# Presentation: 049880

## Research Program of the Cancer Redox Faculty

- Steering Committee: 	Curt Harris, Stefan Ambs, Perwez Hussain LHC/CCR/NCI
- 			David Roberts LP/CCR/NCI
- 			Grace Yeh LM/ CCR/NCI
- 			Terry Moody CCR/NCI
- 			Sophia Wang, DCEG/NCI
- 			Richard Pluta Surgery NINDS,
- 			Mark Gladwin CC/NHLBI
- 			James Mitchell, Murali Krishna, David Wink RBB/CCR/NCI

## Redox Biology in Cancer Research

- Oxidative Stress
- Radicals
- Antioxidants
- Nitrosative Stress

- Carcinogenesis
- Inflammation
- Cancer treatment
- Cancer Prevention

- O2

## Cancer Redox Biology Faculty

- Goal: to bring together researchers within CCR/ NIH and the extramural community to provide a vehicle to discuss and facilitate collaboration in redox biology.

## Redox Biology Course

- Coordinator: Terry Moody CCR/NCI

- Date		Lecture			Speaker
- Sept. 26		Introduction		T. Moody
- 		Redox Chemistry		D.Wink
- Oct. 3		Redox Biology 		D. Wink
- 		Cell Biology		M. Espey
- Oct. 10		Signal Transduction	T. Moody
- 		Carcinogenesis		G. Yeh
- Oct. 17		Physiology		M. Gladwin
- 		Inflammation		P. Hussain/C. Harris
- Oct. 24		Central Nervous System 	R. Pluta
- 		Angiogenesis		D. Roberts
- Oct. 31		Biomarkers		S. Wang
- 		Cancer Therapy		J. Mitchell
- Nov. 15		Immunology		M. Espey
- 		Epidemiology		S. Ambs

## Research Accomplishments: collaborative publications

- Isenberg  JS, Ridnour  L, Espey MG, Wink DA, Roberts DD. Nitric Oxide in Wound Healing (2005) _Microsurgery_ 25(5):442-51
- Thomas DD, Espey MG, Ridnour L, Hofseth LJ, Mancardi D, Harris CC, and Wink DA. HIF-1, ERK and p53 are regulated by distinct threshold nitric oxide concentrations in human breast MCF7 cells (2004) _Proc. Natl. Acd. Sci._ 01(24):8894-9.
- Isenberg JS, Ridnour  LA, Espey MG, Roberts DD, Wink DA. Thrombospondin-1 Inhibits Endothelial Cell Responses to Nitric Oxide in a cGMP-Dependent Manner (2005) _Proc. Natl. Acad Sci._ 102:13141-6
- Ridnour  L, Isenberg JS, Espey MG, Thomas DD, Roberts DD, Wink DA. Nitric Oxide Regulates Angiogenesis through a Functional Switch Involving Thrombospondin-1.  (2005) _Proc. Natl. Acad Sci._ 102:13147-52
- Isenberg JS, Ridnour LA, Thomas DD, Wink DA, Roberts DD, Espey MG (2006) Guanylyl cyclase-dependent chemotaxis of endothelial cells in response to nitric oxide gradients. _Free Radic Biol Med_. 40:1028-33
- Ridnour LA, Thomas DD, Mancardi D, Donzelli S, Paolocci N, Pagliaro P, Miranda KM, Krishna MC, Fukuto J, Grisham MB, Mitchell JB,. Espey MG, and Wink DA.   Antioxidant properties of nitric oxide in cellular physiological and pathophysiological mechanisms.  The implications of biological balance between NO and oxidative stress.  (2004) _Current Med. Chem_. (in Press)
- Thomas DD, Ridnour L, Donzelli S, Espey MG, Mancardi D, Isenberg JS, Feelisch M, Roberts DD, Wink DA. Nitric oxide and Related Nitrogen Oxides: Chemistry of Protein Adducts (Dalle-Donne I, Scaloni A,  Butterfiled A Eds) in *Redox Proteomics: from Protein Modifications to Cellular Dysfunction and Diseases*, Wiley Interscience  NY, NY (in Press)
- Ridnour LA, Thomas DD, Donzelli S, Espey, MG Roberts DD, Wink DA, Isenberg JS (2006) The Biphasic Nature of Nitric Oxide Responses in Tumor Biology Antioxidant and Redox Signaling (in Press)
- Donzelli S, Switzer CH, Thomas DD, Ridnour LA, Espey MG, Isenberg JS, Tocchetti CG, King SB, Lazzarino G, Miranda KM, Roberts DD, Feelisch M, and Wink DA,  (2006)The activation of metabolites of nitric oxide synthase by metals is both redox- and oxygen-dependent: a new feature of nitrogen oxide signaling. Antioxid. Redox Sig. In press.
- Isenberg JS, Wink DA, Roberts DD (2006) Thrombospondin-1 antagonizes nitric oxide-stimulated vascular smooth muscle cell responses Cardiovascul. Res. (in press)
- Thomas DD, Ridnour LA, Espey MG, Donzelli S, Ambs S, Hussain SP, Harris CC, W DeGraff W, Roberts DD, Mitchell JB, and Wink DA (2006) SUPEROXIDE FLUXES LIMIT NITRIC OXIDE-INDUCED SIGNALING  _[J ](javascript:AL_get(this,%20'jour',%20'J%20Biol%20Chem.');)__[Biol ](javascript:AL_get(this,%20'jour',%20'J%20Biol%20Chem.');)__[Chem.](javascript:AL_get(this,%20'jour',%20'J%20Biol%20Chem.');)_ (in press)
- _[Isenberg JS](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Isenberg+JS%22%5BAuthor%5D)_, _[Ridnour ](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Ridnour+LA%22%5BAuthor%5D)__[LA](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Ridnour+LA%22%5BAuthor%5D)_, _[Dimitry ](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Dimitry+J%22%5BAuthor%5D)__[J](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Dimitry+J%22%5BAuthor%5D)_, _[Frazier WA](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Frazier+WA%22%5BAuthor%5D)_, _[Wink DA](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Wink+DA%22%5BAuthor%5D)_, _[Roberts DD](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&itool=pubmed_Abstract&term=%22Roberts+DD%22%5BAuthor%5D)_. (2006) CD47 is necessary for inhibition of nitric oxide-stimulated vascular cell responses by thrombospondin-1.  _[J ](javascript:AL_get(this,%20'jour',%20'J%20Biol%20Chem.');)__[Biol ](javascript:AL_get(this,%20'jour',%20'J%20Biol%20Chem.');)__[Chem.](javascript:AL_get(this,%20'jour',%20'J%20Biol%20Chem.');)_ (in press)
- Roberts DD Isenberg JS, Ridnour LA, Wink DA,. (2006) Nitric oxide and its Gatekeeper Thrombospondin-1 in Tumor Angiogenesis   Clinical  Cancer  Res. (in press)
- Prueitt RL, Boersma BJ, Howe TM, Goodman JE, Thomas DD, Ying L, Pfiester CM, Yfantis HG, Cottrell JR, Lee DH, Remaley AT, Hofseth LJ, Wink DA and Ambs S. Inflammation and IGF-I Activate the Akt Pathway in Breast Cancer (2006)  Int. J. Cancer (in press)

## Current Redox Faculty Focus (2005-2006)

- Redox -Based NSAIDs

- Major advantages of redox-based NSAIDs:
- 	a)  alleviate the gut toxicity conventional NSAIDs
- 	b)  some moieties have anti-thrombotic properties

**Notes:**
These compounds are conventional NSAIDs which are modified with
Redox active compounds

## Redox-Based NSAIDs Current Being Examined by the CRBF

- Aspirin
- Indomethacin
- Sulindac
- Diclofenac

_**Current Collaborators**_
**Piero Del Soldato (CTG)****	**** S-NSAIDs**
**Bruce King ****	****	****Nitrogen Oxide**
**(Wake Forest Univeristy)****	****SOD mimetics**
**Larry Keefer ****	****	****Nitrogen Oxide**
**(LCC/CCR/NCI)**
**Division of Cancer Prevention**

## Chemoprevention Properties Redox-based NSAIDs

**Grace Yeh LM/CCR**

## Summary of Current Findings

**S-Valproate and S-NSAIDs inhibit Phase I enzyme activity**

**NO-Aspirin induces Phase II mRNA expression (Glutamate Cysteine Ligase)**

**Future Direction**
**Investigate S-NSAIDs in PAH-induced mammary and      lung tumor models**
**Identify other moieties from Division of Cancer Prevention which have chemopreventive properties**

## Cancer Treatment

- Goal:  To identify agents that can help increase efficacy of conventional   		therapies: Radiation and Chemotherapy

*In vitro* models
- 	Tumor have similar efficacy in as parent NSAIDs in NSLC
- 		and HT-29 inhibit PGE2 synthesis

*in vitro* data

- S-NSAID in PC3 xenograph show 80% reduction in tumor
- 	growth rate

- Preliminary

## Anti-angiogenic activities of redox NSAIDs in HT-29 colon carcinoma explants

- Conclusions
-   S-NSAIDSs have anti-angiogenic properties
-   NO based NSAIDs have pro-angiogenic properties

## Oxygen and Redox EPR and MRI Imaging with Nitroxides

- Future: NSAID based nitroxides for potential MRI imaging
- 	Marnett “Chemical Biology Workshop”

- Murali Krishna and James Mitchell RBB, CCR

- Determine oxygen status
- Redox status tissue
- Tissue perfusion
- Drug mobility

- _Bruce King Wake Forest University_
- Aspirin-nitroxide
- Indomethacin-nitroxide

- Nitroxides

## Model For Testing Redox Based Compounds Placement of Proposed Personal and Support

- Redox Reagents
- Chemical
- Biochemical

- Cellular Models

- Animal Model

- Clinical TrialsEpidemological Studies