Reversal of Multiple Drug Resistance in Cholangiocarcinoma by the Glutathione S-Transferase-π-Specific Inhibitor O1-Hexadecyl-γ-glutamyl-S-benzylcysteinyl-D-phenylglycine Ethylester
2003
Cholangiocarcinoma is markedly resistant to chemotherapy and has a dismal
prognosis, but its mechanism of drug resistance is unknown. This study
examines whether glutathione S -transferase-π (GSTP1-1) is involved
in resistance to anticancer drugs in cholangiocarcinoma and whether
GSTP1-1-specific inhibitors can overcome this resistance. First,
immunohistochemical examination disclosed strong staining of all our 17
cholangiocarcinoma specimens for GSTP1-1, irrespective of histological type.
Transfection of the GSTP1-1 antisense expression vector into a human
cholangiocarcinoma cell line (HuCCT1) apparently decreased its intracellular
GSTP1-1 concentration, and the sensitivity of transfectants to adriamycin
(ADR), cisplatin, and alkylating agents such as melphalan and
4-hydroxyperoxycyclophosphamide (4-HC) was increased significantly, compared
with that of mock transfectants. We next synthesized GSTP1-1-specific
inhibitors by elongating the carbon chain of the ethylester at the
N -terminal of
γ-glutamyl- S -benzylcysteinyl-phenylglycyl diethylester and
performed a pharmacokinetic study on them. Of six GSTP1-1 inhibitors tested,
O 1 -hexadecyl-γ-glutamyl- S -benzylcysteinyl-d-phenylglycine
ethylester (C16C2) showed the smallest volume of central compartment and
smallest volume of distribution at steady state and the second smallest
clearance, being the most effective inhibitor in vivo. The IC 50 value of ADR or 4-HC for HuCCT1 cells decreased greater by treatment with
C16C2 in a dose-dependent manner, paralleling the decrease in GSTP1-1
activity, than that of ADR or 4-HC alone. The antitumor activity of ADR or
cyclophosphamide was clearly enhanced by combination therapy with C16C2 in a
xenograft model. In conclusion, our results demonstrated that GSTP1-1 is a
resistance factor for anticancer drugs in cholangiocarcinoma and that C16C2, a
GSTP1-1-specific inhibitor, is a potent agent against the resistance.
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