Chloroquine synergizes sunitinib cytotoxicity via modulating autophagic, apoptotic and angiogenic machineries

Abdel-Aziz, Amal Kamal; Shouman, Samia A.; El‐Demerdash, Ebtehal; Elgendy, Mohamed; Abdel-Naim, Ashraf B.

doi:10.1016/j.cbi.2014.04.007

Cited by 80 publications

(69 citation statements)

References 49 publications

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“…Sunitinib however has been shown to induce or block autophagy depending on the cell type (22–26). To determine the effect of sunitinib on autophagy in CCOC cells, we first examined LC3-II and the autophagy-dependent degradation of p62 following sunitinib treatment.…”

Section: Resultsmentioning

confidence: 99%

“…There have been conflicting reports of the effect of sunitinib on autophagy, highlighting that sensitivity to sunitinib-induced autophagy as well as autophagy inhibition varies depending on the tumor type (22–26). In our study, and consistent with these other reports, we found that sunitinib had different effects on autophagy depending on the CCOC cell line tested and on the presence or absence of oxygen.…”

Section: Discussionmentioning

confidence: 99%

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Autophagy Inhibition Enhances Sunitinib Efficacy in Clear Cell Ovarian Carcinoma

DeVorkin

Hattersley

Kim

et al. 2017

Molecular Cancer Research

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Clear cell ovarian carcinoma (CCOC) is an aggressive form of epithelial ovarian cancer that exhibits low response rates to systemic therapy and poor patient outcomes. Multiple studies in CCOC have revealed expression profiles consistent with increased hypoxia, and our previous data suggest that hypoxia is correlated with increased autophagy in CCOC. Hypoxia-induced autophagy is a key factor promoting tumor cell survival and resistance to therapy. Recent clinical trials with the molecular-targeted receptor tyrosine kinase (RTK) inhibitor sunitinib have demonstrated limited activity. Here, it was evaluated whether the hypoxia–autophagy axis could be modulated to overcome resistance to sunitinib. Importantly, a significant increase in autophagic activity was found with a concomitant loss in cell viability in CCOC cells treated with sunitinib. Pharmacologic inhibition of autophagy with the lysosomotropic analog Lys05 inhibited autophagy and enhanced sunitinib-mediated suppression of cell viability. These results were confirmed by siRNA targeting the autophagy-related gene Atg5. In CCOC tumor xenografts, Lys05 potentiated the antitumor activity of sunitinib compared with either treatment alone. These data reveal that CCOC tumors have an autophagic dependency and are an ideal tumor histotype for autophagy inhibition as a strategy to overcome resistance to RTK inhibitors like sunitinib. Implications This study shows that autophagy inhibition enhances sunitinib-mediated cell death in a preclinical model of CCOC.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Autophagy Inhibition Enhances Sunitinib Efficacy in Clear Cell Ovarian Carcinoma

DeVorkin

Hattersley

Kim

et al. 2017

Molecular Cancer Research

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“…Although these results further support our observations, additional studies are required to validate them. Additional therapeutic strategies to sensitize tumors to sunitinib have also been suggested …”

Section: Discussionmentioning

confidence: 99%

Identification of mutations associated with acquired resistance to sunitinib in renal cell cancer

Elgendy

Fusco

Segura

et al. 2019

Intl Journal of Cancer

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Sunitinib is one of the most widely used targeted therapeutics for renal cell carcinoma (RCC), but acquired resistance against targeted therapies remains a major clinical challenge. To dissect mechanisms of acquired resistance and unravel reliable predictive biomarkers for sunitinib in RCC, we sequenced the exons of 409 tumor‐suppressor genes and oncogenes in paired tumor samples from an RCC patient, obtained at baseline and after development of acquired resistance to sunitinib. From newly arising mutations, we selected, using in silico prediction models, six predicted to be deleterious, located in G6PD, LRP1B, SETD2, TET2, SYNE1, and DCC. Consistently, immunoblotting analysis of lysates derived from sunitinib‐desensitized RCC cells and their parental counterparts showed marked differences in the levels and expression pattern of the proteins encoded by these genes. Our further analysis demonstrates essential roles for these proteins in mediating sunitinib cytotoxicity and shows that their loss of function renders tumor cells resistant to sunitinib in vitro and in vivo. Finally, sunitinib resistance induced by continuous exposure or by inhibition of the six proteins was overcome by treatment with cabozantinib or a low‐dose combination of lenvatinib and everolimus. Collectively, our results unravel novel markers of acquired resistance to sunitinib and clinically relevant approaches for overcoming this resistance in RCC.

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“…Sunitinib also inhibits the activity and expression of neuronal nitric oxide synthase (NOS), which has been associated with the neuroprotective effects of sunitinib in vitro and also with reduced vasodilation in animal experiments [25, 26]. Sunitinib combined with chloroquine increases inducible NOS, leading to an increase in reactive nitrogen species and apoptosis while, on the other hand, the increased level of GSH abrogates apoptosis [27]. Whether these effects are relevant as regards tumour growth remains unclear on the basis of the current literature.…”

Section: Tyrosine Kinase Inhibitorsmentioning

confidence: 99%

Reactive Oxygen Species‐Mediated Mechanisms of Action of Targeted Cancer Therapy

Teppo

Soini

Karihtala

2017

Oxidative Medicine and Cellular Longevity

136

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Targeted cancer therapies, involving tyrosine kinase inhibitors and monoclonal antibodies, for example, have recently led to substantial prolongation of survival in many metastatic cancers. Compared with traditional chemotherapy and radiotherapy, where reactive oxygen species (ROS) have been directly linked to the mediation of cytotoxic effects and adverse events, the field of oxidative stress regulation is still emerging in targeted cancer therapies. Here, we provide a comprehensive review regarding the current evidence of ROS-mediated effects of antibodies and tyrosine kinase inhibitors, use of which has been indicated in the treatment of solid malignancies and lymphomas. It can be concluded that there is rapidly emerging evidence of ROS-mediated effects of some of these compounds, which is also relevant in the context of drug resistance and how to overcome it.

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Chloroquine synergizes sunitinib cytotoxicity via modulating autophagic, apoptotic and angiogenic machineries

Cited by 80 publications

References 49 publications

Autophagy Inhibition Enhances Sunitinib Efficacy in Clear Cell Ovarian Carcinoma

Autophagy Inhibition Enhances Sunitinib Efficacy in Clear Cell Ovarian Carcinoma

Identification of mutations associated with acquired resistance to sunitinib in renal cell cancer

Reactive Oxygen Species‐Mediated Mechanisms of Action of Targeted Cancer Therapy

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