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. More recently, JS-K was found to be active against lung cancer in mice, with the observed potency correlating significantly with the level of """"""""reactive oxygen species"""""""" (ROS) produced within the cancer cells;lung tumor cell lines with the highest endogenous ROS output, lowest antioxidant defenses, and poorest DNA repair capacity were most susceptible to JS-K's toxic action, and tumors established with one of these cell lines had their growth rates cut by 85% relative to the vehicle-treated controls. 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011188-02
Application #
8157683
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2010
Total Cost
$789,453
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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
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
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
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
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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