2 cell line.

Anilda Rufino de Jesus Santos Guimarães, Paulo Francisco Veiga Bizerra, Camila Araújo Miranda, Fábio Erminio Mingatto.

  Imidacloprid (IMD) is a neonicotinoid insecticide used in large quantities worldwide in both veterinary and agronomic applications. Several studies have shown adverse effects of IMD on non-target organisms, with the liver being identified as the main affected organ. This study aimed to evaluate the effects of IMD on human hepatoblastoma (HepG2) cells. HepG2 were exposed to IMD (0.25-2.0 mM) for 24 and 48 hours. IMD treatment resulted in cytotoxicity in the HepG2, inhibiting cell proliferation in a dose- and time-dependent manner, starting at concentrations of 0.5 mM (24 hours) and 0.25 mM (48 hours), and reducing cell viability from 0.5 mM onwards (24 and 48 hours). IMD significantly decreased the mitochondrial membrane potential at both time points investigated (2.0 mM), and also induced damage to the cell membrane, demonstrated by significant dose and time-dependent increases in lactate dehydrogenase (LDH) release from concentrations of 1.0 mM (24 hours) and 0.5 mM (48 hours) upwards. IMD treatment also increased the production of reactive oxygen and nitrogen species (ROS/RNS) at rates above 50% following 0.5 mM (24 hours) or 0.25 mM (48 hours) concentrations, and caused a significant decrease in reduced/oxidized glutathione ratio (GSH/GSSG), indicating oxidative stress. Furthermore, the antioxidant dithiothreitol, which reacts with ROS/RNS and acts as a thiol reducing agent, inhibited the cytotoxic effect of IMD. In addition, the metabolite IMD-olefin was more toxic than IMD. Our results indicate that IMD induces cytotoxicity in HepG2 cells and that this effect may be associated with an increase in the generation of ROS/RNS.

Keywords:  cell death; cytotoxicity; insecticide; liver; oxidative stress

DOI:  https://doi.org/10.1080/15376516.2021.1992553
Int J Mol Sci. 2021 Oct 08. pii: 10880. [Epub ahead of print]22(19):

Utilization of Pharmacological Ascorbate to Enhance Hydrogen Peroxide-Mediated Radiosensitivity in Cancer Therapy.

Zain Mehdi, Michael S Petronek, Jeffrey M Stolwijk, Kranti A Mapuskar, Amanda L Kalen, Garry R Buettner, Joseph J Cullen, Douglas R Spitz, John M Buatti, Bryan G Allen.

  Interest in the use of pharmacological ascorbate as a treatment for cancer has increased considerably since it was introduced by Cameron and Pauling in the 1970s. Recently, pharmacological ascorbate has been used in preclinical and early-phase clinical trials as a selective radiation sensitizer in cancer. The results of these studies are promising. This review summarizes data on pharmacological ascorbate (1) as a safe and efficacious adjuvant to cancer therapy; (2) as a selective radiosensitizer of cancer via a mechanism involving hydrogen peroxide; and (3) as a radioprotector in normal tissues. Additionally, we present new data demonstrating the ability of pharmacological ascorbate to enhance radiation-induced DNA damage in glioblastoma cells, facilitating cancer cell death. We propose that pharmacological ascorbate may be a general radiosensitizer in cancer therapy and simultaneously a radioprotector of normal tissue.

Keywords:  hydrogen peroxide; pharmacological ascorbate; radiation therapy; radiosensitization; reactive oxygen species

DOI:  https://doi.org/10.3390/ijms221910880
Int J Mol Sci. 2021 Sep 28. pii: 10454. [Epub ahead of print]22(19):

Ruthenium Half-Sandwich Type Complexes with Bidentate Monosaccharide Ligands Show Antineoplastic Activity in Ovarian Cancer Cell Models through Reactive Oxygen Species Production.

István Kacsir, Adrienn Sipos, Gyula Ujlaki, Péter Buglyó, László Somsák, Péter Bai, Éva Bokor.

  Ruthenium complexes are developed as substitutes for platinum complexes to be used in the chemotherapy of hematological and gynecological malignancies, such as ovarian cancer. We synthesized and screened 14 ruthenium half-sandwich complexes with bidentate monosaccharide ligands in ovarian cancer cell models. Four complexes were cytostatic, but not cytotoxic on A2780 and ID8 cells. The IC50 values were in the low micromolar range (the best being 0.87 µM) and were similar to or lower than those of the clinically available platinum complexes. The active complexes were cytostatic in cell models of glioblastoma, breast cancer, and pancreatic adenocarcinoma, while they were not cytostatic on non-transformed human skin fibroblasts. The bioactive ruthenium complexes showed cooperative binding to yet unidentified cellular target(s), and their activity was dependent on reactive oxygen species production. Large hydrophobic protective groups on the hydroxyl groups of the sugar moiety were needed for biological activity. The cytostatic activity of the ruthenium complexes was dependent on reactive species production. Rucaparib, a PARP inhibitor, potentiated the effects of ruthenium complexes.

Keywords:  cooperative binding; glycosyl heterocycle; half-sandwich; ovarian cancer; oxadiazole; reactive oxygen species production; rucaparib; ruthenium complex; triazole

DOI:  https://doi.org/10.3390/ijms221910454
Adv Healthc Mater. 2021 Oct 10. e2101563

A Versatile Calcium Phosphate Nanogenerator for Tumor Microenvironment-activated Cancer Synergistic Therapy.

Lian-Hua Fu, Chunying Li, Weimin Yin, Yan-Ru Hu, Tuanwei Sun, Yilin Wan, Jing Lin, Zhiming Li, Peng Huang.

  Gas therapy is an emerging "green" cancer treatment strategy; however, its outcome often restricted by the complexity, diversity, and heterogeneity of tumor. Herein, a tumor targeting and tumor microenvironment-activated calcium phosphate nanotheranostic system (denoted as GCAH) is constructed for effective synergistic cancer starvation/gas therapy. GCAH is obtained by a facile biomineralization strategy using glucose oxidase (GOx) as a biotemplate, followed by loading of l-Arginine (L-Arg) and modification of hyaluronic acid (HA) to allow special selectivity for glycoprotien CD44 overexpressed cancer cells. This nanotheranostic system not only exhausts the glucose nutrients in tumor region by the GOx-triggered glucose oxidation, the generated H2 O2 can oxidize L-Arg into NO under acidic tumor microenvironment for enhanced gas therapy. As such, there are significant enhancement effects of starvation therapy and gas therapy through the cascade reactions of GOx and L-Arg, which yields a remarkable synergistic therapeutic effect for 4T1 tumor-bearing mice without discernible toxic side effects.

Keywords:  calcium phosphate; cancer; glucose oxidase; stimuli-responsive; synergistic therapy

DOI:  https://doi.org/10.1002/adhm.202101563