Reversal of multiple drug resistance in cholangiocarcinoma by the glutathione S-transferase-pi-specific inhibitor O1-hexadecyl-gamma-glutamyl-S-benzylcysteinyl-D-phenylglycine ethylester.

Abstract

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-pi (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 gamma-glutamyl-S-benzylcysteinyl-phenylglycyl diethylester and performed a pharmacokinetic study on them. Of six GSTP1-1 inhibitors tested, O1-hexadecyl-gamma-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 IC50 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.

• Authors: Takaharu Nakajima, Tetsuji Takayama, Koji Miyanishi, Atsushi Nobuoka, Tsuyoshi Hayashi, Tomoyuki Abe, Junji Kato, Kiyoyuki Sakon, Yoshimitsu Naniwa, Hirohumi Tanabe, Yoshiro Niitsu
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 306 Issue 3 Pg. 861-9 (Sep 2003) ISSN: 0022-3565 [Print] United States
• PMID: 12805482 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Isoenzymes
• O(1)-hexadecyl-gamma-glutamyl-S-benzylcysteinyl-phenylglycine ethyl ester
• Oligopeptides
• GSTP1 protein, human
• Glutathione S-Transferase pi
• Glutathione Transferase
• Gstp1 protein, mouse

Topics

• Animals
• Antineoplastic Agents (pharmacology, therapeutic use)
• Carcinoma, Hepatocellular (pathology)
• Cholangiocarcinoma (pathology)
• Disease Models, Animal
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Glutathione S-Transferase pi
• Glutathione Transferase (antagonists & inhibitors)
• Humans
• Immunohistochemistry
• Inhibitory Concentration 50
• Isoenzymes (antagonists & inhibitors)
• Liver Neoplasms (pathology)
• Mice
• Mice, Nude
• Neoplasm Transplantation
• Neoplasms, Experimental (drug therapy, prevention & control)
• Oligopeptides (pharmacology, therapeutic use)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays