Sorafenib induces mitochondrial dysfunction and exhibits synergistic effect with cysteine depletion by promoting HCC cells ferroptosis

Li, Yanchun; Xia, Jun; Shao, Fangchun; Zhou, Yan; Yu, Jiaqi; Wu, Hengyu; Du, Jing; Ren, Xueying

doi:10.1016/j.bbrc.2020.10.083

Cited by 77 publications

(49 citation statements)

References 29 publications

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“…Sorafenib is a first-line drug for advanced HCC, however, the development of drug resistance limits its efficacy. Our recent study illustrated that depletion of cysteine acts synergistically with sorafenib and renders HCC cells vulnerable to ferroptosis [ 29 ]. We further explored whether DSF/Cu acts synergistically with sorafenib through induction of ferroptosis, and verified this issue by the following assays: (i) DSF/Cu exacerbates sorafenib-induced ferroptosis in a dose-dependent manner, accompanied by increased ferroptotic events including accelerated superoxide production and lipid peroxidation ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Overcoming the compensatory elevation of NRF2 renders hepatocellular carcinoma cells more vulnerable to disulfiram/copper-induced ferroptosis

et al. 2021

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Hepatocellular carcinoma (HCC) is one of the paramount causes of cancer-related death worldwide. Despite recent advances have been made in clinical treatments of HCC, the general prognosis of patients remains poor. Therefore, it is imperative to develop a less toxic and more effective therapeutic strategy. Currently, series of cellular, molecular, and pharmacological experimental approaches were utilized to address the unrecognized characteristics of disulfiram (DSF), pursuing the goal of repurposing DSF for cancer therapy. We found that DSF/Cu selectively exerted an efficient cytotoxic effect on HCC cell lines, and potently inhibited migration, invasion, and angiogenesis of HCC cells. Importantly, we confirmed that DSF/Cu could intensively impair mitochondrial homeostasis, increase free iron pool, enhance lipid peroxidation, and eventually result in ferroptotic cell death. Of note, a compensatory elevation of NRF2 accompanies the process of ferroptosis, and contributes to the resistance to DSF/Cu. Mechanically, we found that DSF/Cu dramatically activated the phosphorylation of p62, which facilitates competitive binding of Keap1, thus prolonging the half-life of NRF2. Notably, inhibition of NRF2 expression via RNA interference or pharmacological inhibitors significantly facilitated the accumulation of lipid peroxidation, and rendered HCC cells more sensitive to DSF/Cu induced ferroptosis. Conversely, fostering NRF2 expression was capable of ameliorating the cell death activated by DSF/Cu. Additionally, DSF/Cu could strengthen the cytotoxicity of sorafenib, and arrest tumor growth both in vitro and in vivo , by simultaneously inhibiting the signal pathway of NRF2 and MAPK kinase. In summary, these results provide experimental evidence that inhibition of the compensatory NRF2 elevation strengthens HCC cells more vulnerable to DSF/Cu induced ferroptosis, which facilitates the synergistic cytotoxicity of DSF/Cu and sorafenib.

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Section: Resultsmentioning

confidence: 99%

Overcoming the compensatory elevation of NRF2 renders hepatocellular carcinoma cells more vulnerable to disulfiram/copper-induced ferroptosis

et al. 2021

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“…Enhancing the effect of sorafenib is worthy of our attention. Recently, Li et al (2021) revealed that cysteine depletion made HCC cells more vulnerable to sorafenib-induced ferroptosis ( Li et al, 2021 ), which provides us with a new perspective to enhance the effect of sorafenib. Research also showed that DFX can reduce the therapeutic effect of sorafenib in HCC cell lines ( Saeki et al, 2016 ).…”

Section: Ferroptosis In Relevant Malignant Tumorsmentioning

confidence: 99%

A Promising Future of Ferroptosis in Tumor Therapy

Wang

Lin

et al. 2021

Front. Cell Dev. Biol.

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Currently, mechanisms and therapeutic approaches have been thoroughly studied in various prevalent malignant tumors, such as breast and lung cancer. However, there is inevitable tumor progression and drug resistance. Uncovering novel treatment strategies to inhibit tumor development is important. Ferroptosis, a form of cell death associated with iron and lipid peroxidation, has drawn extensive attention. In this paper, we reviewed the underlying mechanisms of ferroptosis (i.e., iron, glutathione, and lipid metabolism) and its role in various tumors (i.e., lung cancer, liver carcinoma, breast cancer, and pancreatic cancer). Moreover, we summarized ferroptosis-related anti-tumor drugs and emphasized the potential of combined treatment of anti-tumor drugs and radiotherapy in an effort to provide novel anti-tumor treatments.

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“…15 Specifically, after sorafenib treatment of HCC cells, mitochondrial morphology and membrane potential collapse and oxidative phosphorylation activity and ATP synthesis are reduced, thereby inducing ferroptosis and cell death. 93 In addition, GSH can rescue the ferroptosis induced by sorafenib and eliminate the accumulation of mitochondrial ROS and lipid peroxides, while cysteine depletion or cysteinase inhibition has the opposite effect. 93 Because of recent interest in ferroptosis as a physiological phenomenon, many research teams have begun to investigate ferroptosis as an outcome in HCC treatment.…”

Section: Ferroptosis In Hcc Treatmentmentioning

confidence: 99%

“…93 In addition, GSH can rescue the ferroptosis induced by sorafenib and eliminate the accumulation of mitochondrial ROS and lipid peroxides, while cysteine depletion or cysteinase inhibition has the opposite effect. 93 Because of recent interest in ferroptosis as a physiological phenomenon, many research teams have begun to investigate ferroptosis as an outcome in HCC treatment. 94 Quiescin sulfhydryl oxidase 1 (QSOX1) contributes to the formation of disulfide bonds of multiple proteins and can also act as a tumor suppressor.…”

Section: Ferroptosis In Hcc Treatmentmentioning

confidence: 99%

Figure 2 The function and possible mechanism of ferroptosis in HCC treatment. Several studies have investigated the induction of ferroptosis as a possible HCC treatment that may provide promising and effective therapy.…”

Section: Ferroptosis In Hcc Treatmentmentioning

confidence: 99%

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Molecular Targets of Ferroptosis in Hepatocellular Carcinoma

Liao

Shi

Wen

et al. 2021

JHC

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Ferroptosis is a special form of regulatory cell death caused by the accumulation of intracellular iron and lipid peroxidation. Here, we summarize the research progress on ferroptosis in hepatocellular carcinoma (HCC), trace the development of the concept of ferroptosis and its key regulatory factors, and discuss the application value of ferroptosis in the treatment of HCC from different perspectives. We believe that exploring the relationship between ferroptosis and HCC and clarifying the metabolism and expression of ferroptosisspecific genes and molecules will accelerate the development of novel ferroptosis-related molecules as HCC markers and therapeutic targets. We hope to provide a theoretical basis for better diagnosis and treatment to effectively improve the prognosis of patients with HCC.

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Sorafenib induces mitochondrial dysfunction and exhibits synergistic effect with cysteine depletion by promoting HCC cells ferroptosis

Cited by 77 publications

References 29 publications

Overcoming the compensatory elevation of NRF2 renders hepatocellular carcinoma cells more vulnerable to disulfiram/copper-induced ferroptosis

Overcoming the compensatory elevation of NRF2 renders hepatocellular carcinoma cells more vulnerable to disulfiram/copper-induced ferroptosis

A Promising Future of Ferroptosis in Tumor Therapy

Molecular Targets of Ferroptosis in Hepatocellular Carcinoma

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