HU-331, a novel cannabinoid-based anticancer topoisomerase II inhibitor.
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.
Kogan
Natalya M
NM
Department of Medicinal Chemistry and Natural Products, School of Pharmacy, The Hebrew University, Jerusalem 91120, Israel. natalyak@ekmd.huji.ac.il
Schlesinger
Michael
M
Priel
Esther
E
Rabinowitz
Ruth
R
Berenshtein
Eduard
E
Chevion
Mordechai
M
Mechoulam
Raphael
R
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002185:Cannabidiol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D063387:Cannabinoid Receptor Antagonists; D053148:Caspase 3 / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D053960:DNA Breaks; D004250:DNA Topoisomerases, Type II; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors*; D019073:HT29 Cells; D006801:Humans; D019169:Jurkat Cells; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D009690:Nucleic Acid Conformation; D017382:Reactive Oxygen Species / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000378:metabolism; D059005:Topoisomerase II Inhibitors
D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D063387:Cannabinoid Receptor Antagonists; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D017382:Reactive Oxygen Species; D043882:Receptors, Cannabinoid; D059005:Topoisomerase II Inhibitors; C073718:cannabidiol hydroxyquinone; D002185:Cannabidiol; D016660:NAD(P)H Dehydrogenase (Quinone); D053148:Caspase 3; D004250:DNA Topoisomerases, Type II