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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.
AuthorsRoberta Cariati, Paola Zancai, Elisabetta Righetti, Silvana Rizzo, Anita De Rossi, Mauro Boiocchi, Riccardo Dolcetti
JournalOncogene (Oncogene) Vol. 22 Issue 6 Pg. 906-18 (Feb 13 2003) ISSN: 0950-9232 [Print] England
PMID12584570 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Antioxidants
  • Morpholines
  • Reactive Oxygen Species
  • Retinoids
  • Lactic Acid
  • mofarotene
  • Adenosine Triphosphate
  • Superoxide Dismutase
  • NADH Dehydrogenase
  • Caspases
Topics
  • Adenosine Triphosphate (metabolism)
  • Antineoplastic Agents (pharmacology)
  • Antioxidants (metabolism)
  • Apoptosis (drug effects)
  • Burkitt Lymphoma (drug therapy)
  • Caspases (drug effects)
  • Cell Division (drug effects)
  • Cell Line
  • Humans
  • Lactic Acid (metabolism)
  • Membrane Potentials (drug effects)
  • Mitochondria (drug effects)
  • Morpholines (pharmacology)
  • NADH Dehydrogenase (drug effects)
  • Oxidative Phosphorylation (drug effects)
  • Reactive Oxygen Species (metabolism)
  • Retinoids (pharmacology)
  • Superoxide Dismutase (antagonists & inhibitors)

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