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

Roberta Cariati, Paola Zancai, Elisabetta Righetti, Silvana Rizzo, Anita De Rossi, Mauro Boiocchi, Riccardo Dolcetti

Research output: Contribution to journalArticlepeer-review

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 thenoyltrittuoroacetone 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.

Original languageEnglish
Pages (from-to)906-918
Number of pages13
JournalOncogene
Volume22
Issue number6
DOIs
Publication statusPublished - Feb 13 2003

Keywords

  • Burkitt's lymphoma
  • Epstein-Barr virus
  • Oxidative phosphorylation
  • Reactive oxygen species
  • Retinoids
  • Ro 40-8757

ASJC Scopus subject areas

  • Cancer Research
  • Genetics
  • Molecular Biology

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