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¹ Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at NIEHS, Research Triangle Park, North Carolina; ² Chemistry Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at Frederick, Frederick, Maryland; and ³ Basic Research Program, Science Applications International Corporation-Frederick, Frederick, Maryland

Requests for reprints: Michael P. Waalkes, Inorganic Carcinogenesis Section, Laboratory of Comparative Carcinogenesis, National Cancer Institute at NIEHS, mail drop F0-09, 111 Alexander Drive, Research Triangle Park, NC 27709. Phone: 919-541-2328; Fax: 919-541-3970. E-mail: Waalkes{at}niehs.nih.gov

Development of chemotherapeutic resistance is a major cause of pharmacologic failure in cancer treatment. One mechanism of resistance in tumor cells is the overexpression of glutathione S-transferases (GSTs) that serve two distinct roles in the development of drug resistance via the formation of glutathione conjugates with drugs for their cellular efflux, and the inhibition of the mitogen-activated protein kinase pathway. To target GST-based resistance to chemotherapeutics, a series of nitric oxide (NO)-releasing diazeniumdiolates was synthesized and shown to release NO on reaction with GST and/or glutathione. Two diazeniumdiolates, JS-K [O²-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate] and CB-3-100 [O²-(2,4-dinitrophenyl) 1-[4-(N,N-diethylcarboxamido)piperazin-1-yl]diazen-1-ium-1,2-diolate], were studied on their ability in reversing arsenic and cisplatin resistance in a rat liver cell line that is tumorigenic and shows acquired tolerance to arsenic and cisplatin, with overexpression of GSTs. The enhanced cytolethality produced by the NO donors was accompanied by increased accumulation of arsenic and platinum within cells and by enhanced activation of mitogen-activated protein kinase members c-jun-NH-kinase and extracellular signal-regulated kinase. Our data indicate that JS-K and CB-3-100 are promising lead compounds for the possible development of a novel class of adjuvant chemotherapeutic agents potentially capable of reversing arsenic and cisplatin resistance in certain tumor cells.

Key Words: NO-releasing diazeniumdiolates • cisplatin • arsenic • cellular accumulation • cytotoxicity

Grant support: National Cancer Institute/NIH under contract NO1-CO-12400.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: Dr. Elaine Leslie is the recipient of a Canadian Institutes of Health Fellowship and the Davis Charitable Foundation Research Fellowship Award.

Received 12/16/03; revised 3/18/04; accepted 4/ 2/04.