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Research Articles: Therapeutics, Targets, and Development

HU-331, a novel cannabinoid-based anticancer topoisomerase II inhibitor

¹ Department of Medicinal Chemistry and Natural Products, School of Pharmacy; Departments of ² Experimental Medicine and Cancer Research, and ³ Cellular Biochemistry and Human Genetics, School of Medicine, The Hebrew University, Jerusalem, Israel; and ⁴ Department of Microbiology and Immunology, Cancer Research Center, Faculty of Health Sciences, Ben-Gurion University, Beer-Sheva, Israel

Requests for reprints: Natalya M. Kogan, Department of Medicinal Chemistry and Natural Products, School of Pharmacy, The Hebrew University, Jerusalem 91120, Israel. Phone: 972-2-6758635; Fax: 972-2-6757076. E-mail: natalyak{at}ekmd.huji.ac.il

Abstract

Anthracyclines, a large group of quinonoid compounds, are used to treat some forms of cancer. Although highly effective in cancer therapy, the mechanism of action of these compounds is not specific; they act on cancer and other cells by numerous mechanisms. A new anticancer quinone (HU-331) was synthesized from cannabidiol. It shows significant high efficacy against human cancer cell lines in vitro and against in vivo tumor grafts in nude mice. In this study, we investigated its mode of action and present evidence on its unique mechanism. HU-331 does not cause cancer cell cycle arrest, cell apoptosis, or caspase activation. HU-331–caused cell death of human cancer cell lines is not mediated by reactive oxygen intermediates/species, as exposure to HU-331 failed to elicit the generation of reactive oxygen species. HU-331 inhibits DNA topoisomerase II even at nanomolar concentrations but has only a slight nonsignificant effect on DNA topoisomerase I action. The cannabinoid quinone HU-331 is a highly specific inhibitor of topoisomerase II, compared with most known anticancer quinones. It might represent a new potent anticancer drug. [Mol Cancer Ther 2007;6(1):173–83]

Grant support: U.S. National Institute on Drug Abuse grant DA-9789 (R. Mechoulam) and Goldhirsch Foundation (M. Schlesinger).

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.

⁵ Unpublished observations.

Received 1/23/06; revised 10/ 3/06; accepted 11/10/06.

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