Effect of diferuloyl methane (curcumin) on radiation-induced inhibition of proliferation and cytotoxicity of pancreatic cancer cells.

Abstract

222 Background: Pancreatic ductal adenocarcinoma carries a dismal prognosis. Unfortunately, the majority of patients present with locally advanced or metastatic disease unamenable to resection, and the benefit of radiation therapy (RT) in this population is not well substantiated. Diferuloyl methane (curcumin) is a naturally occurring polyphenol derived from the spice turmeric. Although it has been shown to have anticancer properties, it has not been well studied with radiation, particularly for pancreatic cancer. Herein, we attempt to determine whether curcumin can sensitize pancreatic cancer cells to radiation. Methods: The pancreatic carcinoma cell lines, MiaPaCa-2 and Panc02, were utilized for studies. Cells were treated with curcumin (10 nM to 1 mM), RT (1 to 9 Gy), or combinations thereof and compared to untreated controls. Cells were irradiated using a 137-Cs GammaCell in a single fraction. If applicable, cells were pretreated with curcumin one hour prior to RT. Cell viability was assessed through reduction of resazurin into fluorescent resorufin. Levels of apoptosis were determined by measuring caspase-3 and -7 activities using a luminescent assay. Results: Treatment with curcumin alone led to minimal inhibition of proliferation until concentrations exceeded 10 uM. The half maximal inhibitory concentration (IC50) was 40 uM and the IC20 was 10 uM. Cells experienced a dose- dependent inhibition of proliferation with increasing RT doses (IC20 of 5 Gy). Combined treatment with IC20 of curcumin and RT led to a synergistic increase in inhibition of proliferation (70%). The RT dose enhancement factor was 2.5 with 100 uM curcumin and 5 Gy. Caspase 3/7 activity was not significantly enhanced by treatment with curcumin alone (10 uM), but increased significantly when RT was added (5 Gy; p<.01). Conclusions: Curcumin is a potent radiosensitizer of pancreatic cancer cells that synergistically enhances the effects of RT. It has minimal effects on proliferation and apoptosis when used as a single agent at lower doses. Curcumin also potentiates RT-induced cytotoxicity through induction of apoptosis. These data are currently being validated in an orthotopic pancreatic cancer model. No significant financial relationships to disclose.