Silencing of NAC1 Expression Induces Cancer Cells Oxidative Stress in Hypoxia and Potentiates the Therapeutic Activity of Elesclomol

Ren, Yi; Wang, Xiao Hui; Ji, Cheng; Guan, Yunqian; Xian, Lu; Liu, Xian Rong; Zhang, Hong Han; Guo, Ling; Xu, Qiong; Zhu, Wei; Ming, Zhi Jun; Yang, Jin Ming; Cheng, Yan; Zhang, Yi

doi:10.3389/fphar.2017.00804

Cited by 20 publications

(17 citation statements)

References 35 publications

(42 reference statements)

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“…Elesclomol shows potent antitumor activity against a broad spectrum of cancers; this activity is exerted via increasing ROS and oxidative stress to levels that are lethal to cells [21]. Flow cytometry showed that the average fluorescence intensity of the elesclomoltreated cells increased as the drug concentration increased, as compared with the negative-control cells (Fig.…”

Section: Elesclomol Promotes Myofibroblast Apoptosis By Increasing Oxidative Stressmentioning

confidence: 93%

“…Elesclomol has received both fast track and orphan drug status from the U.S. Food and Drug Administration for the treatment of metastatic melanoma [17,18] and it is also being used in tumors such as non-small cell lung cancer, breast cancer and sarcoma [19,20]. Recently, elesclomol was shown to induce ROS production in tumor cells in vitro, leading to increased oxidative stress and apoptosis [21,22]. Considering its proapoptotic effects, we speculated that elesclomol may serve as a novel treatment for HS.…”

Section: Introductionmentioning

confidence: 99%

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Targeted apoptosis of myofibroblasts by elesclomol inhibits hypertrophic scar formation

Feng

Sun

et al. 2020

EBioMedicine

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Background: Hypertrophic scar (HS) is characterized by the increased proliferation and decreased apoptosis of myofibroblasts. Myofibroblasts, the main effector cells for dermal fibrosis, develop from normal fibroblasts. Thus, the stimulation of myofibroblast apoptosis is a possible treatment for HS. We aimed to explore that whether over-activated myofibroblasts can be targeted for apoptosis by anticancer drug elesclomol. Methods: 4 0 ,6-diamidino-2-phenylindole staining, flow cytometry, western blotting, collagen gel contraction and immunofluorescence assays were applied to demonstrate the proapoptotic effect of elesclomol in scar derived myofibroblasts and TGF-b1 induced myofibroblasts. The therapeutic potential of elesclomol was investigated by establishing rabbit ear hypertrophic scar models. Findings: Both 4 0 ,6-diamidino-2-phenylindole staining and flow cytometry indicated that elesclomol targets myofibroblasts in vitro. Collagen gel contraction assay showed that elesclomol inhibited myofibroblast contractility. Flow cytometry and western blot analysis revealed that elesclomol resulted in excessive intracellular levels of reactive oxygen species(ROS), and caspase-3 and cytochrome c proteins. Moreover, compared with the control group, the elesclomol group had a significantly lower scar elevation index in vivo. Immunofluorescence assays for TUNEL and a-smooth muscle actin indicated that elesclomol treatment increased the number of apoptotic myofibroblasts. Interpretation: The above results indicate that elesclomol exerted a significant inhibitory effect on HS formation via targeted myofibroblast apoptosis associated with increased oxidative stress. Thus, elesclomol is a promising candidate drug for the treatment of myofibroblast-related diseases such as HS.

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Section: Elesclomol Promotes Myofibroblast Apoptosis By Increasing Oxidative Stressmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

Targeted apoptosis of myofibroblasts by elesclomol inhibits hypertrophic scar formation

Feng

Sun

et al. 2020

EBioMedicine

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“…Several studies have demonstrated that hypoxia-inducible factor (HIF)-1α regulates the expression of pyruvate dehydrogenase kinase 3 (PDK3) and further induces chemotherapy resistance under hypoxic conditions (43,46). Nucleus accumbens-1 mediates the inhibition of mitochondrial function via HIF-1α-mediated PDK3 overexpression, the inhibition of pyruvate dehydrogenase function and the repression of mitochondrial respiration (47). This process can protect cancer cells from apoptosis under hypoxic conditions (47).…”

Section: Pyruvate Kinase (Pkm2)mentioning

confidence: 99%

“…Nucleus accumbens-1 mediates the inhibition of mitochondrial function via HIF-1α-mediated PDK3 overexpression, the inhibition of pyruvate dehydrogenase function and the repression of mitochondrial respiration (47). This process can protect cancer cells from apoptosis under hypoxic conditions (47). Upregulation of PDK4 increases resistance to chemotherapy in hepatocytes and colon cancer cells (48).…”

Section: Pyruvate Kinase (Pkm2)mentioning

confidence: 99%

Altered glycolysis results in drug‑resistant in clinical tumor therapy (Review)

Peng

Cui

et al. 2021

Oncol Lett

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Cancer cells undergo metabolic reprogramming, including increased glucose metabolism, fatty acid synthesis and glutamine metabolic rates. These enhancements to three major metabolic pathways are closely associated with glycolysis, which is considered the central component of cancer cell metabolism. Increasing evidence suggests that dysfunctional glycolysis is commonly associated with drug resistance in cancer treatment, and aberrant glycolysis plays a significant role in drug-resistant cancer cells. Studies on the development of drugs targeting these abnormalities have led to improvements in the efficacy of tumor treatment. The present review discusses the changes in glycolysis targets that cause drug resistance in cancer cells, including hexokinase, pyruvate kinase, pyruvate dehydrogenase complex, glucose transporters, and lactate, as well the underlying molecular mechanisms and corresponding novel therapeutic strategies. In addition, the association between increased oxidative phosphorylation and drug resistance is introduced, which is caused by metabolic plasticity. Given that aberrant glycolysis has been identified as a common metabolic feature of drug-resistant tumor cells, targeting glycolysis may be a novel strategy to develop new drugs to benefit patients with drug-resistance.

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“…In doing so, cancer cells may lose their ability to thrive under environments containing a higher concentration of ROS compared with normal healthy cells. One example is the silencing of nucleus-accumbens-1 (NAC1), which has been shown to facilitate oxidative stress resistance, sensitizing cancer cells to oxidative stress generating chemotherapeutics [121]. Pyrroline-5-carboxylate reductase 1 and 2 (PYCR1, PYCR2) downregulation or silencing could potentially sensitize cancer cells to ROS by inhibiting stress-response protein ribonucleotide reductase small subunit B (RRM2B), a protein implicated in protection from oxidative stress [122].…”

Section: Strategies To Target Mitochondriamentioning

confidence: 99%

Exploiting Mitochondrial Vulnerabilities to Trigger Apoptosis Selectively in Cancer Cells

Nguyen

Pandey

2019

Cancers

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The transformation of normal cells to the cancerous stage involves multiple genetic changes or mutations leading to hyperproliferation, resistance to apoptosis, and evasion of the host immune system. However, to accomplish hyperproliferation, cancer cells undergo profound metabolic reprogramming including oxidative glycolysis and acidification of the cytoplasm, leading to hyperpolarization of the mitochondrial membrane. The majority of drug development research in the past has focused on targeting DNA replication, repair, and tubulin polymerization to induce apoptosis in cancer cells. Unfortunately, these are not cancer-selective targets. Recently, researchers have started focusing on metabolic, mitochondrial, and oxidative stress vulnerabilities of cancer cells that can be exploited as selective targets for inducing cancer cell death. Indeed, the hyperpolarization of mitochondrial membranes in cancer cells can lead to selective importing of mitocans that can induce apoptotic effects. Herein, we will discuss recent mitochondrial-selective anticancer compounds (mitocans) that have shown selective toxicity against cancer cells. Increased oxidative stress has also been shown to be very effective in selectively inducing cell death in cancer cells. This oxidative stress could lead to mitochondrial dysfunction, which in turn will produce more reactive oxygen species (ROS). This creates a vicious cycle of mitochondrial dysfunction and ROS production, irreversibly leading to cell suicide. We will also explore the possibility of combining these compounds to sensitize cancer cells to the conventional anticancer agents. Mitocans in combination with selective oxidative-stress producing agents could be very effective anticancer treatments with minimal effect on healthy cells.

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Silencing of NAC1 Expression Induces Cancer Cells Oxidative Stress in Hypoxia and Potentiates the Therapeutic Activity of Elesclomol

Cited by 20 publications

References 35 publications

Targeted apoptosis of myofibroblasts by elesclomol inhibits hypertrophic scar formation

Targeted apoptosis of myofibroblasts by elesclomol inhibits hypertrophic scar formation

Altered glycolysis results in drug‑resistant in clinical tumor therapy (Review)

Exploiting Mitochondrial Vulnerabilities to Trigger Apoptosis Selectively in Cancer Cells

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