A cannabinoid anticancer quinone, HU-331, is more potent and less cardiotoxic than doxorubicin: a comparative in vivo study.
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.
Kogan
Natalya M
NM
Department of Medicinal Chemistry and Natural Products, Pharmacy School, Ein-Kerem Medical Campus, The Hebrew University, Jerusalem 91120, Israel. natalyak@ekmd.huji.ac.il
Schlesinger
Michael
M
Peters
Maximilian
M
Marincheva
Gergana
G
Beeri
Ronen
R
Mechoulam
Raphael
R
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001772:Blood Cell Count; D001835:Body Weight / Q000187:drug effects; D002185:Cannabidiol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000737:chemistry / Q000494:pharmacology*; D004452:Echocardiography; D019073:HT29 Cells; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008815:Mice, Inbred Strains; D008819:Mice, Nude; D016513:Mice, SCID; D015394:Molecular Structure; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009369:Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D050050:Protein Carbonylation / Q000187:drug effects; D020107:Troponin T / Q000097:blood; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D020107:Troponin T; C073718:cannabidiol hydroxyquinone; D002185:Cannabidiol; D008315:Malondialdehyde; D004317:Doxorubicin