title: Soluble guanylate cyclase stimulators increase sensitivity to cisplatin in head and neck squamous cell carcinoma cells.
abstract: Head and neck squamous cell carcinoma (HNSCC) is an aggressive and often fatal disease. Cisplatin is the most common chemotherapeutic drug in the treatment of HNSCC, but intrinsic and acquired resistance are frequent, and severe side effects occur at high doses. The second messenger cyclic GMP (cGMP) is produced by soluble guanylate cyclase (sGC). We previously reported that activation of the cGMP signaling cascade caused apoptosis in HNSCC cells, while others found that this pathway enhances cisplatin efficacy in some cell types. Here we found that sGC stimulators reduced HNSCC cell viability synergistically with cisplatin, and enhanced apoptosis by cisplatin. Moreover, the sGC stimulators effectively reduced viability in cells with acquired cisplatin resistance, and were synergistic with cisplatin. The sGC stimulator BAY 41-2272 reduced expression of the survival proteins EGFR and β-catenin, and increased pro-apoptotic Bax, suggesting a potential mechanism for the anti-tumorigenic effects of these drugs. The sGC stimulator Riociguat is FDA-approved to treat pulmonary hypertension, and others are being studied for therapeutic use in several diseases. These drugs could provide valuable addition or alternative to cisplatin in the treatment of HNSCC.
authors.affiliation: Department of Cancer Biology, University of Cincinnati School of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Traci R
authors.initials: TR
authors.lastname: Tuttle
authors.affiliation: Department of Radiation Oncology, University of Cincinnati School of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Vinita
authors.initials: V
authors.lastname: Takiar
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Bhavna
authors.initials: B
authors.lastname: Kumar
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Pawan
authors.initials: P
authors.lastname: Kumar
authors.affiliation: Department of Cancer Biology, University of Cincinnati School of Medicine, Cincinnati, OH 45267, USA. Electronic address: Nira.Ben-Jonathan@uc.edu.
authors.forename: Nira
authors.initials: N
authors.lastname: Ben-Jonathan
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000032:analysis; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007191:Indazoles / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D000071756:Soluble Guanylyl Cyclase / Q000502:physiology*; D000077195:Squamous Cell Carcinoma of Head and Neck; D051028:bcl-2-Associated X Protein / Q000032:analysis; D051176:beta Catenin / Q000032:analysis
chemical_list: C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D000970:Antineoplastic Agents; C494826:BAX protein, human; D007191:Indazoles; D019253:Proto-Oncogene Proteins c-bcl-2; D011720:Pyrazoles; D011725:Pyridines; D051028:bcl-2-Associated X Protein; D051176:beta Catenin; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; D066246:ErbB Receptors; D000071756:Soluble Guanylyl Cyclase; D002945:Cisplatin
keywords: BAY 41-2272; EGFR; HNSCC; YC-1; cGMP; sGC