diazeniumdiolate and Neoplasms

The role of nitric oxide (NO) in cancer has been a continuous challenge and particularly the contradictory findings in the literature reporting NO with either anti-cancer properties or pro-cancer properties. This dilemma was largely resolved by the level of NO/inducible nitric oxide synthase in the tumor environment as well as other cancer-associated gene activations in different cancers. The initial findings on the role of NO as an anti-cancer agent was initiated in the late 1990's in Dr. Larry Keefer's laboratory, who had been studying and synthesizing many compounds with releasing NO under different conditions. Using an experimental model with selected NO compounds they demonstrated for the first time that NO can inhibit tumor cell proliferation and sensitizes drug-resistant cancer cells to chemotherapy-induced cytotoxicity. This initial finding was the backbone and the foundation of subsequent reports by the Keefer's laboratory and followed by many others to date on NO-mediated anti-cancer activities and the clinical translation of NO donors in cancer therapy. Our laboratory initiated studies on NO-mediated anti-cancer therapy and chemo-immuno-sensitization following Keefer's findings and used one of his synthesized NO donors, namely, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETANONOate), throughout most of our studies. Many of Keefer's collaborators and other investigators have reported on the selected compound, O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl] diazen-1-ium-1,2-diolate (JS-K), and its therapeutic role in many tumor model systems. Several lines of evidence that investigated the treatment with NO donors in various cancer models revealed that a large number of gene products are modulated by NO, thus emphasizing the pleiotropic effects of NO on cancers and the identification of many targets of therapeutic significance. The present review reports historically of several examples reported in the literature that emanated on NO-mediated anti-cancer activities by the Keefer's laboratory and his collaborators and other investigators including my laboratory at the University of California at Los Angeles.

Topics: Azo Compounds; Humans; Neoplasms; Nitric Oxide; Nitric Oxide Donors

The pioneering studies of Dr. Larry Keefer and colleagues with diazeniumdiolates or NONOates as a platform have unraveled the chemical biology of many nitric oxides and have led to the design of a variety of promising therapeutic agents in oncology, gastroenterology, antimicrobials, wound healing, and the like. This dedication to Dr. Larry Keefer briefly highlights some of his studies using the diazeniumdiolate platform in the cancer arena.

Topics: Azo Compounds; Humans; Neoplasms; Nitric Oxide; Nitric Oxide Donors

Topics: Azo Compounds; Humans; Neoplasms; Nitric Oxide

Due to the involvement of nitric oxide (NO) in numerous and diverse physiological processes, site-directed delivery of therapeutic NO in order to minimize unwanted side-effects is necessary. O(2)-(4-Nitrobenzyl) diazeniumdiolates are designed as substrates for Escherichia coli nitroreductase (NTR), an enzyme that is frequently used to facilitate directed delivery of cytotoxic species to cancers. O(2)-(4-Nitrobenzyl) diazeniumdiolates are found to be stable in aqueous buffer but are metabolized by NTR to produce NO. A cell viability assay revealed that cytotoxic effects of O(2)-(4-nitrobenzyl)1-(2-methylpiperidin-1-yl)diazen-1-ium-1,2-diolate (4b) towards two cancer cell lines is significantly enhanced in the presence of NTR suggesting the potential for use of this compound in nitric oxide-based directed prodrug therapy.

Topics: Antineoplastic Agents; Azo Compounds; Cell Line, Tumor; Escherichia coli; Humans; Neoplasms; Nitric Oxide; Nitric Oxide Donors; Nitroreductases; Prodrugs

JS-K, a diazeniumdiolate-based nitric oxide (NO)-releasing prodrug, is currently in late pre-clinical development as an anti-cancer drug candidate. This prodrug was designed to be activated by glutathione (GSH) to release NO. To increase the potency of JS-K, we are investigating the effect of slowing the reaction of the prodrugs with GSH. Herein, we report the effect of replacement of nitro group(s) by other electron-withdrawing group(s) in JS-K and its homo-piperazine analogues on GSH activation and the drugs' biological activity. We show that nitro-to-cyano substitution increases the half-life of the prodrug in the presence of GSH without compromising the compound's in vivo antitumor activity.

Topics: Animals; Antineoplastic Agents; Apoptosis; Azo Compounds; Drug Stability; Glutathione; Half-Life; Humans; JNK Mitogen-Activated Protein Kinases; Kinetics; Mice; Neoplasms; Nitric Oxide; Prodrugs; Signal Transduction