Towards development of a novel anti-cancer agent in the treatment of kidney cancer

Kidney cancer incidence rates are projected to rise by 26% between 2014 and 2035 (1). Current treatment regimes are ineffective against late stage kidney cancer, therefore novel therapies are required. Curcumin has previously been shown to have a cancer specific cytotoxicity due to its direct effect on cell death-regulating machinery including miRNAs, cell cycle proteins, cell survival signaling (2). Curcumin also induces cell death via caspase dependent and independent mechanisms. It has been found that curcumin at low doses induces apoptosis by down regulation of proteasomes and increasing the level of ROS. While at high doses, it reduces ROS and ATP levels, and induces necrotic cell death (3). Curcumin was also found to sensitize cancer cells to TRAIL-induced apoptosis. TRAIL is a cytokine that is produced by immune cells as part of an anti-cancer immune surveillance (4). However many cancer cells can become resistant to TRAIL induced apoptosis. Some phytochemicals have been shown re-sensitize cancer cells to TRAIL cytotoxicity. A study by Park et al found that targeting breast cancer cells with curcumin plus TRAIL synergistically induced cell death via induction of ROS and downregulation of anti-apoptotic proteins such as IAP, Mcl-1, Akt, and ERK (5). Other studies have shown that curcumin sensitizes cancer cells to TRAIL via ROS-dependent upregulation of TRAIL receptors (6,7). Recent research in our laboratory has also indicated the potential for curcumin to protect normal cells against carcinogenic effects (8).

The overall aim of the work is to investigate the anticancer potential of a phytochemical (curcumin) compound. The molecular and functional mechanisms of the anticancer effect of curcumin will be investigated. The anticancer effect of curcumin will also be investigated in an animal model. Furthermore, a PCR array of inflammatory genes will be analysed using samples from curcumin treated kidney cancer cells. Genes identified will be investigated further as potential novel therapeutic strategies in the ACHN kidney cancer model and also in vivo using xenotransplanation techniques in zebrafish.