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
Basudhar, Debashree; Bharadwaj, Gaurav; Cheng, Robert Y et al. (2013) Synthesis and chemical and biological comparison of nitroxyl- and nitric oxide-releasing diazeniumdiolate-based aspirin derivatives. J Med Chem 56:7804-20
Schoenfeld, Michael P; Ansari, Rafat R; Nakao, Atsunori et al. (2012) A hypothesis on biological protection from space radiation through the use of new therapeutic gases as medical counter measures. Med Gas Res 2:8
Switzer, Christopher H; Cheng, Robert Y-S; Ridnour, Lisa A et al. (2012) Dithiolethiones inhibit NF-?B activity via covalent modification in human estrogen receptor-negative breast cancer. Cancer Res 72:2394-404
Horváth, Béla; Mukhopadhyay, Partha; Kechrid, Malek et al. (2012) ?-Caryophyllene ameliorates cisplatin-induced nephrotoxicity in a cannabinoid 2 receptor-dependent manner. Free Radic Biol Med 52:1325-33
Moody, Terry W; Osefo, Nauramy; Nuche-Berenguer, Bernardo et al. (2012) Pituitary adenylate cyclase-activating polypeptide causes tyrosine phosphorylation of the epidermal growth factor receptor in lung cancer cells. J Pharmacol Exp Ther 341:873-81
Flores-Santana, Wilmarie; Moody, Terry; Chen, Weibin et al. (2012) Nitroxide derivatives of non-steroidal anti-inflammatory drugs exert anti-inflammatory and superoxide dismutase scavenging properties in A459 cells. Br J Pharmacol 165:1058-67
Fukuto, Jon M; Carrington, Samantha J; Tantillo, Dean J et al. (2012) Small molecule signaling agents: the integrated chemistry and biochemistry of nitrogen oxides, oxides of carbon, dioxygen, hydrogen sulfide, and their derived species. Chem Res Toxicol 25:769-93
Flores-Santana, Wilmarie; Salmon, Debra J; Donzelli, Sonia et al. (2011) The specificity of nitroxyl chemistry is unique among nitrogen oxides in biological systems. Antioxid Redox Signal 14:1659-74
Mukhopadhyay, Partha; Rajesh, Mohanraj; Horváth, Béla et al. (2011) Cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death. Free Radic Biol Med 50:1368-81

Showing the most recent 10 out of 21 publications