Advances in Breast Cancer Therapy Using Nitric Oxide and Nitroxyl Donor Agents

Over the past two decades, nitric oxide (NO) has been at the center of multiple contradictory findings regarding its role in cancer biology. With greater understanding, it is now well established that the biphasic effects of NO are concentration dependent. Low flux of NO less than 10 nM is essential for normal physiological functions such as vascular maintenance. Intermediate levels of NO higher than 100 nM affect critical pathways that lead to tumor progression, whereas higher flux NO (>800 nM) induces tumor regression. Nitric oxide synthase (NOS) enzymes, particularly inducible NOS (iNOS), have often been shown to exert both pro- and antitumor effects. The elucidation of the involvement of intermediate NO flux generated by iNOS during cancer progression has led to the rapid development of several classes of NOS inhibitors with potent therapeutic effects. In contrast, the generation of higher NO flux in the tumor microenvironment tips the balance to favor cytostasis and cell killing. Toward this end, several classes of NO donors (e.g., nitrate esters, S-nitrosothiols, and diazeniumdiolates) have been examined both in vitro and in vivo and have demonstrated vast potential as chemotherapeutic agents as well. Recently, nitroxyl (HNO) has emerged as a key player with promising therapeutic potential as it exhibits properties that are often orthogonal to NO. Significant potential of HNO in the treatment of cardiovascular disease, clinical usage as an alcohol deterrent agent, and chemotherapeutic activity are only a few of its properties that have recently been explored. In this chapter, we briefly review some of the key pathways/chemical modifications by which NO and HNO exert their physiological outcome in cancer biology. NOS inhibition and utilization of NO donors as effective therapeutic options for NO-based therapy, HNO donors and their utilization as chemo drugs, and lastly NO/HNO-based hybrid drugs are discussed to show the therapeutic depth and potential for NO and HNO in cancer treatment.