MHY451 induces cell cycle arrest and apoptosis by ROS generation in HCT116 human colorectal cancer cells

Hwang,Na Lam; Kang,Yong Jung; Sung,Bokyung; Hwang,Seong Yeon; Jang,Jung Yoon; Oh,Hye Jin; Ahn,Yu Ra; Kim,Do Hyun; Kim,Su Jeong; Ullah,Sultan; Hossain,Mohammad Akbar; Moon,Hyung Ryong; Chung,Hae Young; Kim,Nam Deuk

doi:10.3892/or.2017.5836

MHY451 induces cell cycle arrest and apoptosis by ROS generation in HCT116 human colorectal cancer cells

Authors:
- Na Lam Hwang
- Yong Jung Kang
- Bokyung Sung
- Seong Yeon Hwang
- Jung Yoon Jang
- Hye Jin Oh
- Yu Ra Ahn
- Do Hyun Kim
- Su Jeong Kim
- Sultan Ullah
- Mohammad Akbar Hossain
- Hyung Ryong Moon
- Hae Young Chung
- Nam Deuk Kim
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Affiliations: Division of Pharmacy, Molecular Inflammation Research Center for Aging Intervention (MRCA), Pusan National University, Busan 46241, Republic of Korea, Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah al Mukarramah 24382, Kingdom of Saudi Arabia
Published online on: July 18, 2017 https://doi.org/10.3892/or.2017.5836
Pages: 1783-1789

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Abstract

Colorectal cancer (CRC) is the third most frequently diagnosed cancer and cause of cancer-related deaths. Despite advancements in conventional therapeutic approaches to CRC, most patients with CRC die of their disease. There is a need to develop novel therapeutic agents for this malignancy. Therefore, the present study aimed to examine the anticancer effects and elucidate the underlying mechanism of MHY451 in HCT116 human colorectal cancer cells. Treatment with MHY451 inhibited cell growth in a time- and concentration-dependent manner. MHY451 increased the accumulation of cell cycle progression at the G2/M phase. This agent decreased the protein level of cyclin B1 and its activating partners, Cdc25c and Cdc2, whereas it increased the cell cycle inhibitor p21WAF/CIP. The induction of apoptosis was observed by decreased viability, cleavage of poly(ADP-ribose) polymerase (PARP), alteration in the ratio of Bax/Bcl-2 protein expression and reduction of procaspase-8 and -9. Pretreatment with Z-VAD-FMK, a pan-caspase inhibitor, inhibited MHY451-induced apoptosis, indicating that apoptotic cell death by MHY451 was mediated through caspases. Moreover, the apoptotic effect of MHY451 was reactive oxygen species (ROS)-dependent, evidenced by the inhibition of MHY451-induced PARP cleavage and ROS generation by N-acetylcysteine-induced ROS scavenging. Taken together, these results demonstrate that MHY451 exerts anticancer effects by regulating the cell cycle, inducing apoptosis through caspase activation and generating ROS. These results suggest that MHY451 has considerable potential for chemoprevention or treatment of CRC or both.

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