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

Abstract

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.

Manganese Superoxide Dismutase in Cancer Prevention

“…Consistent with these results, several studies have reported the chemoresistant potential of MnSOD expression and activity (16,41,53,103,134,154). Thus, the presence of SODs can decrease the efficacy of anticancer drugs with a ROS-dependent mechanism of action, such as mofarotene, adriamycin and mitomycin C (13,50,53).…”

“…It has been demonstrated that delocalized lipophilic cations accumulate within the mitochondria of transformed cell lines due to the constitutively higher mitochondrial membrane potential compared to their normal counterparts (6,89 (13). Although enhanced ROS generation is associated with inhibition of mitochondrial respiration and apoptosis, SODs can be involved in protecting the cell from oxidative injury and survival (10,40,107,126).…”

Functions, Therapeutic Applications, and Synthesis of Retinoids and Carotenoids

“…Mofarotene (Ro 40-8757, 99 , Figure ) is an arotinoid with a morpholine heterocycle that inhibits the growth of various human cancers both in vitro and in vivo, and protects the bone marrow from the toxic effects of cyclophosphamide and 5-fluorouracil (5-FU) in vivo. Mofarotene ( 99 ) induced strong antiproliferative and apoptotic responses in most established Burkitt’s lymphoma (BL) cell lines as well as in primary BL cells . SHetA2 ( 100 ) (Figure ) is the prototype of the flexible heteroarotinoids or FlexHet class of RRMs .…”