Rimonabant-induced apoptosis in leukemia cell lines: activation of caspase-dependent and -independent pathways.
Rimonabant (SR141716), a cannabinoid CB1 receptor antagonist known for anti-obesity activity, has more recently been shown to inhibit tumor cell growth. Here we demonstrated the antitumor potential of SR141716 in leukemia-derived cell lines and its low toxicity in normal cells (PBMC). SR141716 (1-20microM range of doses) reduced Jurkat and U937 cell number by activating death signals as well as affecting cell cycle progression. The most prominent response in U937 to SR141716 was a G(0)/G(1) block, while in Jurkat cells there was activation of cell death processes. SR141716-treated cells exhibited the morphological and biochemical features of apoptosis and to some extent necrosis. Apoptotic mode of cell death was confirmed in both cell lines by analysis of cell morphology, phosphatidylserine exposure and DNA fragmentation. Moreover, the drug was found to induce an early and robust mitochondrial membrane depolarization. In Jurkat cells the apoptotic process was typically caspase-dependent, while in U937 caspase-independent pathways were also activated. The contribution of PARP activation to SR141716-induced apoptosis in U937 was suggested by protein PARylation, AIF release and apoptosis reversal by PARP inhibitors. Moreover, SR141716 negatively modulated, especially in U937, the PI3K/AKT pathways. In conclusion, our data indicate that SR141716 elicits alternative response and/or cell death pathways depending on the cell type affected.
Gallotta
Dario
D
Dipartimento di Scienze Farmaceutiche, Università degli Studi di Salerno, Via Ponte Don Melillo, 84084 Fisciano (SA), Italy.
Nigro
Patrizia
P
Cotugno
Roberta
R
Gazzerro
Patrizia
P
Bifulco
Maurizio
M
Belisario
Maria Antonietta
MA
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D019169:Jurkat Cells; D007938:Leukemia / Q000188:drug therapy / Q000201:enzymology*; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D011720:Pyrazoles / Q000494:pharmacology* / Q000627:therapeutic use; D000077285:Rimonabant; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D020298:U937 Cells
D010880:Piperidines; D011720:Pyrazoles; D020169:Caspases; D000077285:Rimonabant