title: The cyclic GMP/protein kinase G pathway as a therapeutic target in head and neck squamous cell carcinoma.
abstract: Head and neck squamous cell carcinoma (HNSCC) is an aggressive disease with high mortality. Treatments, which can result in significant morbidity, have not substantially changed in three decades. The second messenger cyclic GMP (cGMP), which targets protein kinase G (PKG), is generated by guanylate cyclases (GCs), and is rapidly hydrolyzed by phosphodiesterases (PDEs). Activation of the cGMP/PKG pathway is antineoplastic in several cancer types, but its impact on HNSCC has not been fully exploited. We found differential expression of critical components of this pathway in four HNSCC cell lines. Several activators of soluble GC (sGC), as well as inhibitors of PDE5, increased intracellular cGMP, reduced cell viability, and induced apoptosis in HNSCC cells. The apoptotic effects of the sGC activator BAY 41-2272 and the PDE5 inhibitor Tadalafil (Cialis) were mediated by PKG. Furthermore, Tadalafil substantially reduced the growth of CAL27-derived tumors in athymic mice. Several drugs which either activate sGC or inhibit PDE5 are approved for treatment of nonmalignant conditions. These drugs could be repurposed as novel and effective therapeutics in patients with head and neck cancer.
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: Michelle L
authors.initials: ML
authors.lastname: Mierzwa
authors.affiliation: Division of Oncology, Cancer and Blood Diseases Institute, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: Susanne I
authors.initials: SI
authors.lastname: Wells
authors.affiliation: Department of Cancer Biology, University of Cincinnati School of Medicine, Cincinnati, OH 45267, USA.
authors.forename: Sejal R
authors.initials: SR
authors.lastname: Fox
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: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D006152:Cyclic GMP / Q000502:physiology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology*; D005260:Female; D006162:Guanylate Cyclase / Q000502:physiology; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051379:Mice; D058986:Phosphodiesterase 5 Inhibitors / Q000627:therapeutic use; D011720:Pyrazoles / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology*; D000077195:Squamous Cell Carcinoma of Head and Neck; D000068581:Tadalafil / Q000627:therapeutic use
chemical_list: C423582:3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine; D058986:Phosphodiesterase 5 Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000068581:Tadalafil; D017869:Cyclic GMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D006152:Cyclic GMP
keywords: HNSCC; PDE5; PKG; Tadalafil; cGMP; sGC