High MN1 expression is associated with poor prognosis in acute myeloid leukemia independent of allogeneic progenitor cell transplantation
Authors: Natalya M. Kogan, Manuel Guzman, Ester Priel, Michael Schlesinger, Gergana Marincheva, Ronen Beeri, Raphael Mechoulam
Journal: Cancer Research (2006)

1135A  Introduction: Anthracyclines, a large group of quinonoid compounds, exert antibiotic and antineoplasic effects. They are used to treat some forms of cancer. The development of quinonoid compounds that display antineoplastic and/or anti-angiogenic activity, but are more selective and less toxic is a major therapeutic goal. HU-331 (cannabidiol-hydroxyquinone) was synthesized from cannabidiol. HU-331 shows very high effectivity against human cancer cell lines in vitro and also against in-vivo tumor grafts in nude mice. At 35 days after cancer cell injection, the tumors in the treated group were half the size of the tumors in the controls, a difference that was highly significant. Methods: For assaying the mechanisms of HU-331-mediated cancer cell death several standard methods were used, such as annexin V binding (for assaying apoptotic cell death), PI DNA staining (for cell cycle analysis), intracellular staining with anti-caspase-3 (for assaying caspases involvement), MTT (proliferation) test with HU-331 in presence of CB1/CB2 antagonists or ROS scavengers (for assaying free radicals and cannabinoid receptors involvement). The ability of HU-331 to inhibit topoisomerases was assayed on puc19 plasmid relaxation. The enantiomer of HU-331 was synthesized and tested alongside HU-331 itself. For evaluation of the anti-angiogenic action of HU-331 and some other cannabinoids, collagen-embedded rat aortic rings were incubated for 5–7 days with these compounds in the presence of FGF or VEGF (or with FGF/VEGF alone as positive controls). The ability of cannabinoids to inhibit endothelial cell proliferation was assayed as well. The cardiotoxicity of HU-331 compared to doxorubicin was assayed on mice by echo-cardiography. Results: HU-331 is highly selective HU-331-caused cell death is partially mediated by ROS. (+)HU-331’s potency in killing cells was not lower than that of (-)HU-331, which means that HU-331 does not act through binding to a receptor, but probably enters the cell and acts through its quinone moiety. HU-331 has limited influence on topoisomerase I action, but is able to inhibit topoisomerase II even in nanomolar concentrations. HU-331 is strongly anti-angiogenic. It partially inhibited aortic ring angiogenesis in concentrations as low as 0.1 μg/ml (300nM). The number of new vessels formed was not only lower, but even those that were formed were shorter. HU-331 also lowered endothelial cell proliferation. The tumors treated by HU-331 contaqined much less vessels than control tumors. In echo-cardiography tests HU-331 (15 mg/kg/week) is much less toxic than doxorubicin (2.5 mg/kg/week), while its anticancer activity was much more prominent. Conclusion: The cannabinoid quinone HU-331, which is more selective, more potent and less toxic than some known anticancer quinones, possesses high anti-angiogenic activity, specifically inhibits topoisomerse II and thus has a high potential as a new anticancer drug.