Inhibition of autophagy enhances apoptosis induced by the PI3K/AKT/mTor inhibitor NVP‐BEZ235 in renal cell carcinoma cells

Li, Hongyan; Jin, Xin; Zhang, Zhuo; Yuanyuan, Xing; Kong, Xiangbo

doi:10.1002/cbf.2917

Cited by 46 publications

(34 citation statements)

References 50 publications

(85 reference statements)

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“…However in vivo these agents may prove to be less effective than traditional mTOR inhibitors, because they do not display additional effects on the tumor microenvironment compared to those conferred by classical compounds [62]. Yet another emerging approach to overcome resistance is a use of dual inhibitors targeting autophagy [73]. Dual inhibitors of mTOR in combination with autophagy inhibitors has proven to enhance the suppression of growth and induction of apoptosis in ccRCC cell lines.…”

Section: Novel Dimensions In Comprehensive Approach the Mechanisms Ofmentioning

confidence: 99%

Mammalian Target of Rapamycin Inhibitors Resistance Mechanisms in Clear Cell Renal Cell Carcinoma

Kornakiewicz

Solarek²,

Bielecka³

et al. 2014

CST

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Mammalian target of rapamycin (mTOR) is a kinase protein involved in PI3K/AKT signaling with a central role in the processes of cell growth, survival and angiogenesis. Frequent mutations of this pathway make upstream and downstream components novel targets for tailored therapy design. Two mTOR inhibitors – everolimus and temsirolimus - enable an increase in overall survival (OS) or progression-free survival (PFS) time in a treatment of renal cancer. Despite recent advances in renal cancer treatment, resistance to targeted therapy is common. Understanding of molecular mechanisms is the basis of drug resistance which can facilitate prediction of success or failure in combinational or sequential targeted therapy. The article provides current knowledge on the mTOR signaling network and gives insight into the mechanisms of resistance to mTOR inhibitors from the complex perspective of RCC biology. The mechanisms of resistance developed not only by cancer cells, but also by interactions with tumor microenvironment are analyzed to emphasize the role of angiogenesis in ccRCC pathogenesis. As recent studies have shown the role of PI3K/AKT-mTOR pathway in proliferation and differentiation of cancer stem cells, we discuss cancer stem cell hypothesis and its possible contribution to ccRCC resistance. In the context of drug resistance, we also elaborate on a new approach considering ccRCC as a metabolic disease. In conclusion we speculate on future developments in agents targeting the mTOR pathway taking into consideration the singular biology of ccRCC.

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Section: Novel Dimensions In Comprehensive Approach the Mechanisms Ofmentioning

confidence: 99%

Mammalian Target of Rapamycin Inhibitors Resistance Mechanisms in Clear Cell Renal Cell Carcinoma

Kornakiewicz

Solarek²,

Bielecka³

et al. 2014

CST

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“…Consistent with this observation, Manara et al showed that NVP-BEZ235 induced sarcoma stasis, by arresting cells in G1 phase of the cell cycle, without remarkable effects on apoptosis (13). It was postulated that autophagy induced by NVP-BEZ235 was a pro-survival mechanism which rendered tumor cells capable of anti-apoptosis surviving in the kinase inhibitor (25)(26)(27).…”

Section: Discussionmentioning

confidence: 85%

Oridonin enhances the anticancer activity of NVP-BEZ235 against neuroblastoma cells in vitro and in vivo through autophagy

Zhang

Liu

et al. 2016

International Journal of Oncology

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Abstract. The aberrant activation of PI3K/Akt/mTOR signaling pathway plays an important role in the oncogenesis, prognosis and chemotherapy resistance of neuroblastoma. However, NVP-BEZ235, a potent dual PI3K and mTOR inhibitor have not shown beneficial effects on neuroblastoma especially in terms of apoptosis induction as a single agent. We therefore attempted to explore an effective combination regimen to enhance the anticancer activity of NVP-BEZ235. Interestingly, we found that oridonin, a natural biologically active compound extracted from the Chinese medicinal herb Rabdosia rubescens, combined with NVP-BEZ235 markedly induced apoptosis of neuroblastoma cells. Notably, the synergistic activation of the apoptotic pathway was accompanied with enhanced autophagy as evidenced by significant decreased p62 expression as well as upregulated conversion of LC3-II. Suppression of the Beclin-1, a core component of the autophagy machinery, by means of shRNA resulted in diminished synergistic antitumor effect. Furthermore, the co-treatment with oridonin and NVP-BEZ235 was also much more effective than either agent alone in inhibiting the growth of neuroblastoma xenografts and in inducing tumor cells apoptosis. Taken together, our results suggest that the combination of NVP-BEZ235 and oridonin is a novel and potential strategy for neuroblastoma therapy.

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“…However, studies have shown that induction of autophagy can promote either cell survival or death in RCC cells. Inhibition of mTOR pathway induced autophagy in several RCC cell lines (7,49,104,105), but autophagy inhibitor chloroquine promoted cell death by preventing autophagy and inducing RIP kinase-and ROSmediated necroptosis in RCC cell line (RCC4) and suppressed xenograft growth (7), whereas PI3K/mTOR inhibitor suppressed cell growth and induced apoptosis in RCC cells (786-0) and concomitantly activated autophagy that protected against apoptosis (49,104) (Fig. 7C).…”

Section: Implication Of Kidney Autophagy In Genetic Diseases and Cancermentioning

confidence: 99%

Autophagy in Kidney Health and Disease

Wang

Choi²

2014

Antioxidants & Redox Signaling

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Significance: Autophagy is emerging as an important pathway in many biological processes and diseases. This review summarizes the current progress on the role of autophagy in renal physiology and pathology. Recent Advances: Studies from renal cells in culture, human kidney tissues, and experimental animal models implicate that autophagy regulates many critical aspects of normal and disease conditions in the kidney, such as diabetic nephropathy and other glomerular diseases, tubular injuries, kidney development and aging, cancer, and genetic diseases associated with the kidney. Critical Issues: The importance of autophagy in the kidney has just started to be elucidated. How the process of autophagy is altered in the pathogenesis of kidney diseases and how this alteration is beneficial or detrimental to kidney functions still need to be fully understood. Future Directions: Investigations that uncover the precise mechanism and regulation of autophagy in various kidney diseases may lead to new strategies for therapeutic modulation. Antioxid. Redox Signal. 20, 519-537.

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Inhibition of autophagy enhances apoptosis induced by the PI3K/AKT/mTor inhibitor NVP‐BEZ235 in renal cell carcinoma cells

Cited by 46 publications

References 50 publications

Mammalian Target of Rapamycin Inhibitors Resistance Mechanisms in Clear Cell Renal Cell Carcinoma

Mammalian Target of Rapamycin Inhibitors Resistance Mechanisms in Clear Cell Renal Cell Carcinoma

Oridonin enhances the anticancer activity of NVP-BEZ235 against neuroblastoma cells in vitro and in vivo through autophagy

Autophagy in Kidney Health and Disease

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