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.