Nayman Ayse Hande, Siginc Halime, Zemheri Ebru, Yencilek Faruk, Yildirim Asif, Telci Dilek
Yeditepe University, Faculty of Engineering, Department of Genetics and Bioengineering, Kayisdagi Cad., 34755, Istanbul, Turkey.
Department of Pathology, Umraniye Training and Research Hospital, Istanbul, Turkey.
J Cancer. 2019 Feb 23;10(6):1466-1478. doi: 10.7150/jca.29192. eCollection 2019.
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 findings, we have generated everolimus-resistant RenCa cell line (RenCa) 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.
肾细胞癌（RCC）是肾癌的主要类型。雷帕霉素哺乳动物靶点（mTOR）抑制剂依维莫司目前用作索拉非尼或舒尼替尼难治性转移性RCC患者的二线治疗药物。依维莫司治疗期间面临的临床局限性是出现耐药性，降低了药物疗效。抗凋亡Bcl-2蛋白水平升高被认为是各种癌症类型获得性耐药的一个新出现的反馈回路。在本研究中，Bcl-2抑制剂ABT-737与依维莫司联合使用，以增强其对依维莫司耐药的RCC细胞系的抗肿瘤效果。依维莫司和ABT-737联合使用协同导致原发部位A-498和转移部位Caki-1 RCC细胞系的增殖减少，同时细胞周期蛋白和mTOR信号通路蛋白水平降低。在两种RCC细胞系中，依维莫司-ABT-737联合使用不仅诱导了凋亡、半胱天冬酶和PARP-1的裂解，还降低了Bcl-2蛋白水平，同时伴随着Bim和Noxa水平的升高。为了证实我们的发现，我们构建了依维莫司耐药的RenCa细胞系（RenCa），以建立RCC小鼠异种移植模型。联合使用依维莫司和ABT-737治疗的动物肿瘤生长完全受到抑制，且无明显毒性。因此，本研究提出依维莫司-ABT-737联合用药作为一种治疗RCC的新策略，以克服目前依维莫司耐药的临床问题。
