Curcumin enhances the effects of 5‐fluorouracil and oxaliplatin in mediating growth inhibition of colon cancer cells by modulating EGFR and IGF‐1R

Abstract

Curcumin (diferuloylmethane), which has been shown to inhibit growth of transformed cells, has no discernible toxicity and achieves high levels in colonic mucosa. 5-fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) remains the backbone of colorectal cancer chemotherapeutics, but with limited success. The present investigation was, therefore, undertaken to examine whether curcumin in combination with conventional chemotherapeutic agent(s)/regimen will be a superior therapeutic strategy for colorectal cancer. Indeed, results of our in vitro studies demonstrated that curcumin together with FOLFOX produced a significantly greater inhibition (p < 0.01) of growth and stimulated apoptosis (p < 0.001) of colon cancer HCT-116 and HT-29 cells than that caused by curcumin, 5-FU, curcumin 1 5-FU or FOLFOX. These changes were associated with decreased expression and activation (tyrosine phosphorylation) of EGFR, HER-2, HER-3 (72-100%) and IGF-1R (67%) as well as their downstream effectors such as Akt and cycloxygenase-2 (51-97%). Furthermore, while these agents produced a 2-3-fold increase in the expression of IGF-binding protein-3 (IGFBP-3), curcumin together with FOLFOX caused a 5-fold increase in the same, when compared to controls. This in turn led to increased sequestration of IGF by IGFBP-3 rendering IGF-1 unavailable for binding to and activation of IGF-1R. We conclude that the superior effects of the combination therapy of curcumin and FOLFOX are due to attenuation of EGFRs and IGF-1R signaling pathways. We also suggest that inclusion of curcumin to the conventional chemotherapeutic agent(s)/regimen could be an effective therapeutic strategy for colorectal cancer. ' 2007 Wiley-Liss, Inc.Key words: colorectal cancer; EGFR; IGF-1R; curcumin; chemotherapy; IGFBP3There will be an estimated 148,610 new cases and 55,170 deaths due to colorectal caner (CRC) in 2006 in the USA. 1 CRC is estimated to be the second and third leading cause of cancerrelated deaths in men and women, respectively, in 2006. 1 Surgery and subsequent chemotherapy can cure over 75% colon cancer patients, but more than 30% of these patients develop new neoplastic polyps, and 10% progress to frank second malignancy. [2][3][4] The risk of second malignancy is higher for microsatellite instable tumor (MSI). 5 Metastatic colorectal cancer has poor a prognosis with 5-year survival of less than 10%. 6 As a result of great efforts are being spent on improving chemotherapeutic interventions for metastatic colon cancer, and the median survival has improved to over 20 months of this group of patients. 7 However, this comes at a cost of additional toxicities, some of which are even fatal. 7 The validation of a nontoxic agent that could improve upon the current chemotherapeutic regimen would therefore be highly desirable.Accumulating evidence suggests that the development and progression of many malignancies, including colorectal cancer, are associated with constitutive activation of multiple signaling pathways that promote proliferation, inhibit apoptosis an...

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Autophagy in colorectal cancer: An important switch from physiology to pathology

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