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

• Published in: International journal of oncology Vol. 41; no. 6; pp. 2227 - 2236
• Main Authors: DUONG, HONG-QUAN, HWANG, JAE SEOK, KIM, HEE JEONG, SEONG, YEON-SUN, BAE, INSOO
• Format: Journal Article
• Language: English
• Published: Athens D.A. Spandidos 01.12.2012; Editorial Academy of the International Journal of Oncology; Spandidos Publications UK Ltd
• Subjects: adenosine monophosphate-activated protein kinase; AMP-Activated Protein Kinases - antagonists & inhibitors; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Biological and medical sciences; BML-275; Cancer therapies; Cell culture; Cell cycle; Cell division; Cell growth; Cell Line, Tumor; Deoxyribonucleic acid; DNA; DNA damage; DNA Damage - drug effects; Drug resistance; Enzyme Activation - drug effects; Epithelial Cells - metabolism; G2 Phase Cell Cycle Checkpoints - drug effects; G2/M arrest; Gastroenterology. Liver. Pancreas. Abdomen; Gene Silencing; Humans; Kinases; Liver. Biliary tract. Portal circulation. Exocrine pancreas; M Phase Cell Cycle Checkpoints - drug effects; Medical sciences; Models, Biological; Pancreatic cancer; Pancreatic Neoplasms - genetics; Pancreatic Neoplasms - metabolism; Penicillin; Phosphorylation; Prostate cancer; Proteins; Pyrazoles - pharmacology; Pyrimidines - pharmacology; Reactive Oxygen Species - metabolism; RNA Interference; Tumors; United States > US; Human; BML-275; AMP; Enzyme; G2/M arrest; Transferases; Non-specific serine/threonine protein kinase; DNA damage; Malignant tumor; cAMP-dependent protein kinase; pancreatic cancer; Cancerology; Adenosine kinase; Cell death; Pancreas cancer; Digestive diseases; adenosine monophosphate-activated protein kinase; Inhibitor; Lesion; Tumor cell; Cancer; Pancreatic disease; Apoptosis
• ISSN: 1019-6439; 1791-2423
• DOI: 10.3892/ijo.2012.1672

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.