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CHEMOTHERAPY, ANTIBIOTICS, AND GENE THERAPY

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

Department of Medicinal Chemistry and Natural Products, Pharmacy School, The Hebrew University, Jerusalem, Israel (N.M.K., M.P., R.M.); Department of Experimental Medicine and Cancer Research, School of Medicine, The Hebrew University, Jerusalem, Israel (M.S.); and Heart Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel (G.M., R.B.)

Several quinones have been found to be effective in the treatment of some forms of cancer; however, their cumulative heart toxicity limits their use. The cannabinoid quinone HU-331 [3S,4R-p-benzoquinone-3-hydroxy-2-p-mentha-(1,8)-dien-3-yl-5-pentyl] is highly effective against tumor xenografts in nude mice. We report now a comparison of the anticancer activity of HU-331 and its cardiotoxicity with those of doxorubicin in vivo. General toxicity was assayed in Sabra, nude and SCID-NOD mice. The anticancer activity in vivo was assessed by measurement of the tumors with an external caliper in HT-29 and Raji tumor-bearing mice and by weighing the excised tumors. Left ventricular function was evaluated with transthoracic echocardiography. Myelotoxicity was evaluated by blood cell count. Cardiac troponin T (cTnT) plasma levels were determined by immunoassay. HU-331 was found to be much less cardiotoxic than doxorubicin. The control and the HU-331-treated groups gained weight, whereas the doxorubicin-treated group lost weight during the study. In HT-29 colon carcinoma, the tumor weight in the HU-331-treated group was 54% smaller than in the control group and 30% smaller than in the doxorubicin-treated group. In Raji lymphoma, the tumor weight in the HU-331-treated group was 65% smaller than in the control group and 33% smaller than in the doxorubicin-treated group. In contrast to doxorubicin, HU-331 did not generate reactive oxygen species in mice hearts (measured by protein carbonylation levels and malondialdehyde levels). In vivo, HU-331 was more active and less toxic than doxorubicin and thus it has a high potential for development as a new anticancer drug.

Address correspondence to: Natalya M. Kogan, Department of Medicinal Chemistry and Natural Products, Pharmacy School, Ein-Kerem Medical Campus, The Hebrew University, Jerusalem 91120, Israel. E-mail: natalyak{at}ekmd.huji.ac.il