sildenafil-citrate and Neoplasms

Cyclic guanosine monophosphate (cGMP), an important intracellular second messenger, mediates cellular functional responses in all vital organs. Phosphodiesterase 5 (PDE5) is one of the 11 members of the cyclic nucleotide phosphodiesterase (PDE) family that specifically targets cGMP generated by nitric oxide-driven activation of the soluble guanylyl cyclase. PDE5 inhibitors, including sildenafil and tadalafil, are widely used for the treatment of erectile dysfunction, pulmonary arterial hypertension, and certain urological disorders. Preclinical studies have shown promising effects of PDE5 inhibitors in the treatment of myocardial infarction, cardiac hypertrophy, heart failure, cancer and anticancer-drug-associated cardiotoxicity, diabetes, Duchenne muscular dystrophy, Alzheimer's disease, and other aging-related conditions. Many clinical trials with PDE5 inhibitors have focused on the potential cardiovascular, anticancer, and neurological benefits. In this review, we provide an overview of the current state of knowledge on PDE5 inhibitors and their potential therapeutic indications for various clinical disorders beyond erectile dysfunction.

Topics: Cyclic GMP; Erectile Dysfunction; Humans; Male; Neoplasms; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate

The second messenger cyclic guanosine monophosphate (cGMP) is an important regulator of human (patho-)physiology and has emerged as an attractive drug target. Currently, cGMP-elevating drugs are mainly used to treat cardiovascular diseases, but there is also increasing interest in exploring their potential for cancer prevention and therapy. In this review article, we summarise recent findings in cancer-related cGMP research, with a focus on melanoma, breast cancer, colorectal cancer, prostate cancer, glioma, and ovarian cancer. These studies indicate tremendous heterogeneity of cGMP signalling in tumour tissue. It appears that different tumour and stroma cells, and perhaps different sexes, express different cGMP generators, effectors, and degraders. Therefore, the same cGMP-elevating drug can lead to different outcomes in different tumour settings, ranging from inhibition to promotion of tumourigenesis or therapy resistance. These findings, together with recent evidence that increased cGMP signalling is associated with worse prognosis in several human cancers, challenge the traditional view that cGMP elevation generally has an anti-cancer effect. As cGMP pathways appear to be more stable in the stroma than in tumour cells, we suggest that cGMP-modulating drugs should preferentially target the tumour microenvironment. Indeed, there is evidence that phosphodiesterase 5 inhibitors like sildenafil enhance anti-tumour immunity by acting on immune cells. Moreover, many in vivo results obtained with cGMP-modulating drugs could be explained by effects on the tumour vasculature rather than on the tumour cells themselves. We therefore propose a model that incorporates the NO/cGMP signalling pathway in tumour vessels as a key target for cancer therapy. Deciphering the multifaceted roles of cGMP in cancer is not only a challenge for basic research, but also provides a chance to predict potential adverse effects of cGMP-modulating drugs in cancer patients and to develop novel anti-tumour therapies by precision targeting of the relevant cells and molecular pathways.

Topics: Cyclic GMP; Humans; Male; Neoplasms; Phosphodiesterase 5 Inhibitors; Signal Transduction; Sildenafil Citrate; Tumor Microenvironment

The concepts of drug repurposing and Sildenafil or blue pill are tightly linked over the years. Indeed, in addition to its initial clinical application as an anti-hypertensive drug in the pulmonary system, Sildenafil is also known for its beneficial effects in erectile dysfunction. Moreover, evidence has been accumulated to support its value in anti-cancer therapy, either alone or in combination with other clinically efficient chemotherapy drugs. In this review, we focused on the old and recent in vitro and in vivo studies demonstrating the cellular and molecular rationale for the application of Sildenafil in combination therapy in various types of cancer. We emphasized on the different molecular targets as well as the different signaling pathways involved in cancer cells. The pro-apoptotic effect of Sildenafil through nitric oxide (NO)/ phosphodiesterase type 5 (PDE5)-dependent manner seems to be one of the most common mechanisms. However, the activation of autophagy, as well as the modulation of the anti-tumor immunity, constitutes the other pathways triggered by Sildenafil. Overall, the studies converged to reveal the complexity of the anti-cancer potential of Sildenafil. Thus, through our review, we aimed to present an updated and simplified picture of such repurposing of Sildenafil in the field of oncology.

Topics: Erectile Dysfunction; Humans; Male; Neoplasms; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones

Advances in cancer treatment have greatly improved survival rates of children with cancer. However, these same chemotherapeutic or radiologic treatments may result in long-term health consequences. Anthracyclines, chemotherapeutic drugs commonly used to treat children with cancer, are known to be cardiotoxic, but the mechanism by which they induce cardiac damage is still not fully understood. A higher cumulative anthracycline dose and a younger age of diagnosis are only a few of the many risk factors that identify the children at increased risk of developing cardiotoxicity. While cardiotoxicity can develop at anytime, starting from treatment initiation and well into adulthood, identifying the best cardioprotective measures to minimize the long-term damage caused by anthracyclines in children is imperative. Dexrazoxane is the only known agent to date, that is associated with less cardiac dysfunction, without reducing the oncologic efficacy of the anthracycline doxorubicin in children. Given the serious long-term health consequences of cancer treatments on survivors of childhood cancers, it is essential to investigate new approaches to improving the safety of cancer treatments.

Topics: Adiponectin; Age Factors; Angiotensin-Converting Enzyme Inhibitors; Anthracyclines; Antibiotics, Antineoplastic; Antioxidants; Carbazoles; Cardiolipins; Cardiotonic Agents; Carvedilol; Doxorubicin; Erythropoietin; Heart; Heart Diseases; Humans; Lipid Peroxidation; Liposomes; Neoplasms; Piperazines; Propanolamines; Purines; Razoxane; Risk Factors; Sildenafil Citrate; Sulfones; Survivors; Ventricular Dysfunction, Left

The phenomenon of multidrug resistance (MDR) has decreased the hope for successful cancer chemotherapy. The ATP-binding cassette (ABC) transporter superfamily is the largest transmembrane family. The overexpression of ABC transporters is a major determinant of MDR in cancer cells both in vitro and in vivo. Unfortunately, until recently, most of the strategies used to surmount ABC-transporter-mediated MDR have had limited success. An ideal modulator of MDR would be one that has a low liability to induce toxicity and alter the pharmacokinetic profile of antineoplastic drugs. Sildenafil, an inhibitor of cGMP-specific phosphodiesterase type 5, was found to significantly reverse ABC-transporter-mediated MDR. Our results indicate that sildenafil has differential inhibitory effects on ABC transporters: It significantly decreases the efflux activity of ABCB1 and ABCG2, but has no significant effects on ABCC1. Emerging evidence indicates that sildenafil and other phosphodiesterase type 5 inhibitors may enhance the sensitivity of certain types of cancer to standard chemotherapeutic drugs.

Topics: ATP-Binding Cassette Transporters; Drug Resistance, Neoplasm; Humans; Multidrug Resistance-Associated Proteins; Neoplasms; Piperazines; Purines; Sildenafil Citrate; Sulfones

Topics: Carcinogens; Female; France; Humans; Neoplasms; Orgasm; Piperazines; Purines; Sexual Behavior; Sexual Dysfunctions, Psychological; Sildenafil Citrate; Sulfones; Vasodilator Agents; Virilism

Sildenafil citrate, marketed as Viagra, for the treatment of erectile dysfunction, has a proven record of safety in humans as predicted by the results of extensive pharmacological and toxicological testing in animals and in vitro, and confirmed by pharmacokinetic exposure data. The aim of this paper is to review succinctly the main findings resulting from these experiments. Daily doses of sildenafil, within and far beyond the human therapeutic range, were given to dogs and rodents for up to 1 and 2 y, respectively. Plasma analyses were conducted to determine the exposure to sildenafil. We found species-specific effects in dogs (Beagle pain syndrome), mice (marked intestinal dilatation) and rats (adaptive reversible hepatocellular hypertrophy associated with secondary thyroid hypertrophy). All these effects in rodents and dogs have no relevance to humans. Morphometric thickness measurements of the retinal layers carried out in response to clinical observations of visual disturbances in humans indicated no difference between treated and control rats and dogs after up to 24 months of treatment. There was no evidence of histopathologic damage to any structures of the visual pathway. Sildenafil had no effects on fertility, no teratogenic potential, was not genotoxic and has no carcinogenic potential. In rats and dogs, safety ratios were 40:1 and 28:1, respectively, in terms of exposure over 24 h (AUC24 h) and 19:1 and 8:1, respectively, in terms of peak plasma concentration (Cmax). These safety ratios illustrate the separation between exposure to sildenafil of animals at large nontoxic doses and the much smaller human therapeutic exposure. This profile highlights the very low risk of human toxicity for sildenafil. The favourable results of the nonclinical safety evaluation of sildenafil in established animal models have been confirmed by many years of clinical experience during the development and marketing of sildenafil.

Topics: Abnormalities, Drug-Induced; Animals; Dogs; Drug Evaluation, Preclinical; Female; Fertility; Fetal Development; Humans; Male; Mice; Mutation; Neoplasms; Piperazines; Pregnancy; Purines; Rats; Reproduction; Sildenafil Citrate; Species Specificity; Sulfones

Palmar-plantar erythrodysesthesia (PPE) is a common chemotherapy and anti-VEGF multi-kinase inhibitor class-related toxicity that often results in debilitating skin changes and often limits the use of active anti-cancer regimens. Mechanistic and anecdotal clinical evidence suggested that topical application of sildenafil cream may help reduce the severity of PPE. Therefore, we conducted a randomized, double-blind, placebo-controlled pilot study to evaluate the feasibility, safety and efficacy of topical sildenafil cream for the treatment of PPE.. Eligible subjects were required to have grade 1-3 PPE associated with either capecitabine or sunitinib. Subjects were randomized to receive 1 % topical sildenafil cream to the left extremities or right extremities and placebo cream on the opposite extremity. Two times per day, 0.5 mL of cream was applied to each affected hand/foot. The primary endpoint was improvement in PPE grading at any point on study. Clinical assessments were evaluated by NCI-CTC 4.0 grading and patient self-reported pain.. Ten subjects were enrolled, nine were evaluable for safety and efficacy. Five of nine subjects reported some improvement in foot pain and three of eight subjects for hand pain improvement. One of these subjects noted specific improvement in tactile function. No treatment-related toxicities were observed.. In this limited, single-center study, topical cream containing 1 % sildenafil is feasible to administer, is well-tolerated, and may mitigate PPE-related symptoms due to anti-cancer therapeutic agents. Further validation is necessary.

Topics: Adult; Aged; Antineoplastic Agents; Capecitabine; Deoxycytidine; Double-Blind Method; Female; Fluorouracil; Hand-Foot Syndrome; Humans; Indoles; Male; Middle Aged; Neoplasms; Pilot Projects; Piperazines; Placebos; Protein Kinase Inhibitors; Purines; Pyrroles; Sildenafil Citrate; Sulfonamides; Sunitinib; Vascular Endothelial Growth Factor A

Lactic acid in tumor microenvironment inhibits iNKT cell functions and thus dampens their anti-tumor efficacy. The underlying mechanisms remain unclear. Here, we show that phosphodiesterase-5 inhibitors, sildenafil and tadalafil, promote IFN-γ and IL-4 production in iNKT cells in a cGMP-PKG pathway dependent manner. To favor their cytokine production, iNKT cells reduce Pde5a mRNA lever after activation. In line with the reduction of cytokines caused by lactic acid, lactic acid elevates Pde5a mRNA lever in activated iNKT cells. As a result, phosphodiesterase-5 inhibitor partially restores the cytokine production in lactic acid-treated cells. Our results demonstrate that phosphodiesterase-5 inhibits cytokine production in iNKT cells, and that contributes to the lactic acid-caused dysfunction of iNKT cells.

Topics: Animals; Cell Proliferation; Cyclic Nucleotide Phosphodiesterases, Type 5; Cytokines; Interferon-gamma; Lactic Acid; Mice; Mice, Inbred C57BL; Natural Killer T-Cells; Neoplasms; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Tadalafil

The repurposing of existing drugs has emerged as an attractive additional strategy to the development of novel compounds in the fight against cancerous diseases. Inhibition of phosphodiesterase 5 (PDE5) has been claimed as a potential approach to target various cancer subtypes in recent years. However, data on the treatment of tumors with PDE5 inhibitors as well as the underlying mechanisms are as yet very scarce. Here, we report that treatment of tumor cells with low concentrations of Sildenafil was associated with decreased cancer cell proliferation and augmented apoptosis in vitro and resulted in impaired tumor growth in vivo. Notably, incubation of cancer cells with Sildenafil was associated with altered expression of HSP90 chaperone followed by degradation of protein kinase D2, a client protein previously reported to be involved in tumor growth. Furthermore, the involvement of low doses of PU-H71, an HSP90 inhibitor currently under clinical evaluation, in combination with low concentrations of Sildenafil, synergistically and negatively impacted on the viability of cancer cells in vivo. Taken together, our study suggests that repurposing of already approved drugs, alone or in combination with oncology-dedicated compounds, may represent a novel cancer therapeutic strategy.

Topics: Apoptosis; Cell Line, Tumor; HSP90 Heat-Shock Proteins; Humans; Neoplasms; Phosphodiesterase 5 Inhibitors; Proteolysis; Sildenafil Citrate; TRPP Cation Channels

Cisplatin-induced nephrotoxicity in large proportion of patients. The aim of this work is to clarify the effect of combination of sildenafil and gemfibrozil on cisplatin-induced nephrotoxicity either before or after cisplatin treatment and determination of nephrotoxicity predictors among the measured tissue markers.. Thirty two adult male albino rats were divided into four equal groups (G) GI control, GII received cisplatin, GIII received sildenafil and gemfibrozil before cisplatin, GIV received sildenafil and gemfibrozil after cisplatin. Creatinine and urea were measured and animals were sacrificed and kidney was taken for histopathology. The following tissue markers were measured, heme oxygenase-1 (HO-1) activity, reduced glutathione, quantitative (real-time polymerase chain reaction) RT-PCR for gene expression of tumor necrosis factor alpha (TNF-α) and endothelial nitric oxide synthase (ENOS) level.. GII developed AKI demonstrated by significantly high urea and creatinine and severe diffuse (80-90%) tubular necrosis. TNF-α was highly and significantly elevated while the rest of tissue markers were significantly reduced in GI1 compared to other groups. GIV showed better results compared to GIII. There was a significant positive correlation between creatinine and TNF-α when combining GI and GII while there were significant negative correlation between creatinine and other tissue markers in same groups. Linear regression analysis demonstrated that HO-1 was the independent predictor of AKI demonstrated by elevated creatinine among GI and GII.. Combination of sildenafil and gemfibrozil can be used in treatment of cisplatin-induced nephrotoxicity. HO-1 is a promising target for prevention and/or treatment of cisplatin-induced nephrotoxicity.

Topics: Animals; Antineoplastic Agents; Apoptosis; Biomarkers; Cisplatin; Creatinine; Disease Models, Animal; Drug Therapy, Combination; Gemfibrozil; Glutathione; Heme Oxygenase-1; Humans; Kidney; Male; Neoplasms; Oxidative Stress; Rats; Renal Insufficiency; Sildenafil Citrate; Treatment Outcome; Urea

We have recently demonstrated that multi-kinase inhibitors such as sorafenib and pazopanib can suppress the detection of chaperones by in situ immuno-fluorescence, which is further enhanced by phosphodiesterase 5 inhibitors. Sorafenib and pazopanib inhibited the HSP90 ATPase activity with IC50 values of ~1.0 μM and ~75 nM, respectively. Pazopanib docked in silico with two possible poses into the HSP90 ATP binding pocket. Pazopanib and sildenafil combined to reduce the total protein levels of HSP1H/p105 and c-MYC and to reduce their co-localization. Sorafenib/pazopanib combined with sildenafil in a [GRP78+HSP27] -dependent fashion to: (i) profoundly activate an eIF2α/Beclin1 pathway; (ii) profoundly inactivate mTOR and increase ATG13 phosphorylation, collectively resulting in the formation of toxic autophagosomes. In a fresh PDX isolate of NSCLC combined knock down of [ERBB1+ERBB3] or use of the ERBB1/2/4 inhibitor afatinib altered cell morphology, enhanced ATG13 phosphorylation, inactivated NFκB, and further enhanced [sorafenib/pazopanib + sildenafil] lethality. Identical data to that with afatinib were obtained knocking down PI3K p110α/β or using buparlisib, copanlisib or the specific p110α inhibitor BYL719. Afatinib adapted NSCLC clones were resistant to buparlisib or copanlisib but were more sensitive than control clones to [sorafenib + sildenafil] or [pazopanib + sildenafil]. Lapatinib significantly enhanced the anti-tumor effect of [regorafenib + sildenafil] in vivo; afatinib and BYL719 enhanced the anti-tumor effects of [sorafenib + sildenafil] and [pazopanib] in vivo, respectively.

Topics: Adenosine Triphosphate; Animals; Antineoplastic Agents; Autophagy; Binding Sites; Cell Line, Tumor; Endoplasmic Reticulum Chaperone BiP; ErbB Receptors; Female; Humans; Indazoles; Inhibitory Concentration 50; Mice; Mice, Nude; Microscopy, Fluorescence; Molecular Chaperones; Neoplasms; Phosphatidylinositol 3-Kinases; Protein Kinase Inhibitors; Pyrimidines; Receptor, ErbB-2; Receptor, ErbB-4; RNA, Small Interfering; Sildenafil Citrate; Sulfonamides; Xenograft Model Antitumor Assays

Topics: Animals; Azoles; Bipolar Disorder; Carbazoles; Clinical Trials, Phase II as Topic; Dipyridamole; Drug Approval; Drug Evaluation, Preclinical; Drug Industry; Drug Repositioning; Drugs, Generic; Dry Eye Syndromes; Epilepsy; Humans; Isoindoles; Mice; Multiple Sclerosis; Neoplasms; Off-Label Use; Organoselenium Compounds; Patents as Topic; Sildenafil Citrate; Zidovudine

The present studies determined whether clinically relevant phosphodiesterase 5 (PDE5) inhibitors interacted with a clinically relevant NSAID, celecoxib, to kill tumor cells. Celecoxib and PDE5 inhibitors interacted in a greater than additive fashion to kill multiple tumor cell types. Celecoxib and sildenafil killed ex vivo primary human glioma cells as well as their associated activated microglia. Knock down of PDE5 recapitulated the effects of PDE5 inhibitor treatment; the nitric oxide synthase inhibitor L-NAME suppressed drug combination toxicity. The effects of celecoxib were COX2 independent. Over-expression of c-FLIP-s or knock down of CD95/FADD significantly reduced killing by the drug combination. CD95 activation was dependent on nitric oxide and ceramide signaling. CD95 signaling activated the JNK pathway and inhibition of JNK suppressed cell killing. The drug combination inactivated mTOR and increased the levels of autophagy and knock down of Beclin1 or ATG5 strongly suppressed killing by the drug combination. The drug combination caused an ER stress response; knock down of IRE1α/XBP1 enhanced killing whereas knock down of eIF2α/ATF4/CHOP suppressed killing. Sildenafil and celecoxib treatment suppressed the growth of mammary tumors in vivo. Collectively our data demonstrate that clinically achievable concentrations of celecoxib and sildenafil have the potential to be a new therapeutic approach for cancer.

Topics: Animals; Apoptosis; Autophagy; Celecoxib; Cell Line, Tumor; Drug Synergism; Endoplasmic Reticulum Stress; Female; Humans; Mammary Neoplasms, Experimental; Mice, Nude; Neoplasms; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Pyrazoles; Signal Transduction; Sildenafil Citrate; Sulfonamides

We determined whether the multi-kinase inhibitor sorafenib or its derivative regorafenib interacted with phosphodiesterase 5 (PDE5) inhibitors such as Viagra (sildenafil) to kill tumor cells. PDE5 and PDGFRα/β were over-expressed in liver tumors compared to normal liver tissue. In multiple cell types in vitro sorafenib/regorafenib and PDE5 inhibitors interacted in a greater than additive fashion to cause tumor cell death, regardless of whether cells were grown in 10 or 100% human serum. Knock down of PDE5 or of PDGFRα/β recapitulated the effects of the individual drugs. The drug combination increased ROS/RNS levels that were causal in cell killing. Inhibition of CD95/FADD/caspase 8 signaling suppressed drug combination toxicity. Knock down of ULK-1, Beclin1, or ATG5 suppressed drug combination lethality. The drug combination inactivated ERK, AKT, p70 S6K, and mTOR and activated JNK. The drug combination also reduced mTOR protein expression. Activation of ERK or AKT was modestly protective whereas re-expression of an activated mTOR protein or inhibition of JNK signaling almost abolished drug combination toxicity. Sildenafil and sorafenib/regorafenib interacted in vivo to suppress xenograft tumor growth using liver and colon cancer cells. From multiplex assays on tumor tissue and plasma, we discovered that increased FGF levels and ERBB1 and AKT phosphorylation were biomarkers that were directly associated with lower levels of cell killing by 'rafenib + sildenafil. Our data are now being translated into the clinic for further determination as to whether this drug combination is a useful anti-tumor therapy for solid tumor patients.

Topics: Apoptosis; Cell Proliferation; Cyclic Nucleotide Phosphodiesterases, Type 5; Drug Synergism; Gene Expression Regulation, Enzymologic; Gene Knockdown Techniques; Hep G2 Cells; Humans; Neoplasm Proteins; Neoplasms; Niacinamide; Phenylurea Compounds; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Signal Transduction; Sildenafil Citrate; Sorafenib; Sulfonamides; Xenograft Model Antitumor Assays

Topics: Erectile Dysfunction; Humans; Male; Neoplasms; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones