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Prepublished online as a Blood First Edition Paper on June 28, 2002; DOI 10.1182/blood-2002-01-0075.
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Blood, 1 January 2003, Vol. 101, No. 1, pp. 265-269
NEOPLASIA
Sildenafil and vardenafil, types 5 and 6 phosphodiesterase inhibitors, induce caspase-dependent apoptosis of
B-chronic lymphocytic leukemia cells
Marika Sarfati,
Véronique Mateo,
Sylvie Baudet,
Manuel Rubio,
Christine Fernandez,
Fréderic Davi,
Jacques-Louis Binet,
Jozo Delic, and
Hélène Merle-Béral
From Immunology and Inflammation, Institut Pasteur,
Department of Hematology, Pharmacy, Hôpital
Pitié-Salpêtrière, Paris, and Radiobiology and
Oncology CEA/DRR, Fontenay aux Roses, France.
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- (SDF-1). 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.
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