Cytotoxicity of alpha-tocopheryl succinate, malonate and oxalate in normal and cancer cells in vitro and their anti-cancer effects on mouse melanoma in vivo.
alpha-Tocopheryl succinate (TS), which is known to induce apoptosis selectively in cancer cells, has attracted attention as a chemotherapeutic agent. Recently, we found that alpha-tocopheryl malonate (TM) and alpha-tocopheryl oxalate (TO), among the alpha-tocopheryl esters tested, have high apoptogenic activity as well as TS. In this study, we investigated the characteristics of their cytotoxicity on normal cells and cancer cells in vitro, and their anti-cancer effects on mice inoculated with melanoma B16-F1 cells in vivo. The order of in vitro cytotoxicity was TO > or = TM >> TS in all cell lines examined. Addition of exogenous superoxide dismutase (SOD) and the antioxidant N-acetyl cysteine (NAC) inhibited TS- and TM- but not TO-induced cell deaths. A selective cytotoxic effect on cancer cells was observed with TS but not with TM or TO. c-Jun N-terminal kinase (JNK) inhibitor II prevented cell death induced by TS but did not prevent cell deaths induced either by TM or TO. Intravenous administration of vesiculated TS and TM to mice inoculated with melanoma B16-F1 cells prevented tumor growth and enhanced the mean survival time, but TO administration killed the mice due to its acute high toxicity. From these results, we discussed the characteristics of their selective cytotoxicity toward tumor cells in vitro and anti-cancer effects in vivo.
Kogure
Kentaro
K
Graduate School of Pharmaceutical Sciences, University of Tokushima, Shomachi-1, Tokushima 770-8505, Japan.
Manabe
Sachie
S
Suzuki
Ichiro
I
Tokumura
Akira
A
Fukuzawa
Kenji
K
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D016923:Cell Death / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D051336:Mitochondrial Membranes / Q000187:drug effects; D009368:Neoplasm Transplantation; D013482:Superoxide Dismutase / Q000494:pharmacology; D024505:Tocopherols; D024502:alpha-Tocopherol / Q000031:analogs & derivatives* / Q000494:pharmacology
D000970:Antineoplastic Agents; D000975:Antioxidants; C511700:alpha-tocopheryl malonate; C511701:alpha-tocopheryl oxalate; D013482:Superoxide Dismutase; D024502:alpha-Tocopherol; D024505:Tocopherols; D000111:Acetylcysteine