AMP-activated protein kinase-dependent and -independent mechanisms underlying in vitro antiglioma action of compound C

Ljubica Vucicevic; Maja Misirkic; Kristina Janjetovic; Ljubica Harhaji-Trajkovic; Marko Prica; Darko Stevanovic; Esma Isenovic; Emina Sudar; Mirjana Sumarac-Dumanovic; Dragan Micic; Vladimir Trajkovic

doi:10.1016/j.bcp.2009.03.005

AMP-activated protein kinase-dependent and -independent mechanisms underlying in vitro antiglioma action of compound C

Biochem Pharmacol. 2009 Jun 1;77(11):1684-93. doi: 10.1016/j.bcp.2009.03.005. Epub 2009 Mar 14.

Authors

Ljubica Vucicevic¹, Maja Misirkic, Kristina Janjetovic, Ljubica Harhaji-Trajkovic, Marko Prica, Darko Stevanovic, Esma Isenovic, Emina Sudar, Mirjana Sumarac-Dumanovic, Dragan Micic, Vladimir Trajkovic

Affiliation

¹ Institute of Microbiology and Immunology, School of Medicine, University of Belgrade, Dr. Subotica 1, 11000 Belgrade, Serbia.

PMID: 19428322
DOI: 10.1016/j.bcp.2009.03.005

Abstract

We investigated the effect of compound C, a well-known inhibitor of the intracellular energy sensor AMP-activated protein kinase (AMPK), on proliferation and viability of human U251 and rat C6 glioma cell lines. Compound C caused G(2)/M cell cycle block, accompanied by apoptotic glioma cell death characterized by caspase activation, phosphatidylserine exposure and DNA fragmentation. The mechanisms underlying the pro-apoptotic action of compound C involved induction of oxidative stress and downregulation of antiapoptotic molecule Bcl-2, while no alteration of pro-apoptotic Bax was observed. Compound C diminished AMPK phosphorylation and enzymatic activity, resulting in reduced phosphorylation of its target acetyl CoA carboxylase. AMPK activators metformin and AICAR partly prevented the cell cycle block, oxidative stress and apoptosis induced by compound C. The small interfering RNA (siRNA) targeting of human AMPK mimicked compound C-induced G(2)/M cell cycle arrest, but failed to induce oxidative stress and apoptosis in U251 glioma cells. In conclusion, our data indicate that AMPK inhibition is required, but not sufficient for compound C-mediated apoptotic death of glioma cells.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

AMP-Activated Protein Kinases / antagonists & inhibitors*
Aminoimidazole Carboxamide / analogs & derivatives
Aminoimidazole Carboxamide / pharmacology
Antineoplastic Agents / pharmacology
Antineoplastic Agents / therapeutic use
Antioxidants / pharmacology
Apoptosis / drug effects
Caspases / metabolism
Cell Cycle / drug effects
Cell Death / drug effects
Cell Division / drug effects
Cell Line, Tumor
Enzyme Activation / drug effects
G2 Phase / drug effects
Glioma / drug therapy*
Glioma / enzymology
Glioma / pathology
Humans
Metformin / pharmacology
Pheochromocytoma / drug therapy
Pheochromocytoma / enzymology
Pheochromocytoma / pathology
Proto-Oncogene Proteins c-bcl-2 / drug effects
Proto-Oncogene Proteins c-bcl-2 / genetics
Pyrazoles / pharmacology
Pyrazoles / therapeutic use*
Pyrimidines / pharmacology
Pyrimidines / therapeutic use*
Reactive Oxygen Species / metabolism
Reverse Transcriptase Polymerase Chain Reaction
Ribonucleotides / pharmacology
bcl-2-Associated X Protein / genetics

Substances

Antineoplastic Agents
Antioxidants
BML-275
Proto-Oncogene Proteins c-bcl-2
Pyrazoles
Pyrimidines
Reactive Oxygen Species
Ribonucleotides
bcl-2-Associated X Protein
dorsomorphin
Aminoimidazole Carboxamide
Metformin
AMP-Activated Protein Kinases
Caspases
AICA ribonucleotide