Rimonabant-induced apoptosis in leukemia cell lines: Activation of caspase-dependent and -independent pathways

Abstract

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 anti-tumor potential of SR141716 in leukemia-derived cell lines and its low toxicity in normal cells (PBMC). SR141716(1-20 M 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.

Expression and Functional Relevance of Cannabinoid Receptor 1 in Hodgkin Lymphoma

“…The cell lines L428, L540, KM-H2 and Karpas 422 were treated with CB 1 antagonist AM251 and viability was assessed using MTT-assay. Gallotta and colleagues observed a decrease in viability of Jurkat cells with an IC 50 of around 12 µM using SR141716, a CB 1 -antagonist with an affinity to CB 1 similar to AM251 [34]. Therefore, we tested viability of lymphoma cells using CB 1 ligands at a maximum of 10 µM each.…”

Effect of sesquiterpene lactone coronopilin on leukaemia cell population growth, cell type‐specific induction of apoptosis and mitotic catastrophe

“…Whole lysates for immunoblotting analysis were prepared according to standard protocols. Cytosolic protein extracts for determining cytochrome c were prepared as described previously (16). Briefly, cells were gently lysed for 2 min in ice‐cold lysis buffer containing 0.05% digitonin.…”

Diabetes and cancer II: role of diabetes medications and influence of shared risk factors

“…The appetite suppressants reductil and rimonabant were prescribed for obesity, often in conjunction with DM, but have since been pulled from the market due to high risks for stroke and psychosis, respectively. In in vitro studies, rimonabant has been shown to have some anti-tumor activity [133], but is not safe for use in humans. Development of similar drugs is currently being explored [133].…”

“…In in vitro studies, rimonabant has been shown to have some anti-tumor activity [133], but is not safe for use in humans. Development of similar drugs is currently being explored [133]. Orlistat is a fatty acid synthase inhibitor with FDA approval for weight loss and has been shown to have some anti-tumoral effects in animal models of colorectal cancer [134], but there have been no epidemiological studies examining the effects of orlistat on cancer risk in patients with DM.…”