Nitric Oxide and Cancer Therapy: The Emperor has NO Clothes

Abstract

The role of nitric oxide (NO·) as a mediator of cancer phenotype has led researchers to investigate strategies for manipulating in vivo production and exogenous delivery of this molecule for therapeutic gain. Unfortunately, NO· serves multiple functions in cancer physiology. In some instances, NO· or nitric oxide synthase (NOS) levels correlate with tumor suppression and in other cases they are related to tumor progression and metastasis. Understanding this dichotomy has been a great challenge for researchers working in the field of NO· and cancer therapy. Due to the unique chemical and biochemical properties of NO·, it’s interactions with cellular targets and the subsequent downstream signaling events can be vastly different based upon tumor heterogeneity and microenvironment. Simple explanations for the vast range of NO-correlated behaviors will continue to produce conflicting information about the relevance of NO· and cancer. Paying considerable attention to the chemical properties of NO· and the methodologies being used will remove many of the discrepancies in the field and allow for in depth understanding of when NO-based chemotherapeutics will have beneficial outcomes.

Effect of Nitric Oxide on the Anticancer Activity of the Topoisomerase-Active Drugs Etoposide and Adriamycin in Human Melanoma Cells

“…Likewise, × NO and its nitrogen oxide products can affect cancer therapy either positively or negatively (Hickok and Thomas, 2010). The present study extends our work in vitro to tumor cells and shows significant oxidative chemistry of × NO with VP-16.…”

Unique antineoplastic profile of Saquinavir-NO, a novel NO-derivative of the protease inhibitor Saquinavir, on the in vitro and in vivo tumor formation of A375 human melanoma cells

“…This latter observation may mirror the known dichotomic role of NO in the regulation of oncogenesis that may result in pro-or anti-tumor effects depending on concentration, the microenvironment and local or peripheral localization within the tumor. This bimodal action of NO has led this molecule to be considered both as a target for cancer therapy and an anti-cancer agent (19)(20)(21). The different contribution of endogenously produced and exogenously-administered NO on the dysregulated growth of A375 cells, and possibly other cancer cells, should also be considered.…”

Melatonin-Induced Oncostasis, Mechanisms and Clinical Relevance

“…An increase in inducible nitric oxide synthase (iNOS) expression is associated with early recurrence [114] and metastatic processes [115,116]. Belgorosky et al [117] showed that human colorectal adenocarcinoma cells that express iNOS are more invasive than the non-iNOS-expressing cells.…”