We have synthesized a series of anti-cancer drug candidates known as arylated diazeniumdiolates that, by design, act by releasing cytolytic nitric oxide (NO) within the tumor cell on reaction with cellular nucleophiles such as glutathione, especially on catalysis by glutathione S-transferase. One of these, JS-K, has been reported not only to cut the growth rate of subcutaneously implanted HL-60 human leukemia cells by 50% in a mouse xenograft model, but also to induce significant necrosis in the remaining tumor mass. Similar activity was shown by JS-K in a prostate cancer mouse xenograft model and in an orthotopic rat liver cancer model. JS-K was especially active against a multiple myeloma xenograft model in mice, greatly reducing the growth rate of the tumor and substantially prolonging the animals lifetime. The second-generation arylated diazeniumdiolate PABA/NO proved almost as potent as the clinically important drug cisplatin in slowing the growth of human ovarian cancer xenografts in mice. We believe that such evidence of broad-spectrum anti-cancer activity on the part of this novel drug class merits urgent followup aimed at exploiting any clinical benefits that may be inherent in this technology. Work during the current fiscal year has focused primarily on development issues, including testing different formulations for their ability to prolong the lifetime of the drugs in the blood stream (P. Shami and R. Prud'homme) and designing molecular modifications that might lessen their reactivity (collaboration with X. Ji), thus decreasing their tendency to be activated and lose their NO before reaching the tumor site. Papers published during the current reporting period showed JS-K to synergize with the established anti-cancer drug cytarabine (collaboration with P. Shami), to inhibit ubiquitin E1 (collaboration with Y. Yang and A. Perantoni), and to kill cancer cells possessing wild-type p53. Of special note is current work with a ring-expanded JS-K derivative called JS-36-25. This agent is showing considerable activity against lung cancer xenografts in mice, with a potency that is greatest in tumors that generate the highest levels of reactive oxygen species (ROS) in the cancerous tissue (collaboration with L. Anderson). This finding suggests possible utility in a personalized medicine setting, i.e., to be of special benefit to patients having the highest tumor ROS levels.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Kaczmarek, Monika Z; Holland, Ryan J; Lavanier, Stephen A et al. (2014) Mechanism of action for the cytotoxic effects of the nitric oxide prodrug JS-K in murine erythroleukemia cells. Leuk Res 38:377-82
Maciag, Anna E; Holland, Ryan J; Kim, Youseung et al. (2014) Nitric oxide (NO) releasing poly ADP-ribose polymerase 1 (PARP-1) inhibitors targeted to glutathione S-transferase P1-overexpressing cancer cells. J Med Chem 57:2292-302
Maciag, Anna E; Holland, Ryan J; Robert Cheng, Y-S et al. (2013) Nitric oxide-releasing prodrug triggers cancer cell death through deregulation of cellular redox balance. Redox Biol 1:115-24
Weidensteiner, Claudia; Reichardt, Wilfried; Shami, Paul J et al. (2013) Effects of the nitric oxide donor JS-K on the blood-tumor barrier and on orthotopic U87 rat gliomas assessed by MRI. Nitric Oxide 30:17-25
Kashfi, Khosrow (2012) Nitric Oxide-Releasing Hybrid Drugs Target Cellular Processes Through S-Nitrosylation. For Immunopathol Dis Therap 3:97-108
Holland, Ryan J; Maciag, Anna E; Kumar, Varun et al. (2012) Cross-linking protein glutathionylation mediated by O2-arylated bis-diazeniumdiolate ""Double JS-K"". Chem Res Toxicol 25:2670-7
Kogias, Evangelos; Osterberg, Nadja; Baumer, Brunhilde et al. (2012) Growth-inhibitory and chemosensitizing effects of the glutathione-S-transferase-?-activated nitric oxide donor PABA/NO in malignant gliomas. Int J Cancer 130:1184-94
Weyerbrock, Astrid; Osterberg, Nadja; Psarras, Nikolaos et al. (2012) JS-K, a glutathione S-transferase-activated nitric oxide donor with antineoplastic activity in malignant gliomas. Neurosurgery 70:497-510; discussion 510
Nandurdikar, Rahul S; Maciag, Anna E; Holland, Ryan J et al. (2012) Structural modifications modulate stability of glutathione-activated arylated diazeniumdiolate prodrugs. Bioorg Med Chem 20:3094-9
Maciag, Anna E; Nandurdikar, Rahul S; Hong, Sam Y et al. (2011) Activation of the c-Jun N-terminal kinase/activating transcription factor 3 (ATF3) pathway characterizes effective arylated diazeniumdiolate-based nitric oxide-releasing anticancer prodrugs. J Med Chem 54:7751-8

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