Abstract
Metastatic colorectal cancer remains a serious health concern with poor patient survival. Although 5-Fluorouracil (5-FU) or 5-FU plus oxaliplatin (FOLFOX) is the standard therapy for colorectal cancer, it has met with limited success. Recurrence of the tumor after chemotherapy could partly be explained by the enrichment of the chemo-resistant sub-population of cancer stem cells (CSCs) that possess the ability for self-renewal and differentiation into different lineages in the tumor. Therefore development of therapeutic strategies that target CSCs for successful treatment of this malignancy is warranted. The current investigation was undertaken to examine the effectiveness of the combination therapy of dasatinib (a Src inhibitor) and curcumin (a dietary agent with pleiotropic effect) in inhibiting the growth and other properties of carcinogenesis of chemo-resistant colon cancer cells that are enriched in CSCs sub-population. Remnants of spontaneous adenomas from APCMin +/- mice treated with dasatinib and/or curcumin were analyzed for several cancer stem cell markers (ALDH, CD44, CD133 and CD166). Human colon cancer cells HCT-116 (p53 wild type; K-ras mutant) and HT-29 (p53 mutant; K-ras wild type) were used to generate FOLFOX resistant (referred to as CR) cells. The effectiveness of the combination therapy in inhibiting growth, invasive potential and stemness was examined in colon cancer CR cells. The residual tumors from APCMin +/- mice treated with dasatinib and/or curcumin showed 80-90% decrease in the expression of the CSC markers ALDH, CD44, CD133, CD166. The colon cancer CR cells showed a higher expression of CSCs markers, cell invasion potential and ability to form colonospheres, compared to the corresponding parental cells. The combination therapy of dasatinib and curcumin demonstrated synergistic interactions in CR HCT-116 and CR HT-29 cells, as determined by Calcusyn analysis. The combinatorial therapy inhibited cellular growth, invasion and colonosphere formation and also reduced CSC population as evidenced by the decreased expression of CSC specific markers: CD133, CD44, CD166 and ALDH. Our data suggest that the combination therapy of dasatinib and curcumin may be a therapeutic strategy for re-emergence of chemo-resistant colon cancer by targeting CSC sub-population.
Highlights
Colorectal cancer, the third most common cancer affecting men and women [1], remains a huge health concern
The combination of dasatinib and curcumin is effective in inhibiting cancer stem cell population in remnants of spontaneous adenomas Currently, cancer stem cells (CSCs) are identified by specific surface epitopes
We have recently reported that dasatinib in combination with curcumin is highly effective in inhibiting cellular growth and transformation properties in vitro and induces regression of over 90% of the spontaneous intestinal adenomas in APCMin+/- mice [30]
Summary
Colorectal cancer, the third most common cancer affecting men and women [1], remains a huge health concern. It is the second most common cause of cancer-related deaths in the United States and other developed countries. Most of the colon cancer deaths results from the metastatic spread of chemotherapy-resistant cells to the liver and other organs [4] and metastasis remains a poor prognostic indicator [5]. Distinct and relatively rare populations of tumor-initiating cells or CSCs have been detected by several methods and markers established in a variety of cancers, including the colon [11,12,13]. Development of therapeutic strategies that target CSCs is warranted in reducing the risk of relapse and metastasis
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