The novel anti-cancer agent curcumin induces cytotoxicity in pancreatic cancer cell lines in vitro

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 5673 Pancreatic adenocarcinoma is the fifth leading cause of death from cancer. This cancer is responsible for a death rate which almost equals the incidence rate. Presently, patients can expect a very poor 12-month survival rate of approximately 10%, dropping to 3% for 5-year survival rate post-treatment. In light of this, novel anti-cancer therapeutics are now being investigated. One novel drug of particular interest is the plant derivative curcumin from Curcuma longa . As an initial investigation into the anti-tumour effects of curcumin against the pancreatic cancer cell lines PANC-1, MIA-PaCa-2 and Colo357, we employed the MTT cytotoxicity and [3H]-thymidine proliferation assays to establish if cytotoxicity was induced after incubation with increasing concentration of drug (0.75-250μM) over 16, 24 and 48 hours at 37oC. Cell death due to curcumin exposure was found to increase in both a dose and time-dependent manner in all cell lines. In contrast, no cytotoxic effects were seen with normal cells such as peripheral blood mononuclear cells. Following this, we used AnnexinV/PI staining and flow cytometry to study if cell death due to curcumin was via necrosis or apoptosis. Apoptosis was found to occur and increase with increasing concentration of curcumin. In both assays and with all cell lines, curcumin was found to be up to 200 times more effective than gemcitabine according to IC50 data obtained from proliferation assays. To continue the study of this agent, we have done an initial microarray analysis on Colo357 cells to discover which genes are up- and down-regulated by short-term, low dose curcumin exposure (5μM, 4h incubation at 37oC). Among genes that were upregulated were genes relating to tumour suppression such as SMAD4, involved in modulation of TGFβ and Wnt signaling, and genes relating to increased anti-tumour immune response such as CD1d, the ligand for NKT cells. Also there was downregulation of immunomodulatory genes such as HLA-G, which provide a possible escape from immunosurveillance. Currently we are looking at the ability of curcumin to halt invasion of pancreatic cancer cells using an in vitro Matrigel invasion assay. We are also investigating possible synergy of this drug with other novel and existing chemotherapeutics. Further work will include RT-PCR and Western blot to support Microarray results.