The Novel Functions of cGMP-Specific Phosphodiesterase 5 and its Inhibitors in Carcinoma Cells and Pulmonary/Cardiovascular Vessels

Abstract

PDE5 is a key enzyme involved in the regulation of cGMP-specific signaling pathways in normal physiological processes such as smooth muscle contraction and relaxation. For this reason, inhibition of the enzyme can alter those pathophysiological conditions associated with a lowering cGMP level in tissues. For example, selective PDE5 inhibitors, such as sildenafil (Viagra, Pfizer), tadalafil (Cialis, Lilly-ICOS), and vardenafil (Levitra, Bayer), have been successfully used to treat the condition of human erectile dysfunction. More recently, the involvement of this enzyme has been proposed to influence antiproliferation and proapoptotic mechanism in multiple carcinomas. The data supporting this idea is based on increases in PDE5 activities in many carcinomas and the ability of PDE5 inhibitors such as exisulind and its analogs related to anticancer activities. Inhibition of PDE5 that results in sustained increases in [cGMP](i) are required to modify the process of apoptosis and mitotic arrest in those carcinoma cells with enhanced PDE5 expressions. Increases in PDE5 are also involved in contributing to the pathological changes in the pulmonary system resulting in hyper-proliferative remodeling of both smooth muscle and endothelium in models of pulmonary hypertension. For this reason, the use of PDE5 inhibitors in the treatment of human pulmonary hypertension has met with some success. The differences that we have previously noted in PDE isoenzymes in pulmonary arterial and microvascular endothelial cells may provide a more selective cellular strategy for use of such inhibitor. Additional studies on structure biology of these enzymes should lead to the development of agents with better cellular specificity than currently available drugs. Considering the enormous progress that has been made in the last few years, the future looks promising for agents affecting this enzyme and related systems.

cGMP-Dependent Protein Kinases and cGMP Phosphodiesterases in Nitric Oxide and cGMP Action

“…PKGI activation in colon cancer cells results in phosphorylation and activation of the mitogen-activated protein kinase kinase (MEKK1), activation of the stress-activated protein/ERK kinase 1 (SEK1), and activation of the c-Jun NH 2 -terminal kinase 1 (JNK1) pathway (Soh et al, 2000(Soh et al, , 2001. Elevation of cGMP and activation of PKGI also suppresses growth and promotes apoptosis in some endothelial cells and human colon tumor HT29 cells (Zhu et al, 2005(Zhu et al, , 2009Zhu and Strada, 2007). These effects have prompted efforts to use inhibitors of cGMP-hydrolyzing PDEs for treatment of certain types of cancers.…”

Assessment of the acute effects of tadalafil on the cardiovascular system based on examination of serum oxidative status and paraoxonase activity in men with erectile dysfunction: a preliminary study

“…[1][2][3][4][5] PDE5 inhibitors may even be used in the treatment of cancer, as they contribute to the induction of apoptotic mechanisms. 6 However, controversy remains about the tolerance of PDE5 inhibitors, especially regarding possible life-threatening acute cardiovascular system (CVS) and neurological system events, such as myocardial infarction (MI) and stroke. 7,8 It is well known that oxidative stress leads to impaired vasodilatation of the coronary, pulmonary and peripheral vascular beds.…”

Conformational Variations of Both Phosphodiesterase-5 and Inhibitors Provide the Structural Basis for the Physiological Effects of Vardenafil and Sildenafil

“…Although these four PDE5 inhibitors have been successfully approved as the drugs for treatment of human diseases, the enthusiasm for development of novel PDE5 inhibitors continues. PDE5 inhibitors have been shown to have potential for other medical applications, including improvement of memory and treatment of cancer and heart disease (Blokland et al, 2006;Salem et al, 2006;Stehlik and Movsesian, 2006;Supuran et al, 2006;Padma-Nathan et al, 2007;Palmer et al, 2007;Zhu and Strada, 2007;Sandner et al, 2008). Much attention has been focused on the recent development of the second generation of PDE5 inhibitors that have the same or different scaffolds from the current drugs but different pharmacokinetic profiles (Palmer et al, 2007).…”