title: Sildenafil and vardenafil, types 5 and 6 phosphodiesterase inhibitors, induce caspase-dependent apoptosis of B-chronic lymphocytic leukemia cells.
abstract: Type 4 phosphodiesterase (PDE4) inhibitors reportedly induce apoptosis in chronic lymphocytic leukemia (CLL) cells. Following clinical improvement of one previously untreated CLL patient with sildenafil therapy, we evaluated the in vitro induction of apoptosis in CLL cells by 4 PDE5/6 inhibitors, including sildenafil, vardenafil, zaprinast, and methoxyquinazoline (MQZ). After 24 hours of culture, the various PDE inhibitors differed in their ability to induce apoptosis, with zaprinast displaying no killing effect. Normal B cells isolated from control donors were totally resistant to PDE-induced apoptosis. Vardenafil was 3 and 30 times more potent an inducer of apoptosis than sildenafil and MQZ, respectively. Both vardenafil and sildenafil failed to elevate adenosine 3'5' cyclic monophosphate (cAMP) levels, largely excluding an inhibitory effect on cAMP-PDE3, -PDE4, and -PDE7. Vardenafil- or sildenafil-treated B-CLL cells displayed up to 30% intracellular active caspase 3. Drug-induced apoptosis was inhibited by the caspase inhibitor z-VAD.fmk, prevented by interleukin-4 (IL-4), and significantly reduced by stromal-derived factor1-alpha (SDF-1alpha). We conclude that vardenafil and sildenafil induce caspase-dependent apoptosis of B-CLL cells in vitro and thus might be considered in the treatment of CLL patients. However, further in vivo investigations should be warranted.
authors.affiliation: Immunology and Inflammation, Institut Pasteur, Department of Hematology, Pharmacy, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Marika
authors.initials: M
authors.lastname: Sarfati
authors.forename: Véronique
authors.initials: V
authors.lastname: Mateo
authors.forename: Sylvie
authors.initials: S
authors.lastname: Baudet
authors.forename: Manuel
authors.initials: M
authors.lastname: Rubio
authors.forename: Christine
authors.initials: C
authors.lastname: Fernandez
authors.forename: Fréderic
authors.initials: F
authors.lastname: Davi
authors.forename: Jacques-Louis
authors.initials: JL
authors.lastname: Binet
authors.forename: Jozo
authors.initials: J
authors.lastname: Delic
authors.forename: Hélène
authors.initials: H
authors.lastname: Merle-Beral
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases; D017209:Apoptosis / Q000187:drug effects*; D016022:Case-Control Studies; D020169:Caspases / Q000502:physiology; D018929:Cell Culture Techniques; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000473:pathology*; D007963:Leukocytes, Mononuclear; D008297:Male; D008875:Middle Aged; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; D014227:Triazines; D000069058:Vardenafil Dihydrochloride
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D013450:Sulfones; D014227:Triazines; D000069058:Vardenafil Dihydrochloride; D000068677:Sildenafil Citrate; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D054707:Cyclic Nucleotide Phosphodiesterases, Type 6; C517381:PDE5A protein, human; C517431:PDE6B protein, human; D020169:Caspases