Repurposing phosphodiesterase-5 inhibitors as chemoadjuvants

Amit K Tiwari,Zhe-Sheng Chen

doi:10.3389/fphar.2013.00082

Abstract

Repurposing phosphodiesterase-5 inhibitors as chemoadjuvants

Highlights

PDE5 contributes to the regulation of intracellular cyclic GMP pools that have been shown to be decreased along with protein kinase-G (PKG), a downstream effector of cGMP, in variety of different tumors such as breast cancer, colon cancer and human oral squamous cell carcinoma (Spoto et al, 2003; Zhu and Strada, 2007; Di et al, 2010)
Possible mechanisms of these anticancer effects via PDE5 inhibition mediated caspase-dependent apoptosis and cell growth arrest may be linked to concomitant increases in regulation of downstream pathways through increased cGMP-PKG levels and subsequent effects on, (1) activation of c-Jun NH2-terminal kinase (JNK), especially JNK1 pathways via phosphorylation of mitogen-activated protein kinase kinase kinase 1 (MEKK1) (Bender and Beavo, 2006), (2) decreased Wnt/β-catenin expression and down-regulation of cyclin D1 (Thompson et al, 2000; Li et al, 2002; Tinsley et al, 2011), (3) inhibition of extracellular-signal regulated kinases 1/2 (ERK1/2) and alterations in the regulation of p42/p44 mitogen activated-protein kinase (MAPK) and p21 pathways (Hou et al, 2006; Das et al, 2008)
PDE5 inhibitors, sildenafil and vardenafil induced caspase-dependent apoptosis of B-cell chronic lymphocytic leukemia cells (Sarfati et al, 2003), whereas cytotoxic and growth suppressive effects in various breast cancer, prostate, and colon cells were seen with non-specific PDE5 inhibitors sulindac sulfone and its analogs (Thompson et al, 2000; Piazza et al, 2001; Whitehead et al, 2003; Tinsley et al, 2011)

Summary

Introduction

PDE5 contributes to the regulation of intracellular cyclic GMP (cGMP) pools (see Figure 1) that have been shown to be decreased along with protein kinase-G (PKG), a downstream effector of cGMP, in variety of different tumors such as breast cancer, colon cancer and human oral squamous cell carcinoma (hOSCC) (Spoto et al, 2003; Zhu and Strada, 2007; Di et al, 2010). There is an incomplete understanding of how PDE5 inhibitors act in cancer, yet there are reports of increased apoptosis in different tumor cell types following treatment with PDE5 inhibitors.

Results

Conclusion