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 journalArticle

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

Fingerprint

Burkitt Lymphoma
Oxidative Phosphorylation
Apoptosis
Enzyme Inhibitors
Electron Transport
Human Herpesvirus 4
Adenosine Triphosphate
Electron Transport Complex I
mofarotene
NADH Dehydrogenase
Epstein-Barr Virus Infections
Caspase 9
Retinoids
Mitochondrial Membranes
Caspase 3
Superoxide Dismutase
Reactive Oxygen Species
Lymphoma
Up-Regulation
Down-Regulation

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

Cite this

Inhibition of oxidative phosphorylation underlies the antiproliferative and proapoptotic effects of mofarotene (Ro 40-8757) in Burkitt's lymphoma cells. / Cariati, Roberta; Zancai, Paola; Righetti, Elisabetta; Rizzo, Silvana; De Rossi, Anita; Boiocchi, Mauro; Dolcetti, Riccardo.

In: Oncogene, Vol. 22, No. 6, 13.02.2003, p. 906-918.

Research output: Contribution to journalArticle

Cariati, Roberta ; Zancai, Paola ; Righetti, Elisabetta ; Rizzo, Silvana ; De Rossi, Anita ; Boiocchi, Mauro ; Dolcetti, Riccardo. / Inhibition of oxidative phosphorylation underlies the antiproliferative and proapoptotic effects of mofarotene (Ro 40-8757) in Burkitt's lymphoma cells. In: Oncogene. 2003 ; Vol. 22, No. 6. pp. 906-918.
@article{7ba891fa858a4952abe006b4f719f7de,
title = "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 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.",
keywords = "Burkitt's lymphoma, Epstein-Barr virus, Oxidative phosphorylation, Reactive oxygen species, Retinoids, Ro 40-8757",
author = "Roberta Cariati and Paola Zancai and Elisabetta Righetti and Silvana Rizzo and {De Rossi}, Anita and Mauro Boiocchi and Riccardo Dolcetti",
year = "2003",
month = "2",
day = "13",
doi = "10.1038/sj.onc.1206060",
language = "English",
volume = "22",
pages = "906--918",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "6",

}

TY - JOUR

T1 - Inhibition of oxidative phosphorylation underlies the antiproliferative and proapoptotic effects of mofarotene (Ro 40-8757) in Burkitt's lymphoma cells

AU - Cariati, Roberta

AU - Zancai, Paola

AU - Righetti, Elisabetta

AU - Rizzo, Silvana

AU - De Rossi, Anita

AU - Boiocchi, Mauro

AU - Dolcetti, Riccardo

PY - 2003/2/13

Y1 - 2003/2/13

N2 - 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.

AB - 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.

KW - Burkitt's lymphoma

KW - Epstein-Barr virus

KW - Oxidative phosphorylation

KW - Reactive oxygen species

KW - Retinoids

KW - Ro 40-8757

UR - http://www.scopus.com/inward/record.url?scp=0037434664&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037434664&partnerID=8YFLogxK

U2 - 10.1038/sj.onc.1206060

DO - 10.1038/sj.onc.1206060

M3 - Article

C2 - 12584570

AN - SCOPUS:0037434664

VL - 22

SP - 906

EP - 918

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 6

ER -