Abstract:
Renal cell carcinoma (RCC) is the most difficult-to-treat form of kidney cancer with a median 5-year survival of 10% under metastatic setting. Although cytoreductive nephrectomy is common, approximately 20–30% of patients will develop recurrent cancer after surgery, which highlights the need for an effective therapy. We therefore have elucidated the role of Ketorolac, a modulator Rho-GTPases against RCC through potentiation of tumor suppressor Par-4. The effect of Ketorolac alone and in combination with Sunitinib on proliferation, apoptosis, cell-cycle progression, migration, tumor inhibition and their related markers were studied. Moreover, Ketorolac’s impact on metastasis by influencing Rac-1/HIF-1α/DDX3/β-catenin signalling was studied with respect to its ability to modulate the expression of tumor suppressor Par-4 and this mechanism was confirmed by siRNA knockdown studies. Ketorolac caused significant down regulation of proliferation (Ki-67, Cyclin D1, pRB and DDX3), migration/invasion (Rac-1, Cdc42, and Tiam1), and angiogenesis (HIF-1α and VEGF) markers as studied by gene and protein expression. Importantly, Ketorolac alone and in combination with Sunitinib showed tumor growth inhibition (TGI) of 73% and 86% respectively in xenograft model. This anti-tumor activity was further corroborated by down regulation of Rac-1/ Cdc42/HIF-1α/DDX3/β-catenin signalling. This is the first report which implicates the role of Ketorolac against RCC by acting as a small molecule secretagogue causing upregulation of Par-4 in autocrine and paracrine manner. Consequently, these findings suggest that Par-4 can serve as a valuable therapeutic target and a prognostic marker for the treatment of RCC.
Audience Take Away Notes:
- This presentation will aid the audience to understand the path followed to identify drugs which can be repurposed for indications other than the approved ones
- De novo drug development is a lengthy, complex and costly process. Understanding the path to be followed for identification of approved drugs that can be repurposed can help conserve efforts, resources and at the same time shortening the period for approvals
- Our study has led to the identification of a new mechanism of action of Ketorolac as a Par-4 secretagouge. Par-4, which is a pro-apoptotic factor that brings about its action by both autocrine and paracrine manner is down-regulated in several cancers. Therefore, we think that Par-4 can serve as a valuable therapeutic and prognostic marker not only for RCC but for other solid tumors too
- Using this information More randomised clinical trials could be undertaken to prove their efficacy, and thus reduce financial burden on stressed health systems, particularly in poorer economies
