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Re: Use of Phosphodiesterase Type 5 Inhibitors May Adversely Impact Biochemical Recurrence after Radical Prostatectomy
Phosphodiesterase-5 inhibitors (PDE5Is) represent a group of drugs that are registered for the treatment of erectile dysfunctions predominantly, but recently also for treatment of pulmonary hypertension and benign prostatic hypertrophy. However, more and more research deals with possible antitumor potential of PDE5Is in different types of cancers, including prostate cancer. Prostate cancer represents the one of the most common carcinoma in the male population, whose incidence is continuously increasing. Early detection combined with radical prostatectomy increases the survival rate, but also it is necessary to keep in mind the quality of life of patients undergoing prostatectomy in light of bladder control and erectile function. Authors of various clinical studies presented the results that often lead to totally opposing conclusions. For example, Chavez and colleagues have shown that use of PDE5Is in men with erectile dysfunction decreases the risk of developing prostate cancer, while, on the other hand, Michl and colleagues pointed out the adversely effect of PDE5Is on biochemical recurrence after bilateral nerve sparing radical prostatectomy. In that sense, the aim of this review was to present as many as possible of existing results dealing with of action of PDE5Is in the field of prostatic carcinoma. Taking into account all presented data, it can be concluded that eff ect of PDE5Is on formation, development and outcome of treatment in patients with prostate carcinoma is very intriguing question, whose response requires additional both experimental and clinical research.
We examined the interaction between OSU-03012 (also called AR-12) with phosphodiesterase 5 (PDE5) inhibitors to determine the role of the chaperone GRP78/BiP/HSPA5 in the cellular response. Sildenafil (Viagra) interacted in a greater than additive fashion with OSU-03012 to kill stem-like GBM cells. Treatment of cells with OSU-03012/sildenafil: abolished the expression of multiple oncogenic growth factor receptors and plasma membrane drug efflux pumps and caused a rapid degradation of GRP78 and other HSP70 and HSP90 family chaperone proteins. Decreased expression of plasma membrane receptors and drug efflux pumps was dependent upon enhanced PERK-eIF2α-ATF4-CHOP signaling and was blocked by GRP78 over-expression. In vivo OSU-03012/sildenafil was more efficacious than treatment with celecoxib and sildenafil at killing tumor cells without damaging normal tissues and in parallel reduced expression of ABCB1 and ABCG2 in the normal brain. The combination of OSU-03012/sildenafil synergized with low concentrations of sorafenib to kill tumor cells, and with lapatinib to kill ERBB1 over-expressing tumor cells. In multiplex assays on plasma and human tumor tissue from an OSU-03012/sildenafil treated mouse we noted a profound reduction in uPA signaling and identified FGF and JAK1/2 as response biomarkers for potentially suppressing the killing response. Inhibition of FGFR signaling and to a lesser extent JAK1/2 signaling profoundly enhanced OSU-03012/sildenafil lethality. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
The present studies determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with clinically relevant chemotherapies to kill gastrointestinal / genitourinary (GI/GU) cancer cells. In bladder cancer cells, regardless of H-RAS mutational status, at clinically achievable doses, PDE5 inhibitors interacted in a greater than additive fashion with doxorubicin / mitomycin C / gemcitabine / cisplatin / paclitaxel to cause cell death. In pancreatic tumor cells expressing mutant active K-RAS PDE5 inhibitors interacted in a greater than additive fashion with doxorubicin / gemcitabine / paclitaxel to cause cell death. The most potent PDE5 inhibitor was sildenafil. Knock down of PDE5 expression recapitulated the combination effects of PDE5 inhibitor drugs with chemotherapy drugs. Expression of c-FLIP-s did not significantly inhibit chemotherapy lethality but did significantly reduce enhanced killing in combination with sildenafil. Over-expression of BCL-XL suppressed individual and combination drug toxicities. Knock down of CD95 or FADD suppressed drug combination toxicity. Combination toxicity was also abolished by necrostatin or RIP1 knock down. Treatment with PDE5 inhibitors and chemotherapy drugs promoted autophagy which was maximal at ~24 h -post treatment, and 3-methyl adenine or knock down of Beclin1 suppressed drug combination lethality by ~50%. PDE5 inhibitors enhanced and prolonged the induction of DNA damage as judged by Comet assays and gamma H2AX and CHK2 phosphorylation. Knock down of ATM suppressed gamma H2AX and CHK2 phosphorylation and enhanced drug combination lethality. Collectively our data demonstrate that the combination of PDE5 inhibitors with standard of care chemotherapy agents for GI/GU cancers represents a novel modality.
A recent study reported a detrimental effect of phosphodiesterase type 5 inhibitors (PDE5-Is) on biochemical recurrence (BCR) after radical prostatectomy (RP) for prostate cancer (PCa). We tested the association between PDE5-I use, PDE5-I therapy scheme, number of PDE5-I pills taken, and BCR in 2579 patients treated with bilateral nerve-sparing RP for PCa between 2004 and 2013 at a single center. Patients were categorized according to PDE5-I use within 2 yr after surgery as on demand, rehabilitation schedule (daily PDE5-I use for at least 3 mo), and no PDE5-I use. Multivariable (MVA) Cox regression models tested the association between PDE5-I and BCR. The same analyses were repeated using the number of PDE5-I pills taken by each patient. Overall, 674 patients (26.1%) received PDE5-Is. At MVA analysis, PDE5-I use, type of administration schedule, and number of PDE5-I pills were not significantly associated with higher risk of BCR (all p ≥ 0.2) after accounting for multiple confounders including time from RP to PDE5-I use. While awaiting further studies, patients should not be denied PDE5-I treatment after RP.
Among patients treated with radical prostatectomy, phosphodiesterase type 5 inhibitor use was not associated with an increased risk of biochemical recurrence, regardless of the therapeutic regimen used.
Copyright © 2015 European Association of Urology. Published by Elsevier B.V. All rights reserved.
We evaluated the safety and efficacy of exisulind for delaying disease progression in men with increasing prostate specific antigen (PSA) after radical prostatectomy.
A total of 96 men with increasing PSA after radical prostatectomy were randomized to receive placebo (49) or 250 mg. exisulind twice daily (47) for 12 months. The primary efficacy parameter was the difference in change from baseline PSA between the placebo and exisulind groups. The PSA doubling time was also evaluated before and during study. A subgroup analysis classified patients based on the risk of developing metastatic disease.
Compared with placebo, exisulind significantly suppressed the increase in PSA in all patients (p = 0.017). The results were also statistically significant in men at high risk for metastasis (p = 0.0003) and those who could not be classified according to risk (p = 0.0009). In addition, median PSA doubling time was lengthened in high risk patients on exisulind (2.12 month increase) compared with those on placebo (3.37 month decrease, p = 0.048). Exisulind was well tolerated.
Exisulind inhibited the increase in PSA overall and prolonged PSA doubling time in high risk patients compared with placebo. These results suggest that Exisulind has the potential to extend the time from biochemical recurrence to the need for androgen deprivation therapy. Exisulind was well tolerated in this patient population. Our results support further study of Exisulind in the treatment of patients with prostate cancer.