sildenafil-citrate and Colonic-Neoplasms

Topics: Animals; Cell Proliferation; Chromatography, Liquid; Colonic Neoplasms; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Mice; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate; Tandem Mass Spectrometry

Topics: Animals; Colonic Neoplasms; Colorectal Neoplasms; Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Inflammation; Mice; Mutation; Sildenafil Citrate

Topics: Animals; Chemoprevention; Colonic Neoplasms; Colorectal Neoplasms; Inflammation; Mice; Sildenafil Citrate

Recently, sildenafil was reported to be an inhibitor of P-glycoprotein (P-gp/ABCB1) and breast cancer resistance protein (BCRP/ABCG2) in vitro. We have now investigated the in vivo potency of sildenafil.. By using wild-type and Abcb1; Abcg2 knockout mice we have investigated the effect of sildenafil on the brain penetration of two substrate drugs (docetaxel and topotecan). Next we have investigated if sildenafil was able to improve the efficacy of doxorubicin against P-glycoprotein expressing CT26 colon cancer cells in syngeneic Balb/c mice.. Sildenafil administered orally at a dose of 50mg/kg did not improve the brain penetration of docetaxel and topotecan, although the plasma level of sildenafil was already much higher than can be achieved in humans. On the other hand, sildenafil increased the plasma levels of the cytotoxic drugs, but not by inhibition of Abcb1 or Abcg2, since this effect was also seen in Abcb1;Abcg2 knockout mice. The brain penetration of sildenafil was more than 20-fold higher in Abcb1;Abcg2 mice versus wild-type mice, indicating that sildenafil is a good substrate of the two transporters. Sildenafil was also not able to improve the efficacy of doxorubicin against subcutaneous CT26 tumours. The doxorubicin level in tumour tissue did increase, but so did the concentration of doxorubicin in plasma and heart.. These results demonstrate that the potency and specificity of sildenafil as an inhibitor of ABCB1 and ABCG2 is not sufficient to warrant further clinical testing of this agent in combination with anticancer drugs.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Brain; Cell Line, Tumor; Cell Proliferation; Chromatography, High Pressure Liquid; Colonic Neoplasms; Docetaxel; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Mice; Mice, Inbred BALB C; Mice, Knockout; Piperazines; Purines; Sildenafil Citrate; Sulfones; Taxoids; Topoisomerase I Inhibitors; Topotecan; Tumor Burden; Vasodilator Agents

Nonsteroidal anti-inflammatory drugs (NSAID) display promising antineoplastic activity for colorectal and other cancers, but toxicity from COX inhibition limits their long-term use for chemoprevention. Previous studies have concluded that the basis for their tumor cell growth inhibitory activity does not require COX inhibition, although the underlying mechanism is poorly understood. Here, we report that the NSAID sulindac sulfide inhibits cyclic guanosine 3',5'-monophosphate phosphodiesterase (cGMP PDE) activity to increase intracellular cGMP levels and activate cGMP-dependent protein kinase (PKG) at concentrations that inhibit proliferation and induce apoptosis of colon tumor cells. Sulindac sulfide did not activate the cGMP/PKG pathway, nor affect proliferation or apoptosis in normal colonocytes. Knockdown of the cGMP-specific PDE5 isozyme by siRNA and PDE5-specific inhibitors tadalafil and sildenafil also selectively inhibited the growth of colon tumor cells that expressed high levels of PDE5 compared with colonocytes. The mechanism by which sulindac sulfide and the cGMP/PKG pathway inhibits colon tumor cell growth involves the transcriptional suppression of β-catenin to inhibit Wnt/β-catenin T-cell factor transcriptional activity, leading to downregulation of cyclin D1 and survivin. These observations suggest that safer and more efficacious sulindac derivatives can be developed for colorectal cancer chemoprevention by targeting PDE5 and possibly other cGMP-degrading isozymes.

Topics: Antineoplastic Agents; Apoptosis; Caco-2 Cells; Carbolines; Cell Line; Cell Proliferation; Colonic Neoplasms; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cyclic Nucleotide Phosphodiesterases, Type 5; Cyclin D1; HCT116 Cells; HT29 Cells; Humans; Inhibitor of Apoptosis Proteins; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Sulindac; Survivin; Tadalafil; Wnt Signaling Pathway

Topics: Carcinoid Tumor; Colonic Neoplasms; Humans; Male; Middle Aged; Orbital Neoplasms; Phosphodiesterase Inhibitors; Piperazines; Purines; Sildenafil Citrate; Sulfones; Tomography, X-Ray Computed; Vision Disorders