(S,R)-3-Phenyl-4,5-dihydro-5-isoxazole acetic acid–Nitric Oxide (GIT-27NO) – New Dress for Nitric Oxide Mission

Abstract

Nonsteroidal-anti-inflammatory drugs modified by covalent attachment of nitric oxide (NO) have been recognized as compounds with antitumor properties. By adopting this approach the new compound GIT-27NO was synthesized at GaNiAl Immunotherapeutics Inc. (Wilmington, Delaware, USA) on the basis of the anti-inflammatory isoxazoline derivative VGX-1027. In contrast to the usual modification, i.e., connection via a spacer molecule, GIT-27NO was generated by direct addition of a releasing NO moiety. Contrary to the parental compound which is completely inefficient as an antitumor drug, the modified compound acquired strong anticancer potential. The drug reduced the growth of various cell lines in vitro as well as some solid localized and even metastatic tumors in vivo. Decreased viability of tumor cells was caused by induction of different types of programmed cell death whereas accidental cell death was a secondary event. The outcome of the drug treatment was independent of the type of intracellular response, since the absence or inactivation of key executive mediators of apoptosis, like p53 or caspases, did not affect the death signal triggered by GIT-27NO. Furthermore, cells made resistant to apoptotic stimuli are sensitive to GIT-27NO as well. Although the drug efficacy is explicitly related to NO liberation, GIT-27NO did not function as a simple exogenous donor. Signal for NO release came from cells, and further events included the generation of ROS, RNS and subsequent nitration of tyrosine residues, caspase inhibition, or decreased activity of the YY1 repressor. The drug effect on the MAP signaling pathway was heterogeneous and defined by the cell specificity, the plasticity of the agent’s action, its high efficacy, and low toxicity and suggests that GIT-27NO is a candidate for anticancer drug of the future.