It is anticipated that NO/RNS levels are also heterogeneous in tumors. It will be important to study the effect of NO/NRS-generating agents on this heterogeneity, which may be particularly relevant to understanding how modulation of NO levels within tumors may affect tumor responses when these agents are given concurrently or sequentially with other therapies. In the literature, the response to NO has been described as biphasic [61], with homeostasis at low doses and toxicity at higher

doses. In terms of tumors, NO responses may more closely follow a triphasic response, with cytotoxicity at physiological (and higher) doses, maintenance of homeostasis BMS-354825 manufacturer at hyponitroxic doses, and cytotoxicity again at even lower doses. The exploitation and modulation of hyponitroxia are potentially promising and exciting anticancer strategies, especially because direct approaches to improve the oxygenation of tumors with hyperbaric oxygen or a variety of methods of enhanced delivery have by and large been unsuccessful [62]. By contrast, hyponitroxia may be a more accessible target than hypoxia, indirectly resulting in an alteration

of the oxygen status of the tumor. Because the steady-state concentration of NOx conducive to invasion, angiogenesis, and metastasis is confined to a narrow hyponitroxic range, any significant ABT199 perturbation in the fully coupled ROS/RNS axis in either direction, below or above, is likely to result in antitumor responses, especially in combination with chemotherapy or radiation therapy as mentioned above. In summary, there is a need for discovery identification and study of new agents that target hyponitroxia and exert NADPH-cytochrome-c2 reductase their anticancer activity through modulation of intratumoral NO, thereby tipping the balance from tumor cell survival to cell death and senescence. In addition, further research into new imaging modalities that can capture the effects of NO on tumors will be required [63]. Research into the use of NO/RNS modulation for purposes of signal amplification and attenuation with GTN (and other organic nitrates), RRx-001, and l-NNA may help to elucidate the molecular mechanism of action of

these agents to enable optimization of their use both as single agents and in combination with other therapies on the basis of a better understanding of the underlying biology of hyponitroxia and facilitate the clinical development of new treatment options on the basis of this innovative approach. “
“Accumulating evidence suggests that cells and factors of the tumor microenvironment contribute decisively not only to the survival of primary neoplastic cells but also to subsequent key events of neoplastic disease progression including tumor growth, invasion, and metastasis [1], [2] and [3]. Various and many times interrelated determinants govern this complex tumor-host interaction; among them inflammatory and proteolytic-related phenomena have been shown to be particularly important [4], [5], [6], [7] and [8].