sildenafil-citrate and Carcinoma--Squamous-Cell

Disabling pansclerotic morphea of childhood (DPMC) is a rare and severe variant of scleroderma. This report presents 3 cases that presented to the authors and studies 25 patients from the literature (English language only) for the presence of chronic nonhealing ulcers of skin and skin cancer. The authors identified a total of 30 patients (9 male and 21 female) aged between 1 and 37 years at time of presentation. All cases were less than 14 years old when the disease started. The majority of patients had an aggressive course with deep sclerotic lesions leading to joint contractures and immobility. Five patients suffered from chronic nonhealing leg ulcers (17%), but ulcers were present on other parts of the body (upper limbs, trunk, head) as well (n = 6). Four patients died because of complications of the disease such as sepsis or gangrene. Two patients developed a squamous cell carcinoma at the age of 16 years and 19 years, respectively (6.7%). The available treatment of DMPC-associated ulcers is unsatisfying. Only temporary improvements have been seen in a minority of patients. We report on marked improvement of chronic leg ulcers by a combination of sildenafil 3 x 20 mg/day and repeated application of a porcine small intestinal submucosal acellular matrix.

Topics: Adolescent; Adult; Carcinoma, Squamous Cell; Chronic Disease; Collagen; Combined Modality Therapy; Contracture; Female; Humans; Male; Piperazines; Purines; Scleroderma, Localized; Sildenafil Citrate; Skin Neoplasms; Skin Ulcer; Skin, Artificial; Sulfones; Vasodilator Agents

Phosphodiesterase 5 (PDE5) holds clinical relevance in several pathological states, including lung, breast, and prostate cancer. In this study, we examined PDE5 expression in oral squamous cell carcinoma (OSCC)-derived cell lines and tissues, and the anti-tumour effect of PDE5 inhibitor, sildenafil citrate (SC).. Cell proliferation, cell invasion, and gap closure assays were performed in six OSCC-derived cell lines upon treatment with varying concentrations of SC. PDE5 expression was determined in primary OSCC tissues by western blotting and immunohistochemistry.. Elevated PDE5 expression was observed in all cell lines. A concentration-dependent decrease in cell viability, invasion rate, and migration was observed after SC treatment. A significant correlation (p=0.05) was observed between elevated PDE5 expression and lymphatic infiltration in OSCC tissues.. PDE5 plays an important role in carcinogenesis of OSCC, and the specific inhibition of PDE5 may be an effective chemotherapeutic strategy.

Topics: Blotting, Western; Carcinoma, Squamous Cell; Cell Line; Cell Line, Tumor; Cell Survival; Cyclic Nucleotide Phosphodiesterases, Type 5; Dose-Response Relationship, Drug; Humans; Immunohistochemistry; Mouth Neoplasms; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate

The study focused on identifying the mechanisms or drugs that could sensitize P-glycoprotein (P-gp)-overexpressing resistant KBV20C cancer cells to halaven (HAL) or vincristine (VIC) treatment.. Based on the relatively low dose or IC. DON or SID reduced cell viability, increased G. These results suggest that HAL-FLU or HAL-SID sensitization in KBV20C cells involves both cytotoxic and P-gp inhibitory effects, whereas HAL-DON sensitization may involve only P-gp inhibitory activity of DON.

Topics: Antimitotic Agents; Apoptosis; ATP Binding Cassette Transporter, Subfamily B; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Donepezil; Down-Regulation; Drug Repositioning; Drug Resistance, Neoplasm; Drug Synergism; Furans; Gene Expression Regulation, Neoplastic; Humans; Indans; Ketones; Mouth Neoplasms; Piperidines; Sildenafil Citrate; Vincristine

The RAS/RAF/mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK) kinase/ERK cascade plays a crucial role in melanoma cell proliferation and survival. Sildenafil citrate (Viagra) is a phosphodiesterase (PDE) 5A inhibitor commonly used for erectile dysfunction. Recent studies have shown that BRAF activation down-regulates PDE5A levels, and low PDE5A expression by BRAF activation or sildenafil use increases the invasiveness of melanoma cells, which raises the possible adverse effect of sildenafil use on melanoma risk.. To evaluate the association between sildenafil use and risk of incident melanoma among men in the United States.. Our study is a prospective cohort study. In 2000, participants in the Health Professionals' Follow-up Study were questioned regarding sildenafil use for erectile dysfunction. Participants who reported cancers at baseline were excluded. A total of 25,848 men remained in the analysis.. The incidence of skin cancers, including melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC), was obtained in the self-reported questionnaires biennially. The diagnosis of melanoma and SCC was pathologically confirmed.. We identified 142 melanoma, 580 SCC, and 3030 BCC cases during follow-up (2000-2010). Recent sildenafil use at baseline was significantly associated with an increased risk of subsequent melanoma with a multivariate-adjusted hazard ratio (HR) of 1.84 (95% CI, 1.04-3.22). In contrast, we did not observe an increase in risk of SCC (HR, 0.84; 95% CI, 0.59-1.20) or BCC (1.08; 0.93-1.25) associated with sildenafil use. Moreover, erectile function itself was not associated with an altered risk of melanoma. Ever use of sildenafil was also associated with a higher risk of melanoma (HR, 1.92; 95% CI, 1.14-3.22). A secondary analysis excluding those reporting major chronic diseases at baseline did not appreciably change the findings; the HR of melanoma was 2.24 (95% CI, 1.05-4.78) for sildenafil use at baseline and 2.77 (1.32-5.85) for ever use.. Sildenafil use may be associated with an increased risk of developing melanoma. Although this study is insufficient to alter clinical recommendations, we support a need for continued investigation of this association.

Topics: Aged; Carcinoma, Basal Cell; Carcinoma, Squamous Cell; Erectile Dysfunction; Follow-Up Studies; Humans; Male; Melanoma; Middle Aged; Phosphodiesterase 5 Inhibitors; Piperazines; Prospective Studies; Purines; Sildenafil Citrate; Skin Neoplasms; Sulfones; United States

Sildenafil is a potent and selective inhibitor of the type 5 cGMP (cyclic guanosine 3',5'-monophosphate)-specific phosphodiesterase that is used clinically to treat erectile dysfunction and pulmonary arterial hypertension. Here, we report that sildenafil has differential effects on cell surface ABC transporters such as ABCB1, ABCC1, and ABCG2 that modulate intracompartmental and intracellular concentrations of chemotherapeutic drugs. In ABCB1-overexpressing cells, nontoxic doses of sildenafil inhibited resistance and increased the effective intracellular concentration of ABCB1 substrate drugs such as paclitaxel. Similarly, in ABCG2-overexpressing cells, sildenafil inhibited resistance to ABCG2 substrate anticancer drugs, for example, increasing the effective intracellular concentration of mitoxantrone or the fluorescent compound BODIPY-prazosin. Sildenafil also moderately inhibited the transport of E(2)17βG and methotrexate by the ABCG2 transporter. Mechanistic investigations revealed that sildenafil stimulated ABCB1 ATPase activity and inhibited photolabeling of ABCB1 with [(125)I]-iodoarylazidoprazosin (IAAP), whereas it only slightly stimulated ABCG2 ATPase activity and inhibited photolabeling of ABCG2 with [(125)I]-IAAP. In contrast, sildenafil did not alter the sensitivity of parental, ABCB1-, or ABCG2-overexpressing cells to non-ABCB1 and non-ABCG2 substrate drugs, nor did sildenafil affect the function of another ABC drug transporter, ABCC1. Homology modeling predicted the binding conformation of sildenafil within the large cavity of the transmembrane region of ABCB1. Overall, we found that sildenafil inhibits the transporter function of ABCB1 and ABCG2, with a stronger effect on ABCB1. Our findings suggest a possible strategy to enhance the distribution and potentially the activity of anticancer drugs by jointly using a clinically approved drug with known side effects and drug-drug interactions.

Topics: Adenosine Triphosphatases; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Boron Compounds; Carcinoma, Squamous Cell; Cell Line, Tumor; Drug Resistance, Neoplasm; Drug Synergism; Humans; KB Cells; Methotrexate; Mitoxantrone; Models, Molecular; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Paclitaxel; Piperazines; Prazosin; Purines; Sildenafil Citrate; Sulfones