Combined Treatment with CCI779 and SB203580 Induces Cellular Senescence in Renal Cell Carcinoma Cell Line via p53 Pathway

BACKGROUND: Renal cell carcinoma (RCC) is one of the most common neoplasms that occurs in the kidney and is marked by a unique biology, with a long history of poor response to conventional cancer treatments. In recent years, there have been significant advancements implemented to understanding the biology of RCC, which has led to the introduction of novel targeted therapies in the management of patients with metastatic disease. OBJECTIVE: The present study was designed to evaluate the effects of p38 MAPK inhibitor (SB203580), alone and in combination with mTOR inhibitor (CCI779) on apoptosis and cell proliferation. METHOD: Subtoxic concentrations of inhibitors were selected by MTT assay using A-498, ACHN and primary culture of RCC. RESULTS: All the three types of RCC cells had almost similar response towards these inhibitors. The results revealed that 25µM of SB203580 and 20µM of CCI779 at 48 hrs decreased cell viability by 20% and 30%, respectively, whereas the combination of both inhibitors showed a maximum of 40% reduction in cell viability. CONCLUSION: The study concludes that the combination of SB203580 and CCI779 inhibitors may induce cellular senescence in A-498 cells with higher potency than that of individual inhibitors.