Abstract
Renal cell carcinoma (RCC) is one of the most lethal urinary malignancies and causes about 13,570 estimated cancer-related deaths in the United States in 2012 . RCC accounts for about 500 new cancer cases per year in Taiwan. New targeted therapy focusing on mammalian target of rapamycin (mTOR) and tyrosine kinase for this disease include the Food and Drug Administration (FDA)-approved agents temsirolimus, everolimus, sorafenib, and sunitinib. All of them have been proved to improve clinical outcomes. Because RCC is a highly vascular disease and angiogenesis involves a critical role in development and progression of RCC, the potency to disrupt angiogenesis is responsible for the effectiveness of these agents. However, drug resistance is an emerging problem because most patients with advanced RCC will eventually die of their disease, even clinical response rates improved after treatment with above FDA-approved agents. A new strategy of cocktail targted therapy to improve clinical outcomes is needed. We report here that YM155, a survivin suppressor, synergistically augmented the anticancer activity of mTOR inhibitor, temsirolimus in RCC cell lines in vitro and in xenograft models in vivo. In our study, necrostatin-1 was found to prevent the cell death induced by combined treatment, and could recover the cell shape and the intracellular survivin levels. On the other hand, pan-caspase inhibitor Z-VAD.fmk could not either restore the downregulated suvivin level induced by combined treatment of YM155 and temsirolimus or prevent the cell death. It is concluded that the synergistic effect is mainly through the necroptotic pathway. In addition, the temsirolimus/YM155 combination lead to a strong reduction in angiogenesis. The biomarkers, CD31 and VEGF, were markedly reduced under combined treatment by immunohistochemical stains of tumor graft. These findings suggest that combined treatment of YM155 and temsirolimus may be considered as a new targeted therapy for renal cell carcinoma that is refractory to surgical intervention and/or chemotherapy, and certainly will open an exciting avenue for further investigation.