Nitric Oxide Donor-Based Cancer Therapy: Advances and Prospects

Abstract

The increasing understanding of the role of nitric oxide (NO) in cancer biology has generated significant progress in the use of NO donor-based therapy to fight cancer. These advances strongly suggest the potential adoption of NO donor-based therapy in clinical practice, and this has been supported by several clinical studies in the past decade. In this review, we first highlight several types of important NO donors, including recently developed NO donors bearing a dinitroazetidine skeleton, represented by RRx-001, with potential utility in cancer therapy. Special emphasis is then given to the combination of NO donor(s) with other therapies to achieve synergy and to the hybridization of NO donor(s) with an anticancer drug/agent/fragment to enhance the activity or specificity or to reduce toxicity. In addition, we briefly describe inducible NO synthase gene therapy and nanotechnology, which have recently entered the field of NO donor therapy.

Cytotoxicity of N-nitrosoguanidines in a breast cancer cell model

“…NO is a ubiquitous signaling, regulatory and effector molecule with various biological effects on the human body at the level of the vascular, neuronal and immune systems (1)(2)(3). NO is synthesized in vivo by three different NO synthases (NOS), including nNOS and eNOS, which are constitutively expressed in neuronal and endothelial cells, respectively, and iNOS which is transcriptionally regulated and induced by inflammatory cytokines, oxidative stress, hypoxia and some endotoxins (3).…”

“…NO is synthesized in vivo by three different NO synthases (NOS), including nNOS and eNOS, which are constitutively expressed in neuronal and endothelial cells, respectively, and iNOS which is transcriptionally regulated and induced by inflammatory cytokines, oxidative stress, hypoxia and some endotoxins (3). The wide range of NO-mediated functions occurs mostly through a cGMP-dependent pathway, leading to vasodilation, neurotransmission, inhibition of platelet aggregation, and relaxation of smooth muscle.…”

“…A second cGMP-independent pathway is the NO reaction with molecular oxygen, reactive oxygen species (ROS), thiols, and transition metals. NO can also directly modify proteins without the intervention of enzymes by nitration or nitrosylation (2)(3). S-nitrosylation of thiol groups of cysteine residues is a reversible modification that is involved in several cellular signaling processes, which regulate the function of several intracellular proteins (2)(3).…”

“…Recently, the potential usefulness of such compounds in cancer therapy has been suggested (4). Regarding cancer, NO is known to have a dichotomic effect, with pro-or anti-cancer effects, depending on its concentration, microenvironment and cell type (2)(3). At low concentrations of NO (< 100 nM), there is an association with increased angiogenic and proliferative processes, as well as with resistance to apoptosis.…”

“…On the other hand, high concentrations of NO (> 500 nM) are associated with increased cytotoxicity and apoptosis (1-3). The NO anti-tumor mechanisms include the induction of p53 protein (5), proteosomal degradation of anti-apoptotic molecules, cytochrome C release with increased mitochondrial permeability, Smac / DIABLO complex release, and direct S-nitrosylation of NF-kB, SNAIL and YY1 transcription factors (3,6). The role of NO in cancer therapies is related with hypoxia and hyponitroxia.…”