All ETDs from UAB

Advisory Committee Chair

Gary A Piazza

Advisory Committee Members

Graeme Bolger

William Grizzle

Clinton Grubbs

Dennis Pillion

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Breast cancer remains a major health concern, despite efforts to develop improved therapeutics. Chemoprevention is a promising strategy for reducing breast cancer-related morbidity and mortality. However, with the exception of the selective estrogen receptor modulators (SERMs), which have limited efficacy and severe toxicities, no drugs have been approved for breast cancer chemoprevention. Studies demonstrate that certain nonsteroidal anti-inflammatory drugs (NSAIDs) display promising chemopreventive efficacy. Unfortunately, the depletion of physiologically important prostaglandins due to inhibition of the cyclooxygenase (COX) enzymes results in potentially fatal toxicities, which exclude the use of NSAIDs and COX-2 selective inhibitors for chemoprevention. Ample data, however, suggest that a COX-independent target may be responsible for the anticancer activity of the NSAIDs. Inhibition of cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) and subsequent activation of cGMP signaling has been proposed as one COX-independent mechanism. While cGMP signaling can regulate growth in certain cell types and alterations within this pathway have been noted in human cancers, little is known about its role in human breast cells. Here we demonstrate that selective inhibition of the cGMP specific PDE5 isozyme was sufficient to selectively induce apoptosis of human breast tumor cells through a pathway involving activation of the cGMP-dependent protein kinase (PKG) and subsequent attenuation of oncogenic ß-catenin transcriptional activity. Moreover, PDE5 was found to be overexpressed, while the expression of other PDE isozymes was significantly reduced in breast tumor cells when compared to normal mammary epithelial cells. The NSAID sulindac sulfide (SS) was also found to preferentially inhibit the growth of breast tumor cells through a mechanism involving selective inhibition of PDE5, activation of PKG, and attenuation of ß-catenin transcriptional activity. These effects occured independently of COX inhibition, as novel sulindac derivatives that lacked COX-inhibitory activity demonstrated enhanced anticancer and PDE5-inhibitory activities. These data demonstrate that PDE5 may serve as a novel target for breast cancer chemoprevention. Furthermore, modifying the indene scaffold of sulindac to remove COX-inhibitory activity while enhancing PDE5 inhibitory activity could lead to the development of novel breast cancer chemopreventive agents that are potentially safer and more efficacious than the NSAIDs or the SERMs.

Share

COinS