PMID- 28355296 OWN - NLM STAT- MEDLINE DCOM- 20170905 LR - 20181202 IS - 1932-6203 (Electronic) IS - 1932-6203 (Linking) VI - 12 IP - 3 DP - 2017 TI - Tetraarsenic hexoxide induces G2/M arrest, apoptosis, and autophagy via PI3K/Akt suppression and p38 MAPK activation in SW620 human colon cancer cells. PG - e0174591 LID - 10.1371/journal.pone.0174591 [doi] LID - e0174591 AB - 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, DeltaPsim) 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. FAU - Nagappan, Arulkumar AU - Nagappan A AD - Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, 90 Chilam-dong Jinju, Korea. FAU - Lee, Won Sup AU - Lee WS AD - Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, 90 Chilam-dong Jinju, Korea. FAU - Yun, Jeong Won AU - Yun JW AD - Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, 90 Chilam-dong Jinju, Korea. FAU - Lu, Jing Nan AU - Lu JN AD - Department of Internal Medicine, Institute of Health Sciences, Gyeongsang National University School of Medicine, 90 Chilam-dong Jinju, Korea. FAU - Chang, Seong-Hwan AU - Chang SH AD - Department of Surgery, Konkuk University School of Medicine, Seoul, Korea. FAU - Jeong, Jae-Hoon AU - Jeong JH AD - Research Center for Radiotherapy, Korea Institute of Radiological and Medical Sciences, Seoul, Korea. FAU - Kim, Gon Sup AU - Kim GS AD - Research Institute of Life Science and College of Veterinary Medicine, Gyeongsang National University, 900 Gajwadong, Jinju, Korea. FAU - Jung, Jin-Myung AU - Jung JM AD - Department of Neurosurgery, Institute of Health Sciences, Gyeongsang National University School of Medicine, 90 Chilam-dong Jinju, Korea. FAU - Hong, Soon Chan AU - Hong SC AD - Department of Surgery, Institute of Health Sciences, Gyeongsang National University School of Medicine, 90 Chilam-dong Jinju, Korea. LA - eng PT - Journal Article DEP - 20170329 PL - United States TA - PLoS One JT - PloS one JID - 101285081 RN - 0 (Antineoplastic Agents) RN - 0 (Arsenicals) RN - 0 (CDKN1A protein, human) RN - 0 (Cyclin-Dependent Kinase Inhibitor p21) RN - 0 (Oxides) RN - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand) RN - 136601-57-5 (Cyclin D1) RN - EC 2.7.1.- (Phosphatidylinositol 3-Kinases) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.22 (CDC2 Protein Kinase) RN - EC 2.7.11.22 (CDK1 protein, human) RN - EC 2.7.11.22 (Cyclin-Dependent Kinases) RN - EC 2.7.11.24 (p38 Mitogen-Activated Protein Kinases) RN - S7V92P67HO (Arsenic Trioxide) SB - IM MH - Antineoplastic Agents/pharmacology MH - Apoptosis/*drug effects MH - Arsenic Trioxide MH - Arsenicals/*pharmacology MH - Autophagy/*drug effects MH - Blotting, Western MH - CDC2 Protein Kinase MH - Cell Line, Tumor MH - Cell Survival/drug effects MH - Colonic Neoplasms/metabolism/pathology MH - Cyclin D1/metabolism MH - Cyclin-Dependent Kinase Inhibitor p21/metabolism MH - Cyclin-Dependent Kinases/metabolism MH - Dose-Response Relationship, Drug MH - Enzyme Activation/drug effects MH - G2 Phase Cell Cycle Checkpoints/*drug effects MH - Humans MH - Membrane Potential, Mitochondrial/drug effects MH - Oxides/*pharmacology MH - Phosphatidylinositol 3-Kinases/*metabolism MH - Proto-Oncogene Proteins c-akt/*metabolism MH - Receptors, TNF-Related Apoptosis-Inducing Ligand/metabolism MH - Time Factors MH - p38 Mitogen-Activated Protein Kinases/*metabolism PMC - PMC5371332 COIS- Competing Interests: The authors have declared that no competing interests exist. EDAT- 2017/03/30 06:00 MHDA- 2017/09/07 06:00 PMCR- 2017/03/29 CRDT- 2017/03/30 06:00 PHST- 2016/11/17 00:00 [received] PHST- 2017/03/11 00:00 [accepted] PHST- 2017/03/30 06:00 [entrez] PHST- 2017/03/30 06:00 [pubmed] PHST- 2017/09/07 06:00 [medline] PHST- 2017/03/29 00:00 [pmc-release] AID - PONE-D-16-45678 [pii] AID - 10.1371/journal.pone.0174591 [doi] PST - epublish SO - PLoS One. 2017 Mar 29;12(3):e0174591. doi: 10.1371/journal.pone.0174591. eCollection 2017.