In vitro cytotoxicity of (-)-EGCG octaacetate on MDAMB-231 and SKHep-1 human carcinoma cells: a pharmacological consideration on prodrug design.
Esterification of acetate with generic pharmaceutical compound has been commonly employed to produce ester prodrug for improving its potency when compared with the mother compound. Acetate, on the other hand, has been recognized to have inhibitory effect on the respiratory biochemistry. Here we demonstrate that acetate at a concentration of 400 microM exhibited significant growth inhibitory activity on two human cancer cell lines, the MDAMB-231 breast cancer and the SKHep-1 hepatoma cell lines. To establish the ester prodrug with multi-acetate ester conjugates as our experimental model, one molecule of (-)-epigallocatechin gallate was required to conjugate with eight molecules of acetate forming the corresponding (-)-epigallocatechin gallate octaacetate prodrug. Chemical structure of this epigallocatechin gallate octaacetate ester prodrug was confirmed by both 13C and 1H nuclear magnetic resonance spectra and mass spectrometry. Further cytotoxic assay using both MDAMB-231 and SKHep-1 human carcinoma cell lines showed that acetate at a concentration of 400 microM exhibits an additional cytotoxic effect with (-)-epigallocatechin gallate at a concentration of 50 microM, although the additional effect was not as high as (-)-epigallocatechin gallate octaacetate ester prodrug alone at a concentration of 50 microM. Our results thus raise a pharmacological consideration of using multi-acetate conjugate as the ester prodrug where the release of free acetate by esterase could be part of the explanation for the improved in vitro cytotoxicity.
Kok
Stanton Hon Lung
SH
Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Hong Kong, PR China.
Wong
Raymond Siu Ming
RS
Gambari
Roberto
R
Cheung
Filly
F
Lam
Wing Sze
WS
Lau
Fung Yi
FY
Cheng
Gregory Yin Ming
GY
Cheng
Chor Hing
CH
Lam
Kim Hung
KH
Chan
Sau Hing
SH
Tang
Johnny Cheuk On
JC
Chui
Chung Hin
CH
Ho
Kwok Ping
KP
D000085:Acetates / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002392:Catechin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000085:Acetates; D000970:Antineoplastic Agents; D011355:Prodrugs; D002392:Catechin; C045651:epigallocatechin gallate