Tetraarsenic Hexoxide Induces G2/M Arrest, Apoptosis, and Autophagy Via PI3K/Akt Suppression and P38 MAPK Activation in SW620 Human Colon Cancer Cells

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2017 Mar 30

PMID 28355296

Citations 24

Authors

Arulkumar Nagappan

Won Sup Lee

Jeong Won Yun

Jing Nan Lu

Seong-Hwan Chang

Jae-Hoon Jeong

Gon Sup Kim

Jin-Myung Jung

Soon Chan Hong

Affiliations

Soon will be listed here.

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.

Citing Articles

The protective role of baicalin regulation of autophagy in cancers.

Zhang Q, Guo S, Ge H, Wang H Cytotechnology. 2025; 77(1):33.

PMID: 39760060 PMC: 11699138. DOI: 10.1007/s10616-024-00689-0.

Bioinformatics led discovery of biomarkers related to immune infiltration in diabetes nephropathy.

Wang S, Chen S, Gao Y, Zhou H Medicine (Baltimore). 2023; 102(35):e34992.

PMID: 37656997 PMC: 10476789. DOI: 10.1097/MD.0000000000034992.

Carnosol Induces p38-Mediated ER Stress Response and Autophagy in Human Breast Cancer Cells.

Alsamri H, Alneyadi A, Muhammad K, Ayoub M, Eid A, Iratni R Front Oncol. 2022; 12:911615.

PMID: 35712465 PMC: 9194514. DOI: 10.3389/fonc.2022.911615.

Targeting Cell Death Mechanism Specifically in Triple Negative Breast Cancer Cell Lines.

Pruteanu L, Braicu C, Modos D, Jurj M, Raduly L, Zanoaga O Int J Mol Sci. 2022; 23(9).

PMID: 35563174 PMC: 9099741. DOI: 10.3390/ijms23094784.

New Diterpenoids from with Antiproliferative Activities Modulate Cell Cycle Arrest and Apoptosis in Human Leukemia Cancer Cells.

Huang H, Liaw C, Lin Y, Liao G, Chao C, Chiou C Pharmaceuticals (Basel). 2021; 14(11).

PMID: 34832890 PMC: 8622523. DOI: 10.3390/ph14111108.

References

Thorburn A . Apoptosis and autophagy: regulatory connections between two supposedly different processes. Apoptosis. 2007; 13(1):1-9. PMC: 2601595. DOI: 10.1007/s10495-007-0154-9. View

Park J, Choi Y, Jang M, Baek S, Lim J, Passaniti T . Arsenic trioxide induces G2/M growth arrest and apoptosis after caspase-3 activation and bcl-2 phosphorylation in promonocytic U937 cells. Biochem Biophys Res Commun. 2001; 286(4):726-34. DOI: 10.1006/bbrc.2001.5416. View

Robinson M, Cobb M . Mitogen-activated protein kinase pathways. Curr Opin Cell Biol. 1997; 9(2):180-6. DOI: 10.1016/s0955-0674(97)80061-0. View

De Castro L, Zacharias M . DAPI binding to the DNA minor groove: a continuum solvent analysis. J Mol Recognit. 2002; 15(4):209-20. DOI: 10.1002/jmr.581. View

Munoz-Gamez J, Rodriguez-Vargas J, Quiles-Perez R, Aguilar-Quesada R, Martin-Oliva D, de Murcia G . PARP-1 is involved in autophagy induced by DNA damage. Autophagy. 2008; 5(1):61-74. DOI: 10.4161/auto.5.1.7272. View

Chen G, Zhu J, Shi X, Ni J, Zhong H, Si G . In vitro studies on cellular and molecular mechanisms of arsenic trioxide (As2O3) in the treatment of acute promyelocytic leukemia: As2O3 induces NB4 cell apoptosis with downregulation of Bcl-2 expression and modulation of PML-RAR alpha/PML proteins. Blood. 1996; 88(3):1052-61. View

Zhang X, Jia S, Yang S, Yang Y, Yang T, Yang Y . Arsenic trioxide induces G2/M arrest in hepatocellular carcinoma cells by increasing the tumor suppressor PTEN expression. J Cell Biochem. 2012; 113(11):3528-35. DOI: 10.1002/jcb.24230. View

Chiruvella K, Kari V, Choudhary B, Nambiar M, Ghanta R, Raghavan S . Methyl angolensate, a natural tetranortriterpenoid induces intrinsic apoptotic pathway in leukemic cells. FEBS Lett. 2008; 582(29):4066-76. DOI: 10.1016/j.febslet.2008.11.001. View

Wang S, El-Deiry W . TRAIL and apoptosis induction by TNF-family death receptors. Oncogene. 2003; 22(53):8628-33. DOI: 10.1038/sj.onc.1207232. View

10.

Kang Y, Yi M, Kim M, Park M, Bae S, Kang C . Caspase-independent cell death by arsenic trioxide in human cervical cancer cells: reactive oxygen species-mediated poly(ADP-ribose) polymerase-1 activation signals apoptosis-inducing factor release from mitochondria. Cancer Res. 2004; 64(24):8960-7. DOI: 10.1158/0008-5472.CAN-04-1830. View

11.

Wang R, Zhang Q, Peng X, Zhou C, Zhong Y, Chen X . Stellettin B Induces G1 Arrest, Apoptosis and Autophagy in Human Non-small Cell Lung Cancer A549 Cells via Blocking PI3K/Akt/mTOR Pathway. Sci Rep. 2016; 6:27071. PMC: 4886687. DOI: 10.1038/srep27071. View

12.

Srivastava S, Somasagara R, Hegde M, Nishana M, Tadi S, Srivastava M . Quercetin, a Natural Flavonoid Interacts with DNA, Arrests Cell Cycle and Causes Tumor Regression by Activating Mitochondrial Pathway of Apoptosis. Sci Rep. 2016; 6:24049. PMC: 4828642. DOI: 10.1038/srep24049. View

13.

Van Cutsem E, Cervantes A, Nordlinger B, Arnold D . Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014; 25 Suppl 3:iii1-9. DOI: 10.1093/annonc/mdu260. View

14.

Jung K, Won Y, Oh C, Kong H, Cho H, Lee D . Prediction of cancer incidence and mortality in Korea, 2015. Cancer Res Treat. 2015; 47(2):142-8. PMC: 4398104. DOI: 10.4143/crt.2015.066. View

15.

Chang H, Bae S, Kim Y, Kwak S, Min H, Bae I . Comparison of diarsenic oxide and tetraarsenic oxide on anticancer effects: relation to the apoptosis molecular pathway. Int J Oncol. 2007; 30(5):1129-35. View

16.

Mitsiades C, Mitsiades N, Koutsilieris M . The Akt pathway: molecular targets for anti-cancer drug development. Curr Cancer Drug Targets. 2004; 4(3):235-56. DOI: 10.2174/1568009043333032. View

17.

Qian W, Liu J, Jin J, Ni W, Xu W . Arsenic trioxide induces not only apoptosis but also autophagic cell death in leukemia cell lines via up-regulation of Beclin-1. Leuk Res. 2006; 31(3):329-39. DOI: 10.1016/j.leukres.2006.06.021. View

18.

Wong W, Puthalakath H . Bcl-2 family proteins: the sentinels of the mitochondrial apoptosis pathway. IUBMB Life. 2008; 60(6):390-7. DOI: 10.1002/iub.51. View

19.

Nutt L, Gogvadze V, Uthaisang W, Mirnikjoo B, McConkey D, Orrenius S . Indirect effects of Bax and Bak initiate the mitochondrial alterations that lead to cytochrome c release during arsenic trioxide-induced apoptosis. Cancer Biol Ther. 2005; 4(4):459-67. DOI: 10.4161/cbt.4.4.1652. View

20.

Borutaite V . Mitochondria as decision-makers in cell death. Environ Mol Mutagen. 2010; 51(5):406-16. DOI: 10.1002/em.20564. View