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.