title: Tetraarsenic hexoxide induces G2/M arrest, apoptosis, and autophagy via PI3K/Akt suppression and p38 MAPK activation in SW620 human colon cancer cells.
abstract: Tetraarsenic hexoxide (As4O6) has been used in Korean folk medicines for the treatment of cancer, however its anti-cancer mechanisms remain obscured. Here, this study investigated the anti-cancer effect of As4O6 on SW620 human colon cancer cells. As4O6 has showed a dose-dependent inhibition of SW620 cells proliferation. As4O6 significantly increased the sub-G1 and G2/M phase population, and Annexin V-positive cells in a dose-dependent manner. G2/M arrest was concomitant with augment of p21 and reduction in cyclin B1, cell division cycle 2 (cdc 2) expressions. Nuclear condensation, cleaved nuclei and poly (adenosine diphosphate‑ribose) polymerase (PARP) activation were also observed in As4O6-treated SW620 cells. As4O6 induced depolarization of mitochondrial membrane potential (MMP, ΔΨm) but not reactive oxygen species (ROS) generation. Further, As4O6 increased death receptor 5 (DR5), not DR4 and suppressed the B‑cell lymphoma‑2 (Bcl-2) and X-linked inhibitor of apoptosis protein (XIAP) family proteins. As4O6 increased the formation of AVOs (lysosomes and autophagolysosomes) and promoted the conversion of microtubule-associated protein 1A/1B-light chain 3 (LC3)-I to LC3-II in a dose- and time- dependent manner. Interestingly, a specific phosphoinositide 3-kinase (PI3K)/Akt inhibitor (LY294002) augmented the As4O6 induced cell death; whereas p38 mitogen-activated protein kinases (p38 MAPK) inhibitor (SB203580) abrogated the cell death. Thus, the present study provides the first evidence that As4O6 induced G2/M arrest, apoptosis and autophagic cell death through PI3K/Akt and p38 MAPK pathways alteration in SW620 cells.
authors.affiliation: Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, 90 Chilam-dong Jinju, Korea.
authors.forename: Arulkumar
authors.initials: A
authors.lastname: Nagappan
authors.affiliation: Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, 90 Chilam-dong Jinju, Korea.
authors.forename: Won Sup
authors.initials: WS
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, 90 Chilam-dong Jinju, Korea.
authors.forename: Jeong Won
authors.initials: JW
authors.lastname: Yun
authors.affiliation: Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, 90 Chilam-dong Jinju, Korea.
authors.forename: Jing Nan
authors.initials: JN
authors.lastname: Lu
authors.affiliation: Department of Surgery, Konkuk University School of Medicine, Seoul, Korea.
authors.forename: Seong-Hwan
authors.initials: SH
authors.lastname: Chang
authors.affiliation: Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, Korea.
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Jeong
authors.affiliation: Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, 900 Gajwadong, Jinju, Korea.
authors.forename: Gon Sup
authors.initials: GS
authors.lastname: Kim
authors.affiliation: Department of Neurosurgery, Institute of Health Sciences, Gyeongsang National University School of Medicine, 90 Chilam-dong Jinju, Korea.
authors.forename: Jin-Myung
authors.initials: JM
authors.lastname: Jung
authors.affiliation: Department of Surgery, Institute of Health Sciences, Gyeongsang National University School of Medicine, 90 Chilam-dong Jinju, Korea.
authors.forename: Soon Chan
authors.initials: SC
authors.lastname: Hong
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D016203:CDC2 Protein Kinase; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000378:metabolism / Q000473:pathology; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010087:Oxides / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D013997:Time Factors; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D010087:Oxides; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D019938:Cyclin D1; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077237:Arsenic Trioxide