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.
Cariati
Roberta
R
Immunovirology and Biotherapy Unit, Italy.
Zancai
Paola
P
Righetti
Elisabetta
E
Rizzo
Silvana
S
De Rossi
Anita
A
Boiocchi
Mauro
M
Dolcetti
Riccardo
R
D000255:Adenosine Triphosphate / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D002051:Burkitt Lymphoma / Q000188:drug therapy*; D020169:Caspases / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology*; D009245:NADH Dehydrogenase / Q000187:drug effects; D010085:Oxidative Phosphorylation / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012176:Retinoids / Q000494:pharmacology*; D013482:Superoxide Dismutase / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D000975:Antioxidants; D009025:Morpholines; D017382:Reactive Oxygen Species; D012176:Retinoids; D019344:Lactic Acid; C081137:mofarotene; D000255:Adenosine Triphosphate; D013482:Superoxide Dismutase; D009245:NADH Dehydrogenase; D020169:Caspases