We have been developing strategies to utilize nitric oxide (NO) in cancer treatment. In addition to the use of synthetic NO donors, we are researching the mechanisms that control the endogenous cellular production. We have recently discovered that inhibition of Nitric oxide synthase (NOS) given after chemotherapy or radiation treatment enhances tumor re-growth delay. Given that there are a number of clinically available NOS inhibitors this could have potential clinical applications. We have recently characterized the NO levels that are required to activate and stabilize key proteins involved in carcinogenesis, p53, ERK and HIF. We have extended this work to show that levels of NO are critical to angiogenesis and that NO and TSP-1 regulate each other pathways. Our extension of the understanding of angiogenic responses and nitric oxide has lead us to understand the regulation of Matrix Metalloproteases (MMP) by NO . Our findings suggest that under inflammatory response MMP are regulated by two different mechanisms, biologocal signlaing and direct chemical modification. The first is via TIMP through cGMP. The second are through chemical reactivity of RNS. We demonstrated that MMP9 secreted from macrophage was a critical facotr in the NO mediated wound healing response. This seminal finding sheds light on the potential mechanism of the tumor re-growth delay by NOS inhibitors. Following up on TSP-1 we have found in collaboration with Dr. David Roberts that this can modulate TIMP1 level, a critical inhibitor of MMP. Our investigation of novel redox NSAIDs have found that ADT (dithiol dithione) derived diclofenac and valproic acid have strong efficacy in delaying lung tumor growth in mice. Another sulfur based compound thiolutin, an antifungal agent has both anti-inflammatory and anti-angiogenic properties. More recently we have found that NH2OH a product of nitric oxide synthase and metabolism of NO enhances hydrogen peroxide toxicity. All in all, we are being to move our research to better understand the redox behavior of inflammation and wound healing and accumulate redox-based agents to modulate these effects.
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