title: Resistance to 3-HTMC-Induced Apoptosis Through Activation of PI3K/Akt, MEK/ERK, and p38/COX-2/PGE2Pathways in Human HT-29 and HCT116 Colorectal Cancer Cells.
abstract: Increasing incidence and mortality of colorectal cancer brings the necessity to uncover new possibilities in its prevention and treatment. Chalcones have been identified as interesting compounds having chemopreventive and antitumor properties. In this study, we investigated the effects of the synthetic chalcone derivative 3-hydroxy-3',4,4',5'-tetra-methoxy-chalcone (3-HTMC) on proliferation, cell cycle distribution, apoptosis, and its mechanism of action in human colorectal HT-29 (COX-2 sufficient) and HCT116 (COX-2 deficient) cancer cells. We showed that 3-HTMC decreased cell viability in a dose-dependent manner with a more potent antiproliferative effect on HCT116 than HT-29 cells. Flow cytometric analysis revealed G2/M cell cycle accumulation in HT-29 cells and significant G2/M arrest in HCT116 cells with a subsequent apoptosis shown by appearance of Sub-G1 peak. We demonstrated that 3-HTMC treatment on both cell lines induced apoptotic process associated with overexpression of death receptor DR5, activation of caspase-8 and -3, PARP cleavage, and DNA fragmentation. In addition, 3-HTMC induced activation of PI3K/Akt and MEK/ERK principal survival pathways which delay 3-HTMC-induced apoptosis in both cell lines. Furthermore, COX-2 overexpression in HT-29 cells contributes to apoptosis resistance which explains the difference of sensitivity between HT-29 and HCT116 cells to 3-HTMC treatment. Even if resistance mechanisms to apoptosis reduced chalcone antitumoral potential, our results suggest that 3-HTMC may be considered as an interesting compound for colorectal cancer therapy or chemoprevention. J. Cell. Biochem. 117: 2875-2885, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France.
authors.forename: Josiane
authors.initials: J
authors.lastname: Semaan
authors.affiliation: Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France.
authors.forename: Aline
authors.initials: A
authors.lastname: Pinon
authors.affiliation: Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Rioux
authors.affiliation: Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France.
authors.forename: Lama
authors.initials: L
authors.lastname: Hassan
authors.affiliation: Laboratoire National de Référence (LNR), Université Mohammed VI des Sciences de la Santé, Casablanca, Royaume du Maroc.
authors.forename: Youness
authors.initials: Y
authors.lastname: Limami
authors.affiliation: Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Pouget
authors.affiliation: Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Fagnère
authors.affiliation: Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Sol
authors.affiliation: Molecular Tumorigenesis and Anticancer Pharmacology, EDST, Lebanese University, Hadath, Lebanon.
authors.forename: Mona
authors.initials: M
authors.lastname: Diab-Assaf
authors.affiliation: Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Simon
authors.affiliation: Laboratory of Chemistry of Natural Substances, Faculty of Pharmacy, University of Limoges, FR 3503 GEIST, EA1069, Limoges, France. bertrand.liagre@unilim.fr.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Liagre
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002599:Chalcone / Q000494:pharmacology*; D047188:Chalcones / Q000494:pharmacology*; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C000621985:3-hydroxy-3',4,4',5'-tetramethoxychalcone; D000970:Antineoplastic Agents; D047188:Chalcones; D002599:Chalcone; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human; D015232:Dinoprostone
keywords: 3-HTMC; APOPTOSIS; COLORECTAL CANCER; COX-2; ERK; PI3K/Akt