Sildenafil increases chemotherapeutic efficacy of doxorubicin in prostate cancer and ameliorates cardiac dysfunction.
We have shown that the potent phosphodiesterase-5 (PDE-5) inhibitor sildenafil (Viagra) induces a powerful effect on reduction of infarct size following ischemia/reperfusion injury and improvement of left ventricular dysfunction in the failing heart after myocardial infarction or doxorubicin (DOX) treatment. In the present study, we further investigated the potential effects of sildenafil on improving antitumor efficacy of DOX in prostate cancer. Cotreatment with sildenafil enhanced DOX-induced apoptosis in PC-3 and DU145 prostate cancer cells, which was mediated by enhanced generation of reactive oxygen species, up-regulation of caspase-3 and caspase-9 activities, reduced expression of Bcl-xL, and phosphorylation of Bad. Overexpression of Bcl-xL or dominant negative caspase 9 attenuated the synergistic effect of sildenafil and DOX on prostate cancer cell killing. Furthermore, treatment with sildenafil and DOX in mice bearing prostate tumor xenografts resulted in significant inhibition of tumor growth. The reduced tumor size was associated with amplified apoptotic cell death and increased expression of activated caspase 3. Doppler echocardiography showed that sildenafil treatment ameliorated DOX-induced left ventricular dysfunction. In conclusion, these results provide provocative evidence that sildenafil is both a powerful sensitizer of DOX-induced killing of prostate cancer while providing concurrent cardioprotective benefit.
Das
Anindita
A
Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University Pauley Heart Center, Richmond, VA 23298, USA. adas2@vcu.edu
Durrant
David
D
Mitchell
Clint
C
Mayton
Eric
E
Hoke
Nicholas N
NN
Salloum
Fadi N
FN
Park
Margaret A
MA
Qureshi
Ian
I
Lee
Ray
R
Dent
Paul
P
Kukreja
Rakesh C
RC
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D004317:Doxorubicin / Q000009:adverse effects / Q000627:therapeutic use*; D004357:Drug Synergism; D015150:Echocardiography, Doppler; D006321:Heart / Q000187:drug effects*; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010726:Phosphodiesterase Inhibitors / Q000627:therapeutic use*; D010766:Phosphorylation; D010879:Piperazines / Q000627:therapeutic use*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D011687:Purines / Q000627:therapeutic use; D017382:Reactive Oxygen Species / Q000378:metabolism; D000068677:Sildenafil Citrate; D013450:Sulfones / Q000627:therapeutic use*; D051025:bcl-Associated Death Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
D000970:Antineoplastic Agents; D010726:Phosphodiesterase Inhibitors; D010879:Piperazines; D011687:Purines; D017382:Reactive Oxygen Species; D013450:Sulfones; D051025:bcl-Associated Death Protein; D051020:bcl-X Protein; D004317:Doxorubicin; D000068677:Sildenafil Citrate; D053148:Caspase 3; D053453:Caspase 9