bims-rehoca 2021-10-10 papers

bims-rehoca

Biomed News

on Redox homeostasis in cancer

Issue of 2021–10–10
twelve papers selected by
Vittoria Raimondi, Veneto Institute of Oncology

Disulfiram Chelated with Copper Promotes Apoptosis in Osteosarcoma via ROS/Mitochondria Pathway.
Pharmacological inhibition of serine synthesis enhances temozolomide efficacy by decreasing O6-methylguanine DNA methyltransferase (MGMT) expression and reactive oxygen species (ROS)-mediated DNA damage in glioblastoma.
A camptothecin prodrug induces mitochondria-mediated apoptosis in cancer cells with cascade activations.
Astaxanthin induces NADPH oxidase activation and receptor‑interacting protein kinase 1‑mediated necroptosis in gastric cancer AGS cells.
Reactive oxygen species as a double-edged sword: The role of oxidative enzymes in antitumor therapy.
Enhancing of Nanocatalyst-Driven Chemodynaminc Therapy for Endometrial Cancer Cells Through Inhibition of PINK1/Parkin-Mediated Mitophagy.
Emerging role of ferroptosis in breast cancer: New dawn for overcoming tumor progression.
Mitochondrial stress adaptation promotes resistance to aromatase inhibitor in human breast cancer cells via ROS/calcium up-regulated amphiregulin-estrogen receptor loop signaling.
Hyperglycemia-induced human hepatocellular carcinoma (HepG2) cell proliferation through ROS-mediated P38 activation is effectively inhibited by a xanthophyll carotenoid, lutein.
Effect of TRPM2-Mediated Calcium Signaling on Cell Proliferation and Apoptosis in Esophageal Squamous Cell Carcinoma.
Increased glucosylceramide production leads to decreased cell energy metabolism and lowered tumor marker expression in non-cancerous liver cells.
The Uniqueness of Clear Cell Renal Cell Carcinoma: Summary of the Process and Abnormality of Glucose Metabolism and Lipid Metabolism in ccRCC.

Biol Pharm Bull. 2021 ;44(10): 1557-1564

Disulfiram Chelated with Copper Promotes Apoptosis in Osteosarcoma via ROS/Mitochondria Pathway.

Yelong Ren, Yutian Lin, Jinghao Chen, Yonglong Jin.

  Disulfiram (DSF) chelated with copper has been confirmed to have a strong anti-tumor ability. In this study, we determined that DSF-Cu induced mitochondria-dependent apoptosis in osteosarcoma (OS), reflecting in DSF-Cu induces mitochondrial membrane potential decline, the production of reactive oxygen species (ROS), and inhibiting cells migration and invasion along with decreasing the concentration of intracellular glutathione (GSH) and facilitating the opening of mitochondrial permeability transition pore (PT) in osteosarcoma cells. These anti-tumor activities can be reversed by Cyclosporine A (CsA, PT inhibitors) and N-acetyl-L-cysteine (NAC, antioxidants). Our results suggested that DSF-Cu exerts its anti-tumor effects in OS via regulation of the ROS/Mitochondria pathway. Our findings provide the basis for DSF-Cu to treat osteosarcoma, even might develop as a potential therapy for other tumors.

Keywords:  disulfiram–Cu complex; mitochondrial membrane potential; reactive oxygen species

DOI:  https://doi.org/10.1248/bpb.b21-00466
Lab Invest. 2021 Oct 08.

Pharmacological inhibition of serine synthesis enhances temozolomide efficacy by decreasing O6-methylguanine DNA methyltransferase (MGMT) expression and reactive oxygen species (ROS)-mediated DNA damage in glioblastoma.

Lei Jin, Karrie Mei-Yee Kiang, Stephen Yin Cheng, Gilberto Ka-Kit Leung.

Glioblastoma (GBM) is the most malignant primary tumor in the central nervous system of adults. Temozolomide (TMZ), an alkylating agent, is the first-line chemotherapeutic agent for GBM patients. However, its efficacy is often limited by innate or acquired chemoresistance. Cancer cells can rewire their metabolic programming to support rapid growth and sustain cell survival against chemotherapies. An example is the de novo serine synthesis pathway (SSP), one of the main branches from glycolysis that is highly activated in multiple cancers in promoting cancer progression and inducing chemotherapy resistance. However, the roles of SSP in TMZ therapy for GBM patients remain unexplored. In this study, we employed NCT503, a highly selective inhibitor of phosphoglycerate dehydrogenase (PHGDH, the first rate-limiting enzyme of SSP), to study whether inhibition of SSP may enhance TMZ efficacy in MGMT-positive GBMs. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), flowcytometry and colony formation assays demonstrated that NCT503 worked synergistically with TMZ in suppressing GBM cell growth and inducing apoptosis in T98G and U118 cells in vitro. U118 and patient-derived GBM subcutaneous xenograft models showed that combined NCT503 and TMZ treatment inhibited GBM growth and promoted apoptosis more significantly than would each treatment alone in vivo. Mechanistically, we found that NCT503 treatment decreased MGMT expression possibly by modulating the Wnt/β-catenin pathway. Moreover, intracellular levels of reactive oxygen species were elevated especially when NCT503 and TMZ treatments were combined, and the synergistic effects could be partially negated by NAC, a classic scavenger of reactive oxygen species. Taken together, these results suggest that NCT503 may be a promising agent for augmenting TMZ efficacy in the treatment of GBM, especially in TMZ-resistant GBMs with high expression of MGMT.

DOI: https://doi.org/10.1038/s41374-021-00666-7
Chem Commun (Camb). 2021 Oct 05.

A camptothecin prodrug induces mitochondria-mediated apoptosis in cancer cells with cascade activations.

Xiangjie Luo, Xiaoqin Chi, Yaying Lin, Zhaoxuan Yang, Hongyu Lin, Jinhao Gao.

Mitochondria are crucial regulators of the intrinsic pathway of apoptosis. Herein, we report a photosensitizer-conjugated camptothecin (CPT)-based prodrug for combinative chemo-photodynamic treatment of solid tumors with cascade activations. Upon light irradiation, our prodrug can effectively target the mitochondria of cancer cells, generate singlet oxygen to increase the level of reactive oxygen species (ROS) and trigger ROS-responsive release of CPT, which synergistically induce mitochondrial damage and cause the apoptosis of cancer cells, therefore achieving high therapeutic efficacy for solid tumors and minimized adverse effects to normal tissues. Our prodrug holds great promise as a potent and inspiring means for cancer treatment.

DOI: https://doi.org/10.1039/d1cc04379j
Mol Med Rep. 2021 Dec;pii: 837. [Epub ahead of print]24(6):

Astaxanthin induces NADPH oxidase activation and receptor‑interacting protein kinase 1‑mediated necroptosis in gastric cancer AGS cells.

Sori Kim, Hanbit Lee, Joo Weon Lim, Hyeyoung Kim.

  Astaxanthin (ASX), a red‑colored xanthophyll carotenoid, functions as an antioxidant or pro‑oxidant. ASX displays anticancer effects by reducing or increasing oxidative stress. Reactive oxygen species (ROS) promote cancer cell death by necroptosis mediated by receptor‑interacting protein kinase 1 (RIP1) and RIP3. NADPH oxidase is a major source of ROS that may promote necroptosis in some cancer cells. The present study aimed to investigate whether ASX induces necroptosis by increasing NADPH oxidase activity and ROS levels in gastric cancer AGS cells. AGS cells were treated with ASX with or without ML171 (NADPH oxidase 1 specific inhibitor), N‑acetyl cysteine (NAC; antioxidant), z‑VAD (pan‑caspase inhibitor) or Necrostatin‑1 (Nec‑1; a specific inhibitor of RIP1). As a result, ASX increased NADPH oxidase activity, ROS levels and cell death, and these effects were suppressed by ML171 and NAC. Furthermore, ASX induced RIP1 and RIP3 activation, ultimately inducing mixed lineage kinase domain‑like protein (MLKL) activation, lactate dehydrogenase (LDH) release and cell death. Moreover, the ASX‑induced decrease in cell viability was reversed by Nec‑1 treatment and RIP1 siRNA transfection, but not by z‑VAD. ASX did not increase the ratio of apoptotic Bax/anti‑apoptotic Bcl‑2, the number of Annexin V‑positive cells, or caspase‑9 activation, which are apoptosis indices. In conclusion, ASX induced necroptotic cell death by increasing NADPH oxidase activity, ROS levels, LDH release and the number of propidium iodide‑positive cells, as well as activating necroptosis‑regulating proteins, RIP1/RIP3/MLKL, in gastric cancer AGS cells. The results of this study demonstrated the necroptotic effect of ASX on gastric cancer AGS cells, which required NADPH oxidase activation and RIP1/RIP3/MLKL signaling in vitro.

Keywords:  NADPH oxidase; astaxanthin; gastric cancer cells; reactive oxygen species; receptor interacting protein kinase 1

DOI:  https://doi.org/10.3892/mmr.2021.12477
Biofactors. 2021 Oct 04.

Reactive oxygen species as a double-edged sword: The role of oxidative enzymes in antitumor therapy.

Elena Rosini, Loredano Pollegioni.

  A number of approaches have been developed over the years to manage cancer, such as chemotherapy using low-molecular-mass molecules and radiotherapy. Here, enzymes can also find useful applications. Among them, oxidases have attracted attention because of their ability to produce reactive oxygen species (ROS, especially hydrogen peroxide) in tumors and potentially modulate the production of this cytotoxic compound when enzymes active on substrates present in low amounts are used, such as the d-amino acid oxidase and d-amino acid couple system. These treatments have been also developed for additional cancer treatment approaches, such as phototherapy, nutrient starvation, and metal-induced hydroxyl radical production. In addition, to improve tumor specificity and decrease undesired side effects, oxidases have been targeted by means of nanotechnologies and protein engineering (i.e., by designing chimeric proteins able to accumulate in the tumor). The most recent advances obtained by using six different oxidases (i.e., the FAD-containing enzymes glucose oxidase, d- and l-amino acid oxidases, cholesterol oxidase and xanthine oxidase, and the copper-containing amine oxidase) have been reported. Anticancer therapy based on oxidase-based ROS production has now reached maturity and can be applied in the clinic.

Keywords:  cancer therapy; cytotoxicity; drug delivery; enzyme prodrug therapy; flavoprotein oxidases; nanoparticles; nanoreactors; oxidative stress; reactive oxygen species

DOI:  https://doi.org/10.1002/biof.1789
Int J Nanomedicine. 2021 ;16 6661-6679

Enhancing of Nanocatalyst-Driven Chemodynaminc Therapy for Endometrial Cancer Cells Through Inhibition of PINK1/Parkin-Mediated Mitophagy.

Xiaodi Gong, Xin Pu, Jing Wang, Linlin Yang, Yunxia Cui, Lijuan Li, Xiao Sun, Jichang Liu, Jingfeng Bai, Yudong Wang.

   Purpose: Iron-based nanomaterials have recently been developed as excellent and potent Fenton reagents to reactive oxygen species (ROS) during chemodynamic therapy (CDT). The performance of the materials, however, can be impaired by the intrinsic antioxidant defense mechanism in organisms, such as autophagy.
Methods: The nanoscale metal-organic frameworks (nMOFs), nMIL-100 (Fe), were exploited and characterized. Also, the Fenton-like catalytic characteristics, anti-endometrial cancer (EC) effects and potential mechanisms of nMIL-100 (Fe) nanoparticles were investigated in vitro.
Results: The synthesized nMIL-100 (Fe) nanocatalyst catalyzed hydroxyl radicals (·OH) production in the presence of hydrogen peroxide (H2O2) and simultaneously depleted intracellular glutathione (GSH). Combining with H2O2, nMIL-100 (Fe) nanoparticles exhibited enhanced cytotoxicity for EC cells, especially for progesterone treatment-insensitive KLE cells, probably due to relatively lower expression of the catalase gene. The accumulated ·OH initiated PTEN induced putative kinase 1 (PINK1)/E3 ubiquitin-protein ligase Parkin-mediated cytoprotective mitophagy in turn to partially rescue ·OH-induced cell apoptosis. Furthermore, both pretreatments of EC cells with siRNA-mediated Parkin knockdown and Mdivi-1 (a mitophagy inhibitor) addition were sufficient to ensure nMIL-100 (Fe) synergizing with H2O2-induced oxidative damages.
Conclusion: These results suggest that the degree of mitophagy should be taken into consideration to optimize therapeutic efficiency when developing ROS based-CDT for EC cancer therapies. Therefore, a nMIL-100 (Fe)-guided, elevated ROS and overwhelmed mitophagy-mediated therapeutic strategy may have greater promise for EC therapy compared with current treatment modalities.

Keywords:  chemodynamic therapy; endometrial cancer; metal-organic frameworks; mitophagy; nanocatalyst

DOI:  https://doi.org/10.2147/IJN.S329341
Pharmacol Ther. 2021 Oct 01. pii: S0163-7258(21)00194-7. [Epub ahead of print] 107992

Emerging role of ferroptosis in breast cancer: New dawn for overcoming tumor progression.

Shiyao Sui, Shouping Xu, Da Pang.

  Breast cancer has become a serious threat to women's health. Cancer progression is mainly derived from resistance to apoptosis induced by procedures or therapies. Therefore, new drugs or models that can overcome apoptosis resistance should be identified. Ferroptosis is a recently identified mode of cell death characterized by excess reactive oxygen species-induced lipid peroxidation. Since ferroptosis is distinct from apoptosis, necrosis and autophagy, its induction successfully eliminates cancer cells that are resistant to other modes of cell death. Therefore, ferroptosis may become a new direction around which to design breast cancer treatment. Unfortunately, the complete appearance of ferroptosis in breast cancer has not yet been fully elucidated. Furthermore, whether ferroptosis inducers can be used in combination with traditional anti- breast cancer drugs is still unknown. Moreover, a summary of ferroptosis in breast cancer progression and therapy is currently not available. In this review, we discuss the roles of ferroptosis-associated modulators glutathione, glutathione peroxidase 4, iron, nuclear factor erythroid-2 related factor-2, superoxide dismutases, lipoxygenase and coenzyme Q in breast cancer. Furthermore, we provide evidence that traditional drugs against breast cancer induce ferroptosis, and that ferroptosis inducers eliminate breast cancer cells. Finally, we put forward prospect of using ferroptosis inducers in breast cancer therapy, and predict possible obstacles and corresponding solutions. This review will deepen our understanding of the relationship between ferroptosis and breast cancer, and provide new insights into breast cancer-related therapeutic strategies.

Keywords:  Breast cancer; Coenzyme Q; Ferroptosis; Glutathione; Glutathione peroxidase 4; Iron; Lipoxygenase; Nuclear factor erythroid-2 related factor-2; Superoxide dismutases

DOI:  https://doi.org/10.1016/j.pharmthera.2021.107992
Cancer Lett. 2021 Oct 02. pii: S0304-3835(21)00504-8. [Epub ahead of print]

Mitochondrial stress adaptation promotes resistance to aromatase inhibitor in human breast cancer cells via ROS/calcium up-regulated amphiregulin-estrogen receptor loop signaling.

Sheng-Fan Wang, Yuh-Lih Chang, Yen-Dun Tony Tzeng, Chun-Ling Wu, Yuan-Zhong Wang, Ling-Ming Tseng, Shiuan Chen, Hsin-Chen Lee.

  Many breast cancer patients harbor high estrogen receptor (ER) expression in tumors that can be treated with endocrine therapy, which includes aromatase inhibitors (AI); unfortunately, resistance often occurs. Mitochondrial dysfunction has been thought to contribute to progression and to be related to hormone receptor expression in breast tumors. Mitochondrial alterations in AI-resistant breast cancer have not yet been defined. In this study, we characterized mitochondrial alterations and their roles in AI resistance. MCF-7aro AI-resistant breast cancer cells were shown to have significant changes in mitochondria. Low expressions of mitochondrial genes and proteins could be poor prognostic factors for breast cancer patients. Long-term mitochondrial inhibitor treatments-mediated mitochondrial stress adaptation could induce letrozole resistance. ERα-amphiregulin (AREG) loop signaling was activated and contributed to mitochondrial stress adaptation-mediated letrozole resistance. The up-regulation of AREG-epidermal growth factor receptor (EGFR) crosstalk activated the PI3K/Akt/mTOR and ERK pathways and was responsible for ERα activation. Moreover, mitochondrial stress adaptation-increased intracellular levels of reactive oxygen species (ROS) and calcium were shown to induce AREG expression and secretion. In conclusion, our results support the claim that mitochondrial stress adaptation contributes to AI resistance via ROS/calcium-mediated AREG-ERα loop signaling and provide possible treatment targets for overcoming AI resistance.

Keywords:  Amphiregulin; Aromatase inhibitor resistance; Calcium; Mitochondrial stress adaptation; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.canlet.2021.09.043
Diabet Med. 2021 Oct 06. e14713

Hyperglycemia-induced human hepatocellular carcinoma (HepG2) cell proliferation through ROS-mediated P38 activation is effectively inhibited by a xanthophyll carotenoid, lutein.

Tehreem Maradagi, Ravi Kumar, Ganesan Ponesakki.

   AIMS: Diabetic populations have a two to three-fold increased risk of developing liver cancer, and hyperglycemia is a prime causative factor that propends the tumor cells to undergo aggressive metabolic growth. In this study, we aimed to examine the molecular mechanism by which lutein inhibits hyperglycemia-induced human hepatocarcinoma (HepG2) cell proliferation.
METHODS: The effect of lutein on high glucose-induced proliferation was measured using the WST-1 reagent. Its effect on intracellular reactive oxygen species (ROS) levels was measured by DCF assay. The effect on the expression of antioxidant enzymes, cell cycle regulatory proteins, and intracellular protein kinases was analyzed by western blotting. The modulatory effect of lutein on different phases of the cell cycle was analyzed by flow cytometry.
RESULTS: The data showed that lutein at 5 µM concentration significantly blocked glucose-promoted HepG2 cell proliferation. Suppression of high glucose-induced cell proliferation by lutein was not associated with apoptosis induction, but it was linked with inhibition of hyperglycemia-mediated elevated ROS and upregulated expression of high glucose-mediated repressed heme oxygenase 1 (HO1). Further, G2/M phase cell cycle arrest and associated phosphorylation of Cdk1 and P53 were found to be linked with suppressed hyperglycemia-mediated cell proliferation by lutein. In addition, lutein inhibited hyperglycemia-induced activation of P38 which relates to high glucose-induced ROS-mediated growth suppression and modulated the phosphorylation of Erk, JNK, and Akt in hyperglycemic HepG2 cells.
CONCLUSION: Our findings portray that sufficient intake of lutein may offer a negative impact on diabetes-associated tumor growth.

Keywords:  P38; cell cycle arrest; hepatocarcinoma; hyperglycemia; lutein

DOI:  https://doi.org/10.1111/dme.14713
Technol Cancer Res Treat. 2021 Jan-Dec;20:20 15330338211045213

Effect of TRPM2-Mediated Calcium Signaling on Cell Proliferation and Apoptosis in Esophageal Squamous Cell Carcinoma.

Xingbang Wang, Yong Xiao, Mingming Huang, Bing Shen, Haowei Xue, Kaile Wu.

  Esophageal squamous cell carcinoma (ESCC) is the sixth leading cause of death due to cancer, indicating that finding new therapeutic targets or approaches for ESCC treatment is imperative. Transient Receptor Potential cation channel subfamily M, member 2 (TRPM2) is a calcium-permeable, nonselective cation channel that responds to reactive oxygen species (ROS), which are found in the tumor microenvironment and are important regulators of tumorigenesis, cell proliferation, apoptosis, and the therapeutic response. Here, we used immunohistochemical analysis of tumor tissue derived from patients with ESCC to find that the TRPM2 channel protein expression level was increased in tumor tissue compared with adjacent normal tissue. Intracellular calcium concentration measurements, western blotting, and ROS and cell viability assays were used with a human ESCC cell line (TE-1 cells) to find that TRPM2 participated in the ROS hydrogen peroxide-induced increase in intracellular calcium. This increased calcium inhibited cell proliferation and enhanced apoptosis. Pretreatment of cells with the anticancer agent 5-fluorouracil (5-FU) significantly increased ROS production, which potentiated TRPM2-mediated calcium signaling, decreased cell proliferation, and increased apoptosis in TE-1 cells, suggesting that the therapeutic effect of 5-FU in ESCC cells may be mediated by the TRPM2 channel-mediated calcium influx. These findings offer a potential treatment target and provide mechanistic insight into the therapeutic effects of 5-FU in patients with ESCC.

Keywords:  5-fluorouracil; TRPM2 channels; apoptosis; esophageal squamous cell carcinoma; proliferation; reactive oxygen species

DOI:  https://doi.org/10.1177/15330338211045213
Cell Mol Life Sci. 2021 Oct 09.

Increased glucosylceramide production leads to decreased cell energy metabolism and lowered tumor marker expression in non-cancerous liver cells.

Marthe-Susanna Wegner, Nina Schömel, Ellen M Olzomer, Sandra Trautmann, Catherine Olesch, Frances L Byrne, Bernhard Brüne, Robert Gurke, Nerea Ferreirós, Andreas Weigert, Gerd Geisslinger, Kyle L Hoehn.

  Hepatocellular carcinoma (HCC) is one of the most difficult cancer types to treat. Liver cancer is often diagnosed at late stages and therapeutic treatment is frequently accompanied by development of multidrug resistance. This leads to poor outcomes for cancer patients. Understanding the fundamental molecular mechanisms leading to liver cancer development is crucial for developing new therapeutic approaches, which are more efficient in treating cancer. Mice with a liver specific UDP-glucose ceramide glucosyltransferase (UGCG) knockout (KO) show delayed diethylnitrosamine (DEN)-induced liver tumor growth. Accordingly, the rationale for our study was to determine whether UGCG overexpression is sufficient to drive cancer phenotypes in liver cells. We investigated the effect of UGCG overexpression (OE) on normal murine liver (NMuLi) cells. Increased UGCG expression results in decreased mitochondrial respiration and glycolysis, which is reversible by treatment with EtDO-P4, an UGCG inhibitor. Furthermore, tumor markers such as FGF21 and EPCAM are lowered following UGCG OE, which could be related to glucosylceramide (GlcCer) and lactosylceramide (LacCer) accumulation in glycosphingolipid-enriched microdomains (GEMs) and subsequently altered signaling protein phosphorylation. These cellular processes lead to decreased proliferation in NMuLi/UGCG OE cells. Our data show that increased UGCG expression itself does not induce pro-cancerous processes in normal liver cells, which indicates that increased GlcCer expression leads to different outcomes in different cancer types.

Keywords:  GEMs; Glycolysis; HCC marker; Mitochondrial ROS; Oxidative phosphorylation

DOI:  https://doi.org/10.1007/s00018-021-03958-9
Front Oncol. 2021 ;11 727778

The Uniqueness of Clear Cell Renal Cell Carcinoma: Summary of the Process and Abnormality of Glucose Metabolism and Lipid Metabolism in ccRCC.

Xiaochen Qi, Quanlin Li, Xiangyu Che, Qifei Wang, Guangzhen Wu.

  Kidney cancer is a cancer with an increasing incidence in recent years. Clear cell renal cell carcinoma (ccRCC) accounts for up to 80% of all kidney cancers. The understanding of the pathogenesis, tumor progression, and metastasis of renal carcinoma is not yet perfect. Kidney cancer has some characteristics that distinguish it from other cancers, and the metabolic aspect is the most obvious. The specificity of glucose and lipid metabolism in kidney cancer cells has also led to its being studied as a metabolic disease. As the most common type of kidney cancer, ccRCC has many characteristics that represent the specificity of kidney cancer. There are features that we are very concerned about, including the presence of lipid droplets in cells and the obesity paradox. These two points are closely related to glucose metabolism and lipid metabolism. Therefore, we hope to explore whether metabolic changes affect the occurrence and development of kidney cancer by looking for evidence of changes on expression at the genomic and protein levels in glucose metabolism and lipid metabolism in ccRCC. We begin with the representative phenomenon of abnormal cancer metabolism: the Warburg effect, through the collection of popular metabolic pathways and related genes in the last decade, as well as some research hotspots, including the role of ferroptosis and glutamine in cancer, systematically elaborated the factors affecting the incidence and metastasis of kidney cancer. This review also identifies the similarities and differences between kidney cancer and other cancers in order to lay a theoretical foundation and provide a valid hypothesis for future research.

Keywords:  Warburg effect; cholesterol; clear cell renal cell carcinoma; glucose metabolism; lipid metabolism

DOI:  https://doi.org/10.3389/fonc.2021.727778