Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis.
The present study reports for the first time a dual antiglioma effect of the well-known antidiabetic drug metformin. In low-density cultures of the C6 rat glioma cell line, metformin blocked the cell cycle progression in G(0)/G(1) phase without inducing significant cell death. In confluent C6 cultures, on the other hand, metformin caused massive induction of caspase-dependent apoptosis associated with c-Jun N-terminal kinase (JNK) activation, mitochondrial depolarization and oxidative stress. Metformin-triggered apoptosis was completely prevented by agents that block mitochondrial permeability transition (cyclosporin A) and oxygen radical production (N-acetylcisteine), while the inhibitors of JNK activation (SP600125) or glycolysis (sodium fluoride, iodoacetate) provided partial protection. The antiglioma effect of metformin was reduced by compound C, an inhibitor of AMP-activated protein kinase (AMPK), and was mimicked by the AMPK agonist AICAR. Similar effects were observed in the human glioma cell line U251, while rat primary astrocytes were completely resistant to the antiproliferative and proapoptotic action of metformin.
Isakovic
A
A
Institute of Biochemistry, School of Medicine, University of Belgrade, Belgrade, Serbia.
Harhaji
L
L
Stevanovic
D
D
Markovic
Z
Z
Sumarac-Dumanovic
M
M
Starcevic
V
V
Micic
D
D
Trajkovic
V
V
D055372:AMP-Activated Protein Kinases; D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005434:Flow Cytometry; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008687:Metformin / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D009097:Multienzyme Complexes / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D013997:Time Factors
D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007004:Hypoglycemic Agents; D009097:Multienzyme Complexes; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D008687:Metformin; D006861:Hydrogen Peroxide; D017346:Protein Serine-Threonine Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D055372:AMP-Activated Protein Kinases; D020169:Caspases