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Sildenafil Increases Chemotherapeutic Efficacy of Doxorubicin in Prostate

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Sildenafil Increases Chemotherapeutic Efficacy of Doxorubicin in Prostate Sildenafil increases chemotherapeutic efficacy of doxorubicin in prostate cancer and ameliorates cardiac dysfunction Anindita Dasa,1, David Durranta, Clint Mitchellb, Eric Maytona, Nicholas N. Hokea, Fadi N. Sallouma, Margaret A. Parkb, Ian Qureshia, Ray Leeb, Paul Dentb, and Rakesh C. Kukrejaa,1 aDivision of Cardiology, Department of Internal Medicine, Virginia Commonwealth University Pauley Heart Center and bDepartment of Biochemistry and Molecular Biology, Virginia Commonwealth University Medical Center, Richmond, VA 23298 Edited* by Herbert Weissbach, Florida Atlantic University, Boca Raton, FL, and approved August 17, 2010 (received for review May 25, 2010) We have shown that the potent phosphodiesterase-5 (PDE-5) enocarcinoma, bladder squamous carcinoma, and lung cancers inhibitor sildenafil (Viagra) induces a powerful effect on reduction (15–17), suggesting its potential role in controlling tumor cell of infarct size following ischemia/reperfusion injury and improve- growth and death. Sildenafil and vardenafil suppress tumor cell ment of left ventricular dysfunction in the failing heart after growth and induce caspase-dependent apoptosis in B-cell chronic myocardial infarction or doxorubicin (DOX) treatment. In the present lymphatic leukemia (18, 19). Another PDE-5 inhibitor, exisulind study, we further investigated the potential effects of sildenafilon (sulindac sulfone), and its higher affinity analogs also induce ap- improving antitumor efficacy of DOX in prostate cancer. Cotreat- optosis and inhibit cell proliferation in colon tumor cells lines by ment with sildenafil enhanced DOX-induced apoptosis in PC-3 and activating PKG and phosphorylation of β-catenin (20). These DU145 prostate cancer cells, which was mediated by enhanced gen- compounds also inhibit growth and induce apoptosis in several eration of reactive oxygen species, up-regulation of caspase-3 and human prostate cancer cell lines and prostate cancer xenografts in caspase-9 activities, reduced expression of Bcl-xL, and phosphoryla- nude mice (21–23). A low dose combination of colecoxib, tion of Bad. Overexpression of Bcl-xL or dominant negative caspase a cyclooxygenase-2 (COX-2) inhibitor, with exisulind prevents 9 attenuated the synergistic effect of sildenafil and DOX on prostate prostate carcinogenesis by altering key molecular events (24). cancer cell killing. Furthermore, treatment with sildenafil and DOX in In the present study, we tested whether sildenafil potentiates PHARMACOLOGY mice bearing prostate tumor xenografts resulted in significant in- the antitumor efficacy of DOX in prostate cancer. Our results hibition of tumor growth. The reduced tumor size was associated show that DOX and sildenafil induce a potent antitumor effect with amplified apoptotic cell death and increased expression of ac- in prostate cancer while simultaneously providing a cardiopro- tivated caspase 3. Doppler echocardiography showed that sildenafil tective effect. treatment ameliorated DOX-induced left ventricular dysfunction. In conclusion, these results provide provocative evidence that sildena- Results fil is both a powerful sensitizer of DOX-induced killing of prostate Sildenafil Potentiates DOX-Induced Killing of Prostate Cancer Cells. cancer while providing concurrent cardioprotective benefit. First, we examined the dose-dependent effect of DOX treatment in PC-3 and DU145 cells. Cell growth was reduced in a dose-de- apoptosis | phosphodiesterase-5 | reactive oxygen species pendent manner with DOX in both cells (Fig. 1 A and B). Cotreatment with sildenafil resulted in an additive effect on DOX- rostate cancer remains among the most frequently diagnosed induced reduction of proliferation (Fig. 1 A and B). Cell killing Psolid tumors in men and is one of the leading causes of cancer- assessed by trypan blue exclusion assay also confirmed similar ad- related deaths in Western countries (1). Treatment options are ditive effect (Fig. 1 C and D). DOX treatment also increased ap- limited and are associated with significant morbidity and mortality. optosis as evaluated by TUNEL assays (Fig. 1 E and F). The Doxorubicin [(DOX) Adriamycin] is a broad-spectrum antitumor sildenafil and DOX combination further enhanced apoptosis in PC- antibiotic that has been widely used for treatment of several can- 3 and DU145 cells, whereas sildenafil alone had no effect. Colony cers, including breast, ovarian, and prostate cancers (2). The ef- formation assays performed using median dose effect isobologram fectiveness of DOX is limited due to its high toxicity and side effects, analysis further corroborated the synergistic effect of sildenafiland including myelosuppression, alopecia, acute nausea, vomiting, DOX in enhancing cell killing (Fig. 2A). In contrast, DOX treat- stomatitis, cumulative cardiotoxicity (3), and strong multidrug re- ment induced cell death in the normal prostate epithelial cells sistance response in tumor cells after repeated administration (4). (PrEC), which was significantly reduced by sildenafil (Fig. 2B). Sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) Sildenafil treatment alone had no effect on cell death in the PrEC or inhibit phosphodiesterase-5 (PDE-5), the predominant enzyme in prostate cancer cells. the corpus cavernosum that plays an essential role in vascular Apoptosis was also quantified using Annexin-V-FITC and smooth muscle contraction through specific regulation of cGMP propidium iodide (PI) staining followed by flow cytometry anal- (5). We have demonstrated that sildenafil and other PDE-5 ysis. The cells in the subpopulations labeled by staining of inhibitors induce a powerful protective effect against ischemia/ Annexin-V-FITC(+)/PI(−) were indicative of early apoptotic reperfusion injury (6–10), DOX-induced cardiomyopathy (11), and myocardial infarction-induced heart failure (12). The cardiopro- tective effect is attributed to limiting apoptosis and necrosis Author contributions: A.D. and R.C.K. designed research; A.D., D.D., C.M., E.M., N.N.H., through several mechanisms. These include enhanced expression F.N.S., M.A.P., and I.Q. performed research; R.L. and P.D. contributed new reagents/ana- of nitric oxide synthase (NOS), particularly the endothelial NOS lytic tools.; A.D. and D.D. analyzed data; and A.D. and R.C.K. wrote the paper. (eNOS) and inducible NOS (iNOS); activation of protein kinase C The authors declare no conflict of interest. and protein kinase G (PKG); phosphorylation of ERK1/2; PKG- *This Direct Submission article had a prearranged editor. dependent phosphorylation of GSK-3β; up-regulation of Bcl-2/ Freely available online through the PNAS open access option. Bax; and opening of the mitochondrial KATP channels (6–9, 12–14). 1To whom correspondence may be addressed. E-mail: [email protected] or [email protected]. It has been shown that PDE-5 expression is increased in multiple This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. human carcinomas including metastatic breast cancers, colon ad- 1073/pnas.1006965107/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1006965107 PNAS Early Edition | 1of6 Downloaded by guest on September 26, 2021 A B 120 120 DOX DOX 110 DOX+ Sild 100 DOX+Sild 100 * 80 90 60 80 * * 70 40 Viable cells (% Control) of Viable cells * (% Control) of 60 * * 20 * * 50 0 40 0.00 0.25 0.50 0.75 1.00 0.00 0.25 0.50 0.75 1.00 1.25 1.50 DOX ( M) DOX ( M) C D 35 45 * * 40 30 35 25 30 25 20 * 15 20 * 15 10 Cell Death (%)Cell Death Cell(%) Death 10 5 5 0 0 l o X d ld O il Sild ntr D S DOX X+Si Control Co O D DOX+Sild Fig. 1. Sildenafil (Sild) enhances DOX-induced cell death. Viability of (A) PC-3 and (B) DU145 cells after 72 h of treat- ment with different concentrations of DOX and/or Sild E F (10 μM). Red line represents DOX only; green line represents 40 70 DOX + Sild (10 μM) (*P < 0.001 vs. respective concentration of 60 30 * DOX; n = 6). Cell death assessed by trypan blue exclusion 50 * assay after 24 h of treatment of (C) PC-3 with 1.5 μM DOX ± 40 * 20 μ μ ± μ < * 30 10 M Sild and (D) DU145 with 0.5 M DOX 10 M Sild (*P α 20 0.001 vs. control and P < 0.001 vs. DOX; n = 6). Sild enhances 10 (% of Cells) Total (% of Total Cells) 10 TUNEL Positive Cells DOX-induced apoptosis. Percentage of TUNEL-positive nuclei TUNEL PositiveCells 0 0 in (E) PC-3 cells after 72 h of treatment with 1.5 μM DOX ± ol X ld l X d O ro ild il ntr D Sild μ t S 10 M Sild and (F) DU145 cells after 72 h of treatment with n DO +S Co α Co X DOX+Si μ ± μ < < DO 0.5 M DOX 10 M Sild (*P 0.001 vs. control and P 0.001 vs. DOX; n = 3). Results are presented as means ± SE. cells, whereas those labeled by Annexin-V-FITC(+)/PI(+) were cotreatment with both sildenafil and DOX in PC-3 and DU145 indicative of late apoptotic/necrotic cells. DOX induced apoptosis cells (Fig. 5A). Bcl-2 expression was diminished in DU145 cells after 72 h of treatments in PC-3 (7.52%) and DU145 cells but remained unaltered in PC-3 cells following treatment with (45.01%) compared with control (5.49% in PC-3 and 5.52% in sildenafil and DOX (Fig. 5B and Fig. S4A). Similarly, the ex- DU145) (Fig. S1 A and B). Cotreatment with sildenafil and DOX pression of the antiapoptotic protein Bcl-xL was reduced with increased apoptosis relative to DOX alone in both cell lines sildenafil and DOX compared with individual treatments or (18.71% in PC-3 and 56.82% in DU145 cells) (Fig. S1 A and B). control in both cell lines (Fig. S4B). Bad belongs to the proa- Moreover, the combination treatment increased apoptotic cell poptotic members of the Bcl-2 family and forms a complex with death in other cancer cell types including sarcoma OSAC-1 (Fig.
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