J Cancer 2019; 10(6):1466-1478. doi:10.7150/jca.29192

Research Paper

Dual-Inhibition of mTOR and Bcl-2 Enhances the Anti-tumor Effect of Everolimus against Renal Cell Carcinoma In Vitro and In Vivo

Ayse Hande Nayman1, Halime Siginc1, Ebru Zemheri2, Faruk Yencilek3, Asif Yildirim4, Dilek Telci1✉

1. Yeditepe University, Faculty of Engineering, Department of Genetics and Bioengineering, Kayisdagi Cad., 34755, Istanbul, Turkey
2. Department of Pathology, Umraniye Training and Research Hospital, Istanbul, Turkey
3. Yeditepe University, Faculty/School of Medicine, Yeditepe University Hospital, Istanbul, Turkey
4. Department of Urology/Faculty of Medicine, Medeniyet University, Istanbul, Turkey

Abstract

Renal cell carcinoma (RCC) is the predominant type of kidney cancer. Mammalian target of rapamycin (mTOR) inhibitor everolimus is currently used as a second-line therapy for sorafenib or sunitinib-refractory metastatic RCC patients. The clinical limitation confronted during everolimus therapy is the onset of drug resistance that decreases the efficacy of the drug. Elevated level of anti-apoptotic Bcl-2 protein is proposed to be an emerging feedback loop for the acquired drug-resistance in various cancer types. In this study, the Bcl-2 inhibitor ABT-737 was used in combination with everolimus to enhance its anti-tumor effectiveness in everolimus-resistant RCC cell lines. Everolimus and ABT-737 combination synergistically led to a decrease in the proliferation of primary site A-498 and metastatic site Caki-1 RCC cell lines, which was accompanied by a reduction in protein levels of cell cycle and mTOR pathway proteins. In both RCC cell lines, everolimus-ABT-737 combination not only induced apoptosis, caspase and PARP-1 cleavage but also a decrease in Bcl-2 protein levels in parallel with a concomitant increase in Bim and Noxa levels.

In order to confirm our in vitro findings, we have generated everolimus-resistant RenCa cell line (RenCares) to establish a RCC mouse xenograft model. Animals co-treated with everolimus and ABT-737 exhibited a complete suppression of tumor growth without any notable toxicity. This study thus proposes the everolimus-ABT-737 combination as a novel therapeutic strategy for the treatment of RCC to overcome the current clinical problem of everolimus resistance.

Keywords: Bcl-2, Everolimus-ABT 737 combination, mTOR, Renal Cell Carcinoma

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How to cite this article:
Nayman AH, Siginc H, Zemheri E, Yencilek F, Yildirim A, Telci D. Dual-Inhibition of mTOR and Bcl-2 Enhances the Anti-tumor Effect of Everolimus against Renal Cell Carcinoma In Vitro and In Vivo. J Cancer 2019; 10(6):1466-1478. doi:10.7150/jca.29192. Available from http://www.jcancer.org/v10p1466.htm