Non steroidal anti inflammatory drugs (NSAIDs) have been used in a wide range of treatments including cancer. Studies have shown that some types of cancer, like breast lung, prostate and colon cancer respond to NSAIDs. Given in conjunction with radiation and chemotherapy improve patient outcome. In cancer prevention studies NSAIDs and other cyclo-oxygenase inhibitors (COX-2) have shown 30-50% efficacy in preventing a variety of cancer. Despite these positive effects, it has been shown that NSAIDs can cause gut ulceration as well as increased risk of heart attacks and strokes. Despite the promise of COX- specific inhibitors the risk of thrombosis remained. More recently, a new class of NSAIDs have emerged which can release nitric oxide and other small redox active molecules (hydrogen sulfide) which overcome both these side effects. In conjunction with Cancer Redox Biology Faculty and chemist in the extramural progam and inducstry, we have been evaluating a variety of redox active NSAIDs in various models of cancer treatment and prevention. We have focused on NSAIDs that modified with anethole dithiolthione (ADT) a know cancer prevention agent that releases hydrogen sulfide. In addition we have developed novel NSAIDs tha contain nitroxide that act like ROS scavengers and superoxide scavengers. The presence of the nitroxide greatly improved the tolerance from gut toxicity. In addition to inhibition of COX it also inhibited LOX thus being a complete ecosinoid inhibitor. We have begun to focus our effort on developing PP2A agonist. It was found from project one that NO and COX2 mediated much of the signaling through a variety of pathways that the tumor suppressor PP2A. We have not only identified the ADT like compounds but also APOE mimetic peptides. These peptides target the PP2A inhibitor protein SET which also inhibits the antimetastatic protein NM23. These results indicate that targeting SET maybe an important target node for the multipathway activation by Redox inflammation mechanism mediated by nitric oxide and ROS.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010899-06
Application #
8763269
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$469,518
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Miranda, Katrina M; Wink, David A (2014) Persulfides and the cellular thiol landscape. Proc Natl Acad Sci U S A 111:7505-6
MacDonald, Christopher J; Cheng, Robert Y S; Roberts, David D et al. (2009) Modulation of carcinogen metabolism by nitric oxide-aspirin 2 is associated with suppression of DNA damage and DNA adduct formation. J Biol Chem 284:22099-107
Mancardi, Daniele; Penna, Claudia; Merlino, Annalisa et al. (2009) Physiological and pharmacological features of the novel gasotransmitter: hydrogen sulfide. Biochim Biophys Acta 1787:864-72