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

Oncogene volume 22, pages 906–918 (2003)Cite this article

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.

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Acknowledgements

This work was supported in part by grants from the Italian Association for Cancer Research (AIRC) (to R.D.) and from MIUR, Progetto Strategico “Oncologia” (SP/4), Legge 449/97, No. 02.00268.ST97. The authors thank Dr Werner Bollag (Hoffmann-La Roche S.p.A.) for supplying Ro 40-8757, Dr J Menezés for providing the LMP-1-transfected BJAB cells and the S12 antibody, Dr JT Greenamyre for the kind gift of anti-ND1 antibody; and Dr P Tonel and Mrs P Pistello for help with the manuscript. PZ and RC are recipients of fellowships from the Italian Foundation for Cancer Research (FIRC)

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Authors and Affiliations

  1. Immunovirology and Biotherapy Unit, Italy

    Roberta Cariati, Paola Zancai, Silvana Rizzo & Riccardo Dolcetti

  2. Division of Experimental Oncology 1, Department of Pre-clinical and Epidemiological Research, Centro di Riferimento Oncologico, IRCCS – National Cancer Institute, Aviano (PN), Italy

    Mauro Boiocchi

  3. Department of Oncology and Surgical Sciences, AIDS Reference Center, Padova, Italy

    Elisabetta Righetti & Anita De Rossi

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  1. Roberta Cariati
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Correspondence to Mauro Boiocchi.

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Cariati, R., Zancai, P., Righetti, E. et al. Inhibition of oxidative phosphorylation underlies the antiproliferative and proapoptotic effects of mofarotene (Ro 40-8757) in Burkitt's lymphoma cells. Oncogene 22, 906–918 (2003). https://doi.org/10.1038/sj.onc.1206060

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