Inhibition of oxidative phosphorylation underlies the antiproliferative and proapoptotic effects of mofarotene (Ro 40-8757) in Burkitt's lymphoma cells

In the search for retinoids active against Burkitt's lymphoma (BL), we found that the arotinoid mofarotene (Ro 40-8757) induced strong antiproliferative and apoptotic responses in most established BL cell lines as well as in primary BL cells. Ro 40-8757-induced Apoptosis is associated with mitochondrial membrane depolarization, activation of Caspase-3 and -9, and enhanced production of Reactive Oxygen Species. These effects were related to a transient drop in intracellular ATP content, probably favored by a downregulation of NADH dehydrogenase subunit-1, a component of the mitochondrial respiratory chain (MRC) Complex I. Inhibition of MRC with thenoyltrifluoroacetone suppressed both the ATP recovery and Apoptosis, confirming that the effects of Ro 40-8757 are mediated by changes in mitochondrial function. Compared to EBV-negative lines, EBV-carrying BLs were more resistant to Ro 40-8757-induced Apoptosis. EBV Infection and ectopic LMP-1 expression increased the resistance of BL cells to Ro 40-8757-induced Apoptosis, probably through Bcl-2 upregulation. Finally, we also show that 2-methoxyoestradiol, an inhibitor of the scavenger Enzymes superoxide dismutases, enhanced Ro 40-8757-mediated Apoptosis. These findings provide the rationale for evaluating the clinical efficacy of Ro 40-8757 in BL patients and suggest that the combination of Ro 40-8757 with inhibitors of scavenger Enzymes may be a promising therapeutic approach for this aggressive lymphoma.