The cyclic GMP/protein kinase G pathway as a therapeutic target in head and neck squamous cell carcinoma. Issue 2 (28th January 2016)

• Record Type: Journal Article
• Authors: Tuttle, Traci R.; Mierzwa, Michelle L.; Wells, Susanne I.; Fox, Sejal R.; Ben-Jonathan, Nira
• Is Part Of: Cancer letters. Volume 370:Issue 2(2016)
• Page Start: 279
• Page End: 285
• Publication Date: 2016-01-28
• Subjects: cGMP -- PKG -- sGC -- PDE5 -- HNSCC -- Tadalafil; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2015.10.024
• Languages: English
• ISSNs: 0304-3835

Abstract

Highlights: Critical enzymes in the sGC/PDE/PKG pathway are expressed in HNSCC cell lines. Guanylate cyclase stimulators and PDE5 inhibitors increase cGMP in HNSCC cells. Drugs that increase cGMP reduce proliferation and induce apoptosis in HNSCC cells. The PDE5 inhibitor Tadalafil reduces xenograft growth in athymic mice. 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.