Omega-3 Eicosapentaenoic Acid Decreases CD133 Colon Cancer Stem-Like Cell Marker Expression While Increasing Sensitivity to Chemotherapy

Abstract

Colorectal cancer is the third leading cause of cancer-related death in the western world. In vitro and in vivo experiments showed that omega-3 polyunsaturated fatty acids (n-3 PUFAs) can attenuate the proliferation of cancer cells, including colon cancer, and increase the efficacy of various anticancer drugs. However, these studies address the effects of n-3 PUFAs on the bulk of the tumor cells and not on the undifferentiated colon cancer stem-like cells (CSLCs) that are responsible for tumor formation and maintenance. CSLCs have also been linked to the acquisition of chemotherapy resistance and to tumor relapse. Colon CSLCs have been immunophenotyped using several antibodies against cellular markers including CD133, CD44, EpCAM, and ALDH. Anti-CD133 has been used to isolate a population of colon cancer cells that retains stem cells properties (CSLCs) from both established cell lines and primary cell cultures. We demonstrated that the n-3 PUFA, eicosapentaenoic acid (EPA), was actively incorporated into the membrane lipids of COLO 320 DM cells. 25 uM EPA decreased the cell number of the overall population of cancer cells, but not of the CD133 (+) CSLCs. Also, we observed that EPA induced down-regulation of CD133 expression and up-regulation of colonic epithelium differentiation markers, Cytokeratin 20 (CK20) and Mucin 2 (MUC2). Finally, we demonstrated that EPA increased the sensitivity of COLO 320 DM cells (total population) to both standard-of-care chemotherapies (5-Fluorouracil and oxaliplatin), whereas EPA increased the sensitivity of the CD133 (+) CSLCs to only 5-Fluorouracil.

Omega-3 polyunsaturated fatty acids and cancer: lessons learned from clinical trials

“…In the same context, De Carlo et al reported that EPA increases the sensitivity of COLO 320 DM cells to both drugs 5-FU+Oxaliplatin. EPA also increased the sensitivity of the CSLCs-bearing colon cancer marker CD133 to 5-FU [127].…”

Lipidome in colorectal cancer

“…ω3 EPA also decreased markers of CD133 + colon cancer stem-like cells (CSLCs) while increases the sensitivity to chemotherapy [89]. A Phase II double-blind, placebo-controlled trial of EPA-FFA in patients undergoing liver resection surgery for CRC liver metastases (CRCLM) showed that EPA-FFA therapy has antiangiogenic properties and is safe and well tolerated [90].…”

ω3 Polyunsaturated Fatty Acids as Immunomodulators in Colorectal Cancer: New Potential Role in Adjuvant Therapies

“…Thus, novel anticancer strategies have been designed to selectively target CSC, and to this purpose, natural compounds, including ω3 PUFA, might have a relevant role. In colon cancer stem-like cells (CSLC), De Carlo et al showed that EPA has a pre-differentiating effect and this finding could, at least in part, explain the increased cellular sensitivity to 5-FU (82). In keeping with these observations, Yang and colleagues demonstrated that EPA and DHA, in a single or combined treatment, enhanced the chemotherapeutic sensitivity effect of 5-FU and mitomycin C by inducing apoptotic cell death of CSLC (83).…”