Possible contribution of β-glycosidases and caspases in the cytotoxicity of novel glycoconjugates in colon cancer cells

被引:18
作者
Arafa, Hossam M. M. [1 ]
机构
[1] Al Azhar Univ, Fac Pharm, Dept Pharmacol & Toxicol, Cairo, Egypt
关键词
Glycoconjugates; Curcumin beta-glucoside; Perillyl alcohol beta-glucoside; Diethylstilbesterol beta-glucoside; Perillyl alcohol beta-galactoside; Diethylstilbesterol beta-galactoside; Caco-2; HT29; T84; Cytotoxicity; Apoptosis; Caspase-3; Caspase-9; IN-VITRO; INTESTINAL-ABSORPTION; DOXORUBICIN; APOPTOSIS; ACTIVATION; GLUCOSIDE; RECEPTOR; PRODRUG; DRUGS; CHEMOTHERAPY;
D O I
10.1007/s10637-009-9248-2
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Glycoconjugates represent a recent trend in cancer chemotherapy that adopts the concept of selective prodrug/drug targeting of tumor cells by selectively binding to specific transmembrane glucose transporters. Following preferential uptake of sugar conjugates into cancer cells, they are presumably subject to enzymatic cleavage by specific beta-glycosidases to liberate the free active cytotoxic aglycones that act selectively on cancer cells and spare other noncancerous ones. In this sense, the cytotoxicity of an array of newly synthesized glycoconjugates, including curcumin beta-glucoside, perillyl alcohol beta-glucoside, perillyl alcohol beta-galactoside, diethylstilbesterol beta-glucoside and diethylstilbesterol beta-galactoside have been investigated over 24-96 h in a panel of human colon cancer cells namely, Caco-2, HT29 and T84 cells. The role of beta-glycosidases and caspases in the bioactivation and cytotoxicity of these compounds has been addressed in the current study. All the glycoconjugates have proven cytotoxic efficacy in a time-dependent manner. Curcumin beta-glucoside was the most potent amongst all glycoconjugates tested. The sensitivity rank order of tumor cells towards all beta-glucosides was Caco-2 > HT29 > T84. This sensitivity ranking was well correlated with beta-glucosidase activity assessed in these cell lines. Unlike perillyl alcohol galactoside, the cytotoxicity rank order for diethylstilbesterol beta-galactoside was not coping with the beta-galactosidase activity detected. Apoptosis was assessed by fluorometric assay of caspase-3 and caspase-9 activities. Initiation and activation of apoptosis were increased in all colon cancer cells following exposure to most of the glycoconjugates, and this was well correlated with the cytotoxicity rank order of these prodrugs. Enzymatic cleavage of glycoconjugates was accomplished using a host of hydrolytic enzymes and cleavage kinetics was determined using HPLC. The glycoconjugates were only cleaved by beta-glucosidases and beta-galactosidases, but not by pancreatic lipase or hepatic esterase. Taken together, one could conclude that beta-glucosidases and beta-galactosidases are crucial for the bioactivation and cytotoxicity of these glycoconjugates. Also, initiation and activation of apoptosis in tumor cells may contribute, at least partly, for the cytotoxicity of these sugar conjugates.
引用
收藏
页码:306 / 317
页数:12
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