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

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.

• Authors: Hong-Quan Duong, Jae Seok Hwang, Hee Jeong Kim, Yeon-Sun Seong, Insoo Bae
• Journal: International journal of oncology (Int J Oncol) Vol. 41 Issue 6 Pg. 2227-36 (Dec 2012) ISSN: 1791-2423 [Electronic] Greece
• PMID: 23076030 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• BML-275
• Pyrazoles
• Pyrimidines
• Reactive Oxygen Species
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (antagonists & inhibitors, genetics, metabolism)
• Apoptosis (drug effects, genetics)
• Cell Line, Tumor
• DNA Damage (drug effects)
• Enzyme Activation (drug effects)
• Epithelial Cells (metabolism)
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Gene Silencing
• Humans
• M Phase Cell Cycle Checkpoints (drug effects)
• Models, Biological
• Pancreatic Neoplasms (genetics, metabolism)
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• RNA Interference
• Reactive Oxygen Species (metabolism)