Curcumin (
diferuloylmethane), which has no discernible toxicity, inhibits initiation, promotion and progression of
carcinogenesis.
5-Fluorouracil (5-FU) or
5-FU plus
oxaliplatin (FOLFOX) remains the backbone of
colorectal cancer chemotherapeutics, but produces an incomplete response resulting in survival of cells (chemo-surviving cells) that may lead to
cancer recurrence. The present investigation was, therefore, undertaken to examine whether addition of
curcumin to FOLFOX is a superior therapeutic strategy for chemo-surviving cells. Forty-eight-hour treatment of
colon cancer HCT-116 and HT-29 cells with FOLFOX resulted in 60-70% survival, accompanied by a marked activation of
insulin like growth factor-1 receptor (IGF-1R) and minor to moderate increase in
epidermal growth factor receptor (EGFR), v-erb-b2 erythroblastic
leukemia viral oncogene homolog 2 (HER-2) as well as v-akt murine
thymoma viral oncogene homolog 1 (AKT),
cyclooxygenase-2 (COX-2) and cyclin-D1. However, inclusion of
curcumin to continued FOLFOX treatment for another 48 h greatly reduced the survival of these cells, accompanied by a concomitant reduction in activation of EGFR, HER-2, IGF-1R and AKT, as well as expression of COX-2 and cyclin-D1. More importantly, EGFR
tyrosine kinase inhibitor gefitinib or attenuation of IGF-1R expression by the corresponding si-
RNA caused a 30-60% growth inhibition of chemo-surviving HCT-116 cells. However,
curcumin alone was found to be more effective than both
gefitinib and IGF-1R si-
RNA mediated growth inhibition of chemo-surviving HCT-116 cells and addition of FOLFOX to
curcumin did not increase the growth inhibitory effect of
curcumin. Our data suggest that inclusion of
curcumin in conventional chemotherapeutic regimens could be an effective strategy to prevent the emergence of chemoresistant
colon cancer cells.