Research Article: Tetraarsenic hexoxide induces G2/M arrest, apoptosis, and autophagy via PI3K/Akt suppression and p38 MAPK activation in SW620 human colon cancer cells

Date Published: March 29, 2017

Publisher: Public Library of Science

Author(s): 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, Salvatore V. Pizzo.


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.

Partial Text

Colorectal cancer (CRC) is the third most common type of cancer and the second leading cause of cancer related death in the world [1]. CRC represents a major public health problem and the incidence of CRC has recently been increasing especially in Korea [2]. Most of the colorectal cancers belong to the adenocarcinomas accounting with approximately 95% of cases. The 5 years survival rates are very poor for patients, those diagnosed at their advanced stages. Recently survival rates of CRC patients have improved with the help of advanced modality in the cancer research. Despite treatments for CRC including surgery, radiation therapy and/or chemotherapy are generally available, its application still very limited and cause severe side effects [3]. Thus, there is necessity for development of novel therapeutic potential for the CRC prevention and therapy.

In our previous study, was demonstrated that anticancer activity of As4O6 through suppression of NF-κB activity in SW620 cells [23]. The present study was designed to investigate the further mechanisms for the anti-cancer effects of As4O6, especially on the cell death. The results revealed that As4O6 induced G2/M arrest, apoptosis and autophagy in SW620 cells. The anti-cancer effects of As4O6 was associated with PI3K/Akt and p38 MAPK-mediated pathways. To our knowledge, this is the first study report showing multiple anti-cancer mechanisms of As4O6 in SW620 cells; As4O6 induced G2/M arrest, apoptosis and autophagy via PI3K/Akt and p38 MAPK-mediated pathways, which is unique from other studies.

In the present study, we have demonstrated that the anti-cancer mechanism for As4O6-induced G2/M arrest, apoptosis and autophagy in SW620 cells. Furthermore, As4O6 suppressed the PI3K/Akt and activated the p38 MAPK. These activities might play a critical role in As4O6-induced cell death of SW620 cells. Lastly, this study provides the evidence that As4O6 has an anti-cancer effects; it might be useful for the understanding the clinical cases showing long-term stable disease with central necrosis.




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