Activation of mitochondrial apoptotic pathway in mantle cell lymphoma: high sensitivity to mitoxantrone in cases with functional DNA-damage response genes.
Mantle cell lymphoma (MCL) is a mature B-cell proliferation characterized by the presence of translocation t(11;14)(q13;q32), an aggressive clinical course, and poor response to chemotherapy. The majority of drugs currently used in the treatment of lymphoproliferative disorders induce cell death by triggering apoptosis, but few data concerning drug-induced apoptosis in MCL have been reported. We have analysed the mechanisms of drug-induced cell death in four cell lines with the t(11;14) and in primary cells from 10 patients with MCL. Mitoxantrone, a topoisomerase II inhibitor, induced a strong cytotoxic effect in three cell lines (JVM-2, REC-1, and Granta 519), and in primary MCL cells. This cytotoxic effect due to apoptosis induction was observed despite the presence of either p53 or ATM abnormalities. However, no cytotoxic effect was detected after incubation with DNA-damaging agents in the NCEB-1 cell line, carrying p53 and ATM alterations, despite the presence of functional mitochondrial machinery. These results support that mitoxantrone can be effective in the treatment of MCL but that this activity requires the integrity of functional DNA-damage response genes.
Department of Hematology, Hematopathology Unit, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi I Sunyer, University of Barcelona, Spain.
Ana
A
Ferrer
Silvia
S
Marcé
Beatriz
B
Bellosillo
Neus
N
Villamor
Francesc
F
Bosch
Armando
A
López-Guillermo
Blanca
B
Espinet
Francesc
F
Solé
Emili
E
Montserrat
Elias
E
Campo
Dolors
D
Colomer
D017304:Annexin A5 / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D002453:Cell Cycle; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival; D004396:Coloring Agents / Q000494:pharmacology; D003520:Cyclophosphamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D016158:Genes, p53; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D020522:Lymphoma, Mantle-Cell / Q000473:pathology*; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology*; D008942:Mitoxantrone / Q000494:pharmacology*; D011506:Proteins / Q000737:chemistry; D017382:Reactive Oxygen Species; D019311:Staurosporine / Q000494:pharmacology; D013997:Time Factors; D014178:Translocation, Genetic; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism / Q000502:physiology; D014740:Vidarabine / Q000031:analogs & derivatives* / Q000494:pharmacology
D017304:Annexin A5; D000970:Antineoplastic Agents; D004396:Coloring Agents; D004791:Enzyme Inhibitors; D011506:Proteins; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; C048341:mafosfamide; D003520:Cyclophosphamide; D008942:Mitoxantrone; D014740:Vidarabine; D019311:Staurosporine; C024352:fludarabine