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Rituximab modifies the cisplatin-mitochondrial signaling pathway, resulting in apoptosis in cisplatin-resistant non-Hodgkin's lymphoma.
Clin Cancer Res. 2002 Mar; 8(3):836-45.CC

Abstract

PURPOSE

Rituximab (chimeric anti-CD20) can reverse the cisplatin-resistant phenotype of AIDS-related non-Hodgkin's lymphoma cell lines and results in cisplatin-mediated apoptosis. The mechanism by which apoptosis is achieved by the combination treatment was examined.

EXPERIMENTAL DESIGN

The AIDS-related lymphoma (ARL) cell line 2F7 was treated with rituximab, cisplatin, and a combination of the two and analyzed by Western blot analyses for signaling proteins involved in the death receptor-mediated and mitochondrial pathways.

RESULTS

Rituximab selectively inhibited the expression of Bcl-2 in the ARL cells. However, other proteins analyzed [namely, Apaf-1, Bax, Bid, caspase-3, caspase-8, caspase-9, X-linked inhibitor of apoptosis protein (XIAP), cellular inhibitor of apoptosis protein (cIAP)-1, cIAP-2, cytochrome c, Fas, Fas ligand, FLIP, p53, and poly(ADP-ribose) polymerase] were not affected by either rituximab or cisplatin. Treatment with cisplatin induced the generation of mitochondrial reactive oxygen species, specifically intracellular peroxides. Furthermore, cisplatin alone was unable to induce the mitochondrial apoptotic events; however, the rituximab-cisplatin combination was able to synergistically induce significant apoptosis and mitochondria-mediated apoptotic events [mitochondrial membrane depolarization (DeltaPsi(m)), cytochrome c release from mitochondria, and caspase-3 and -9 activation]. The combination treatment facilitated the down-regulation of Bcl-2 by rituximab at an early time point. Decreased expression of additional proteins (Apaf-1, cIAP-1, cIAP-2, and XIAP) paralleled apoptosis detected at 24 h.

CONCLUSIONS

These findings show that the selective down-regulation of Bcl-2 by rituximab leading to apoptosis in ARL cells by cisplatin is through the mitochondria-dependent caspase pathway.

Authors+Show Affiliations

Department of Microbiology, Immunology, and Molecular Genetics, University of California Los Angeles School of Medicine and Jonsson Comprehensive Cancer Center, University of California, Los Angeles, California 90095, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

11895917

Citation

Alas, Steve, et al. "Rituximab Modifies the Cisplatin-mitochondrial Signaling Pathway, Resulting in Apoptosis in Cisplatin-resistant non-Hodgkin's Lymphoma." Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, vol. 8, no. 3, 2002, pp. 836-45.
Alas S, Ng CP, Bonavida B. Rituximab modifies the cisplatin-mitochondrial signaling pathway, resulting in apoptosis in cisplatin-resistant non-Hodgkin's lymphoma. Clin Cancer Res. 2002;8(3):836-45.
Alas, S., Ng, C. P., & Bonavida, B. (2002). Rituximab modifies the cisplatin-mitochondrial signaling pathway, resulting in apoptosis in cisplatin-resistant non-Hodgkin's lymphoma. Clinical Cancer Research : an Official Journal of the American Association for Cancer Research, 8(3), 836-45.
Alas S, Ng CP, Bonavida B. Rituximab Modifies the Cisplatin-mitochondrial Signaling Pathway, Resulting in Apoptosis in Cisplatin-resistant non-Hodgkin's Lymphoma. Clin Cancer Res. 2002;8(3):836-45. PubMed PMID: 11895917.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rituximab modifies the cisplatin-mitochondrial signaling pathway, resulting in apoptosis in cisplatin-resistant non-Hodgkin's lymphoma. AU - Alas,Steve, AU - Ng,Chuen-Pei, AU - Bonavida,Benjamin, PY - 2002/3/16/pubmed PY - 2002/7/4/medline PY - 2002/3/16/entrez SP - 836 EP - 45 JF - Clinical cancer research : an official journal of the American Association for Cancer Research JO - Clin Cancer Res VL - 8 IS - 3 N2 - PURPOSE: Rituximab (chimeric anti-CD20) can reverse the cisplatin-resistant phenotype of AIDS-related non-Hodgkin's lymphoma cell lines and results in cisplatin-mediated apoptosis. The mechanism by which apoptosis is achieved by the combination treatment was examined. EXPERIMENTAL DESIGN: The AIDS-related lymphoma (ARL) cell line 2F7 was treated with rituximab, cisplatin, and a combination of the two and analyzed by Western blot analyses for signaling proteins involved in the death receptor-mediated and mitochondrial pathways. RESULTS: Rituximab selectively inhibited the expression of Bcl-2 in the ARL cells. However, other proteins analyzed [namely, Apaf-1, Bax, Bid, caspase-3, caspase-8, caspase-9, X-linked inhibitor of apoptosis protein (XIAP), cellular inhibitor of apoptosis protein (cIAP)-1, cIAP-2, cytochrome c, Fas, Fas ligand, FLIP, p53, and poly(ADP-ribose) polymerase] were not affected by either rituximab or cisplatin. Treatment with cisplatin induced the generation of mitochondrial reactive oxygen species, specifically intracellular peroxides. Furthermore, cisplatin alone was unable to induce the mitochondrial apoptotic events; however, the rituximab-cisplatin combination was able to synergistically induce significant apoptosis and mitochondria-mediated apoptotic events [mitochondrial membrane depolarization (DeltaPsi(m)), cytochrome c release from mitochondria, and caspase-3 and -9 activation]. The combination treatment facilitated the down-regulation of Bcl-2 by rituximab at an early time point. Decreased expression of additional proteins (Apaf-1, cIAP-1, cIAP-2, and XIAP) paralleled apoptosis detected at 24 h. CONCLUSIONS: These findings show that the selective down-regulation of Bcl-2 by rituximab leading to apoptosis in ARL cells by cisplatin is through the mitochondria-dependent caspase pathway. SN - 1078-0432 UR - https://www.unboundmedicine.com/medline/citation/11895917/Rituximab_modifies_the_cisplatin_mitochondrial_signaling_pathway_resulting_in_apoptosis_in_cisplatin_resistant_non_Hodgkin's_lymphoma_ L2 - http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=11895917 DB - PRIME DP - Unbound Medicine ER -