Regorafenib Enhances Lethality of Sildenafil and Curcumin in Colorectal Cancer Cells

In the United States, more than 130,000 people will be diagnosed with colorectal cancer (CRC) each year and an estimated 50,000 people will die from the disease. Standard of care (SOC) therapies for CRC combine multiple cytotoxic chemotherapeutic drugs. These combinations have varying degrees of effectiveness and can often result in significant patient morbidity. For second recurrence patients, the multi-kinase inhibitor, regorafenib, is an approved agent, but is often poorly tolerated at current doses. In the current study, we propose to develop therapeutic regime of combining agents with modest toxicity profiles: curcumin and sildenafil with regorafenib. Using clinically achievable enterohepatic drug concentrations (~2.0 μM), our laboratory has shown that both sildenafil and curcumin interact to synergistically down regulate the expression of multiple cyto-protective molecular chaperones and kill CRC cells in a greater than additive manner in vitro and suppress the growth of colon cancer tumors in vivo. In this study, the expression of PDGFRb and PDGF in the plasma was increased in colon tumor bearing mice previously exposed to curcumin and sildenafil. Further, the in vitro killing potential of curcumin and sildenafil was shown to be reduced in evolved tumor cells from these mice. The purpose of this study was to determine whether down regulation of PDGFRb using regorafenib would increase the lethality of curcumin and sildenafil in colorectal cancer cell lines in vitro and in vivo. In the current study, we have shown that with the [2μM curcumin + 2μM sildenafil + 2μM regorafenib] drug combination reduces of cyto-protective proteins, enhances cytotoxicity and creates a carnage of CRC cells in a greater than additive in vitro. The combination also suppressed growth of colon cancer tumors in vivo, when compared to curcumin and sildenafil alone. In addition we have shown that the [2μM curcumin + 2μM sildenafil + 2μM regorafenib] drug combination can modulate immune checkpoint proteins in vitro. These results suggest that this drug combination may enhanced the anti-tumor efficacy of anti-PD-1 and anti-CTLA4 antibodies