BML-275, an AMPK inhibitor, induces DNA damage, G2/M arrest and apoptosis             in human pancreatic cancer cells.
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.
Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057, USA.
Hong-Quan
HQ
Duong
Jae Seok
JS
Hwang
Hee Jeong
HJ
Kim
Yeon-Sun
YS
Seong
Insoo
I
Bae
D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D045744:Cell Line, Tumor; D004249:DNA Damage / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D004847:Epithelial Cells / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D020868:Gene Silencing; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects*; D008954:Models, Biological; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism
C579800:BML-275; D011720:Pyrazoles; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D055372:AMP-Activated Protein Kinases