Flavopiridol-induced iNOS downregulation during apoptosis of chronic lymphocytic leukemia cells is caspase-dependent.
We previously reported that flavopiridol-induced apoptosis of B cell chronic lymphocytic leukemia (CLL) patients' cells ex vivo is associated with downregulation of both the inducible nitric oxide (NO) synthase (iNOS) that produces the antiapoptotic molecule NO, and the CDK inhibitor p27kip1 that is thought to block the cell cycle of CLL cells. Here, we show that iNOS downregulation is caspase-dependent and thus can be considered as one of the effector mechanisms of apoptosis, but not a primary triggering event induced by flavopiridol. Furthermore, we also find that this flavone favors the entry into the S and G2 phases of the cell cycle of a subpopulation of the leukemic cells, confirming that flavopiridol might be useful for improving the efficacy of cell cycle-dependent cytostatic agents in the therapy of CLL.
Billard
Christian
C
INSERM U872 (équipe 18), Université Pierre et Marie Curie-Paris 6, Paris, France. cbillard@bhdc.jussieu.fr
Menasria
Faouzia
F
Quiney
Claire
C
Faussat
Anne-Marie
AM
Kolb
Jean-Pierre
JP
D000590:Amino Acid Chloromethyl Ketones / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000502:physiology*; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors* / Q000235:genetics; D010880:Piperidines / Q000494:pharmacology*
D000590:Amino Acid Chloromethyl Ketones; D000970:Antineoplastic Agents; D005419:Flavonoids; D010880:Piperidines; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; C077990:alvocidib; D052247:Nitric Oxide Synthase Type II; D020169:Caspases