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

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]

A Cannabinoid Anticancer Quinone, HU-331, Is More Potent and Less Cardiotoxic Than Doxorubicin: A Comparative in Vivo Study

“…The BE colon carcinoma cell line has a point mutation and lacks DT-diaphorase [NAD(P)H:quinone oxidoreductase]; the HT-29 cell line is the same line but without the mutation. The two cell lines were affected by HU-331 to the same extent, which indicates that HU-331 does not act through one-electron reduction (Kogan et al, 2007). Apparently, the one-electron reduction of the quinone moiety in HU-331 is less effective than in doxorubicin, and this effect may be a further reason for the lack of cardiotoxicity of HU-331.…”

“…It is strongly antiangiogenic, both in vitro and in vivo (Kogan et al, 2006), making this compound a promising scaffold for new antiangiogenic drugs. It specifically inhibits topoisomerase II (Kogan et al, 2007). Here, we report that HU-331, although more active than doxorubicin in a HT-29 colon carcinoma model in nude mice and a Raji model in SCID-NOD mice, is significantly less cardiotoxic.…”

“…Thus, it seemed logical to assay HU-331 for its ability to generate free radicals in the hearts of mice by measuring biochemical surrogates of oxidative stress, such as protein carbonyls. Although HU-331 was previously shown by us to be incapable of generating free radicals in cancer cells (Kogan et al, 2007), we investigated heart tissue, assuming that it could possibly react differently. We checked the level of protein carbonyls, a biochemical surrogate of oxidative stress, in the hearts of mice acutely exposed to high doses of either HU-331 or doxorubicin.…”

Antitumorigenic Effects of Cannabinoids beyond Apoptosis

“…According to Kogan et al (2006), HU-331 inhibits angiogenesis by directly inducing apoptosis of vascular endothelial cells without changing the expression of pro-and antiangiogenic factors and their receptors. In a subsequent study, HU-331 has been reported to mediate its antitumorigenic action mainly via inhibition of topoisomerase II (Kogan et al, 2007).…”

Cannabis and lung cancer

“…The burgeoning literature on telomeres demonstrates that this field is intimately involved in pathways of both ageing and tumourigenesis. Key DNA repair enzymes topoisomerase II [7] and Rad51 have been shown to be inhibited by cannabinoids. Germ line chromosomal abnormalities in addition to MAPK stimulation constitute putative pathways of inheritable oncogenesis.…”