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BML-275, an AMPK inhibitor, induces DNA damage, G2/M arrest and apoptosis in human pancreatic cancer cells

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Author(s)
HONG-QUAN DUONGJAE SEOK HWANGHEE JEONG KIMYEON-SUN SEONGINSOO BAE
Keimyung Author(s)
Hwang, Jae Seok
Department
Dept. of Internal Medicine (내과학)
Journal Title
International Journal of Oncology
Issued Date
2012
Volume
41
Issue
6
Abstract
. Adenosine monophosphate-activated protein kinase (AMPK) is a principal intracellular energy sensor which regulates energy producing pathways and energy requiring pathways when the cellular AMP/ATP ratio is altered. BML-275 (compound C), a well-known inhibitor of AMPK, has been found to induce apoptosis in myeloma, glioma and prostate cancer cells. However, the mechanisms responsible for the selective apoptotic effect(s) by BML-275 in cancer cells remain unknown. In the present study, BML-275 was investigated for its antitumor effect(s) in human pancreatic cancer cell lines. BML-275 inhibited the cell proliferation of 4 human pancreatic cancer cell lines (MIA PaCa-2, Panc-1, Colo-357 and AsPC-1). In addition, BML-275 significantly increased the generation of intracellular reactive oxygen species (ROS), followed by induction of DNA damage signaling and apoptosis. Furthermore, BML-275 induced cell cycle arrest in the G2/M phase. The inhibition of ROS generation by N-acetyl cysteine (NAC) significantly prevented the induction of DNA damage and apoptosis, but failed to prevent the induction of G2/M arrest by BML-275. Small interfering RNA (siRNA)-mediated knockdown of AMPKα increased the generation of intracellular ROS, DNA damage signaling and apoptosis without cell cycle arrest at the G2/M phase. These findings suggest that BML-275 exerts its antitumor effects by inducing ROS generation, DNA damage and apoptosis via inhibition of the AMPK pathway and by inducing G2/M arrest via a pathway independent of AMPK, implicating its potential application as an antitumor agent for pancreatic cancer.
Keimyung Author(s)(Kor)
황재석
Publisher
School of Medicine
Citation
HONG-QUAN DUONG et al. (2012). BML-275, an AMPK inhibitor, induces DNA damage,
G2/M arrest and apoptosis in human pancreatic cancer cells. International Journal of Oncology, 41(6), 2227–2236. doi:  10.3892/ijo.2012.1672
Type
Article
ISSN
1019-6439
DOI
 10.3892/ijo.2012.1672
URI
https://kumel.medlib.dsmc.or.kr/handle/2015.oak/35964
Appears in Collections:
1. School of Medicine (의과대학) > Dept. of Internal Medicine (내과학)
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