Flavopiridol circumvents Bcl-2 family mediated inhibition of apoptosis and drug resistance in B-cell chronic lymphocytic leukaemia.
Flavopiridol, a synthetic flavone, is currently under clinical investigation for the treatment of B-cell chronic lymphocytic leukaemia (B-CLL). In this study, we examined the in vitro effects of flavopiridol and fludarabine on B-CLL cells from 64 patients (36 treated and 28 untreated) in terms of apoptosis induction and Bcl-2 family expression. Both flavopiridol and fludarabine induced apoptosis in all the samples tested with mean LD(50) values (+/- SD) of 59.7 nmol/l (+/- 36.5) and 6.2 micromol/l (+/- 7.5) respectively. Mean flavopiridol LD(50) values were not significantly different between the treated and untreated patient groups (P = 0.35), whereas the fludarabine LD(50) values were significantly higher in the previously treated patient group (P = 0.01). Bcl-2 and Mcl-1 expression were downregulated in both flavopiridol and fludarabine-induced apoptotic cells, but the increase in Bax expression that accompanied fludarabine-induced apoptosis was not evident in flavopiridol-treated cells. In addition, Bcl-2:Bax ratios were not predictive of flavopiridol cytotoxicity (P = 0.82), whereas they were highly predictive of in vitro responsiveness to fludarabine (P = 0.001). Overall, these findings suggest that flavopiridol exerts its cytotoxic effect through a novel cell-death pathway that is not subject to the Bcl-2 family mediated resistance mechanisms that reduce the efficacy of many conventional chemotherapeutic drugs.
Pepper
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C
Department of Haematology, Llandough Hospital, Penarth, South Glamorgan, UK.
Thomas
A
A
Hoy
T
T
Fegan
C
C
Bentley
P
P
D000970:Antineoplastic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005419:Flavonoids / Q000627:therapeutic use*; D005434:Flow Cytometry; D006801:Humans; D007928:Lethal Dose 50; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000378:metabolism; D008214:Lymphocytes / Q000187:drug effects; D010880:Piperidines / Q000627:therapeutic use*; D011518:Proto-Oncogene Proteins / Q000032:analysis; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D014740:Vidarabine / Q000031:analogs & derivatives / Q000627:therapeutic use; D051028:bcl-2-Associated X Protein
D000970:Antineoplastic Agents; C494826:BAX protein, human; D005419:Flavonoids; D010880:Piperidines; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016159:Tumor Suppressor Protein p53; D051028:bcl-2-Associated X Protein; C077990:alvocidib; D014740:Vidarabine; C024352:fludarabine