title: Omega-3 fatty acid is a potential preventive agent for recurrent colon cancer.
abstract: Increasing evidence supports the contention that many malignancies, including sporadic colorectal cancer, are driven by the self-renewing, chemotherapy-resistant cancer stem/stem-like cells (CSC/CSLC), underscoring the need for improved preventive and therapeutic strategies targeting CSCs/CSLCs. Omega-3 polyunsaturated fatty acids (ω-3 PUFA), have been reported to inhibit the growth of primary tumors, but their potential as a preventive agent for recurring cancers is unexplored. The primary objectives of this investigation are (i) to examine whether eicosapentaenoic acid (EPA; one of the ω-3 PUFA) synergizes with FuOx (5-FU+Oxaliplatin), the backbone of colon cancer chemotherapy, and (ii) whether EPA by itself or in combination with conventional chemotherapy prevents the recurrence of colon cancer via eliminating/suppressing CSCs/CSLCs. FuOx-resistant (chemoresistant; CR) colon cancer cells, highly enriched in CSCs, were used for this study. Although EPA alone was effective, combination of EPA and FuOx was more potent in (i) inhibiting cell growth, colonosphere formation, and sphere-forming frequency, (ii) increasing sphere disintegration, (iii) suppressing the growth of SCID mice xenografts of CR colon cancer cells, and (iv) decreasing proinflammatory metabolites in mice. In addition, EPA + FuOx caused a reduction in CSC/CSLC population. The growth reduction by this regimen is the result of increased apoptosis as evidenced by PARP cleavage. Furthermore, increased pPTEN, decreased pAkt, normalization of β-catenin expression, localization, and transcriptional activity by EPA suggests a role for the PTEN-Akt axis and Wnt signaling in regulating this process. Our data suggest that EPA by itself or in combination with FuOx could be an effective preventive strategy for recurring colorectal cancer.
authors.affiliation: Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan.
authors.forename: Anita
authors.initials: A
authors.lastname: Vasudevan
authors.affiliation: Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan. Department of Internal Medicine, Wayne State University, Detroit, Michigan.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Yu
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, Michigan. Department of Pathology, Wayne State University, Detroit, Michigan.
authors.forename: Sanjeev
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan.
authors.forename: James
authors.initials: J
authors.lastname: Woods
authors.affiliation: Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan. Department of Internal Medicine, Wayne State University, Detroit, Michigan.
authors.forename: Lulu
authors.initials: L
authors.lastname: Farhana
authors.affiliation: Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan.
authors.forename: Sindhu G
authors.initials: SG
authors.lastname: Rajendra
authors.affiliation: Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan.
authors.forename: Aamil
authors.initials: A
authors.lastname: Patel
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, Michigan.
authors.forename: Gregory
authors.initials: G
authors.lastname: Dyson
authors.affiliation: Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan. Department of Pathology, Wayne State University, Detroit, Michigan.
authors.forename: Edi
authors.initials: E
authors.lastname: Levi
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, Michigan. Department of Pathology, Wayne State University, Detroit, Michigan. Lipidomics Core Facility, Wayne State University, Detroit, Michigan.
authors.forename: Krishna Rao
authors.initials: KR
authors.lastname: Maddipati
authors.affiliation: Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan. Department of Internal Medicine, Wayne State University, Detroit, Michigan. Karmanos Cancer Institute, Wayne State University, Detroit, Michigan. a.majumdar@wayne.edu makkerp@karmanos.org.
authors.forename: Adhip P N
authors.initials: AP
authors.lastname: Majumdar
authors.affiliation: Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan. Department of Internal Medicine, Wayne State University, Detroit, Michigan. Karmanos Cancer Institute, Wayne State University, Detroit, Michigan. a.majumdar@wayne.edu makkerp@karmanos.org.
authors.forename: Pratima
authors.initials: P
authors.lastname: Nangia-Makker
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D003106:Colon / Q000473:pathology; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D015118:Eicosapentaenoic Acid / Q000494:pharmacology; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D007249:Inflammation; D051379:Mice; D016513:Mice, SCID; D009364:Neoplasm Recurrence, Local; D014411:Neoplastic Stem Cells / Q000166:cytology; D009944:Organoplatinum Compounds / Q000008:administration & dosage; D000077150:Oxaliplatin; D010641:Phenotype; D012008:Recurrence; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism
chemical_list: D016588:Anticarcinogenic Agents; D014408:Biomarkers, Tumor; D015525:Fatty Acids, Omega-3; D009944:Organoplatinum Compounds; D051176:beta Catenin; D000077150:Oxaliplatin; D015118:Eicosapentaenoic Acid; D005472:Fluorouracil