Concurrent inhibition of mTORC1 and mTORC2 by WYE-687 inhibits renal cell carcinoma cell growth in vitro and in vivo

Pan, Xiao-dong; Gu, Danan; Mao, Jiahui; Zhu, Hua; Chen, Xinfeng; Zheng, Bing; Shan, Yuxi

doi:10.1371/journal.pone.0172555

Cited by 15 publications

(18 citation statements)

References 40 publications

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“…in vivo and in vitro observation showed that blocking mTOR1 and mTORC2 activation results in prevention of tumor progression in TSC +/− mice. In accordance with our data, similar recent findings show that new mTOR kinase inhibitor (WYE-687) increased apoptosis and blocked activation of both mTORC1 and mTORC2 through the feedback activation of p-Akt in renal cancer cells as well as the oral administration of WYE-687 potently suppressed tumor growth in nude mice injected with renal cancer cells [ 33 ]. These findings suggest that suppressing the HIF-2 may be an important therapeutic strategy for the treatment of tumorigenesis in TSC patients.…”

Section: Discussionsupporting

confidence: 92%

A new drug combination significantly reduces kidney tumor progression in kidney mouse model

et al. 2018

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Tuberous sclerosis complex (TSC) disease is associated with tumors in many organs, particularly angiomyolipoma (AML) in the kidneys. Loss or inactivation of TSC1/2 results in high levels of HIF-α activity and VEGF expression. mTOR inhibitor (rapamycin) and the AMPK activator 5-aminoimidazole-4-carboxamide (AICA)-riboside (AICAR) are currently used separately to treat cancer patients. Here, we investigated the effect of a novel combination of rapamycin and AICAR on tumor progression. Our data show that treatment of AML human cells with drug combinations resulted in 5-7-fold increase in cell apoptosis compared to each drug alone. In addition, drug combinations resulted in 4-5-fold decrease in cell proliferation compared to each drug alone. We found that drug combinations abolished Akt and HIF activity in AML cells. The drug combinations resulted in decrease in cell invasion and cell immigration by 70% and 84%, respectively in AML cells. The combined drugs also significantly decreased the VEGF expression compare to each drug alone in AML cells. Drug combinations effectively abolished binding of HIF-2α to the putative Akt site in the nuclear extracts isolated from AML cells. Treatment TSC mice with drug combinations resulted in 75% decrease in tumor number and 88% decrease in tumor volume compared to control TSC mice. This is first evidence that drug combinations are effective in reducing size and number of kidney tumors without any toxic effect on kidney. These data will provide evidence for initiating a new clinical trial for treatment of TSC patients.

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Section: Discussionsupporting

confidence: 92%

A new drug combination significantly reduces kidney tumor progression in kidney mouse model

et al. 2018

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“…Cells were obtained by rinsing and filtering. Primary ccRCC cells were cultured in FBS-DMEM/F12 medium supplemented with 10 ng/mL basic fibroblast growth factor (bFGF) and 10 ng/mL epidermal growth factor (EGF) [32] . After 3 to 6 passages, primary ccRCC cells were used in our study.…”

Section: Primary Culture Of Human Rcc Cellsmentioning

confidence: 99%

RETRACTED ARTICLE: Hispidulin mediates apoptosis in human renal cell carcinoma by inducing ceramide accumulation

Gao

Peng

et al. 2017

Acta Pharmacol Sin

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Hispidulin, a polyphenolic flavonoid extracted from the traditional Chinese medicinal plant S involucrata, exhibits anti-tumor effects in a wide array of human cancer cells, mainly through growth inhibition, apoptosis induction and cell cycle arrest. However, its precise anticancer mechanisms remain unclear. In this study, we investigated the molecular mechanisms that contribute to hispidulin-induced apoptosis of human clear-cell renal cell carcinoma (ccRCC) lines Caki-2 and ACHN. Hispidulin (10, 20 μmol/L) decreased the viability of ccRCC cells in dose- and time-dependent manners without affecting that of normal tubular epithelial cells. Moreover, hispidulin treatment dose-dependently increased the levels of cleaved caspase-8 and caspase-9, but the inhibitors of caspase-8 and caspase-9 only partly abrogated hispidulin-induced apoptosis, suggesting that hispidulin triggered apoptosis via both extrinsic and intrinsic pathways. Moreover, hispidulin treatment significantly inhibited the activity of sphingosine kinase 1 (SphK1) and consequently promoted ceramide accumulation, thus leading to apoptosis of the cancer cells, whereas pretreatment with K6PC-5, an activator of SphK1, or overexpression of SphK1 significantly attenuated the anti-proliferative and pro-apoptotic effects of hispidulin. In addition, hispidulin treatment dose-dependently activated ROS/JNK signaling and led to cell apoptosis. We further demonstrated in Caki-2 xenograft nude mice that injection of hispidulin (20, 40 mg·kg·d, ip) dose-dependently suppressed tumor growth accompanied by decreased SphK1 activity and increased ceramide accumulation in tumor tissues. Our findings reveal a new explanation for the anti-tumor mechanisms of hispidulin, and suggest that SphK1 and ceramide may serve as potential therapeutic targets for the treatment of ccRCC.

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“…Our in vivo and in vitro findings showed that blocking mTOR and activating AMPK prevented tumor progression in a tumor xenograft mouse model. In agreement with our findings, it was recently reported that a new mTOR kinase inhibitor, WYE‐687, increased apoptosis and blocked activation of both mTORC1 and mTORC2 through the feedback activation of p‐Akt in RCC cells, and oral administration of WYE‐687 potently suppressed tumor growth in nude mice injected with 786‐O cells (Pan et al ., ). Induction of VEGF expression is dependent on HIF‐mTOR activation, which indicates a critical function of the HIF‐mTOR pathway in regulating angiogenesis (Land and Tee, ).…”

Section: Discussionmentioning

confidence: 97%

“…Activation of the Akt/mTOR signaling pathway positively regulates HIF (Woo et al, 2015), making mTOR inhibitors attractive anticancer agents. The use of mTOR inhibitors in the treatment of various types of cancer has been actively studied both preclinically and clinically (Jacinto et al, 2004;Mayer and Grummt, 2006;Pan et al, 2017;Sarbassov et al, 2006). On the other hand, AMP kinase (AMPK) is the primary energy sensor in cells that activates tumor suppressor genes to block HIF activity (Tong et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Preclinical evidence of the enhanced effectiveness of combined rapamycin and AICAR in reducing kidney cancer

Liang

Medina

et al. 2018

Molecular Oncology

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Loss of Von Hippel‐Lindau in renal carcinoma cells results in upregulation of the activity of hypoxia‐inducible factor (HIF‐α), a major transcription factor involved in kidney cancer. Rapamycin as mammalian target of rapamycin inhibitor and 5‐aminoimidazole‐4‐carboxamide‐riboside (AICAR) as AMPK activator are used separately to treat cancer patients. In the current study, the possible additive effect of drug combinations in reducing kidney tumorigenesis was investigated. Treatment with drug combinations significantly decreased cell proliferation, increased cell apoptosis, and abolished Akt phosphorylation and HIF‐2α expression in renal cell carcinoma cells, including primary cells isolated from kidney cancer patients. Significant decreases in cell migration and invasion were detected using drug combinations. Drug combinations effectively abolished binding of HIF‐2α to the Akt promoter and effected formation of the DNA‐protein complex in nuclear extracts from 786‐O cells, as demonstrated using electromobility shift assay and examination of Akt promoter activity. Importantly, we tested the effect of each drug and the combined drugs on kidney tumor size in the nude mouse model. Our data show that treatment with rapamycin, AICAR, and rapamycin+AICAR decreased tumor size by 38%, 36%, and 80%, respectively, suggesting that drug combinations have an additive effect in reducing tumor size compared with use of each drug alone. Drug combinations effectively decreased cell proliferation, increased apoptotic cells, and significantly decreased p‐Akt, HIF‐2α, and vascular endothelial growth factor expression in tumor kidney tissues from mice. These results show for the first time that drug combinations are more effective than single drugs in reducing kidney tumor progression. This study provides important evidence that may lead to the initiation of pre‐clinical trials in patients with kidney cancer.

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Concurrent inhibition of mTORC1 and mTORC2 by WYE-687 inhibits renal cell carcinoma cell growth in vitro and in vivo

Cited by 15 publications

References 40 publications

A new drug combination significantly reduces kidney tumor progression in kidney mouse model

A new drug combination significantly reduces kidney tumor progression in kidney mouse model

RETRACTED ARTICLE: Hispidulin mediates apoptosis in human renal cell carcinoma by inducing ceramide accumulation

Preclinical evidence of the enhanced effectiveness of combined rapamycin and AICAR in reducing kidney cancer

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