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Role of glutathione, glutathione S-transferases and multidrug resistance-related proteins in cisplatin sensitivity of head and neck cancer cell lines

Author: Welters, M.J.P. · Fichtinger-Schepman, A.M.J. · Baan, R.A. · Flens, M.J. · Scheper, R.J. · Braakhuis, B.J.M.
Type:article
Date:1998
Institution: Centraal Instituut voor Voedingsonderzoek TNO
Source:British Journal of Cancer, 4, 77, 556-561
Identifier: 234371
Keywords: Nutrition · Cisplatin · Glutathione · Glutathione S-transferase · Head and neck cancer · Multidrug resistance · Calcein · Glycoprotein p · Multidrug resistance protein · Cancer cell culture · Controlled study · Drug sensitivity · Drug transport · Head and neck cancer · Human cell · Immunocytochemistry · Membrane transport · Antineoplastic Agents · ATP-Binding Cassette Transporters · Drug Resistance, Multiple · Drug Resistance, Neoplasm · Enzyme Inducti · Glutathione Transferase · Head and Neck Neoplasms · Humans · Multidrug Resistance-Associated Proteins · Neoplasm Proteins · P-Glycoprotein · Vault Ribonucleoprotein Particles

Abstract

Resistance to chemotherapy is a major problem in the treatment of patients with head and neck squamous cell carcinoma (HNSCC). Important factors involved are drug detoxification by glutathione (GSH) and reduced drug accumulation due to active transport out of the cell by so-called 'multidrug resistance-related proteins'. We have studied a panel of eight HNSCC cell lines showing differences in sensitivity to the anti-cancer drug cisplatin. Our previous studies indicated that the IC50 values were inversely correlated with the intracellular accumulation of platinum (Pt). In the present study, cellular GSH levels were found not to be related to the IC50 values. The expression levels of the enzymes glutathione S-transferase (GST) α, μ and π, the multidrug resistance-related proteins P-glycoprotein (P-gp), multidrug resistance-associated protein (MRP) and the lung resistance protein (LRP) were determined semiquantitatively by means of immunocytochemistry. The levels of the GSTs, P-gp and LRP were not found to be correlated with the IC50 values of the HNSCC cell lines. Surprisingly, however, an inverse correlation was found between MRP levels and IC50 values. The MRP expression levels were in agreement with the results of the MRP functional assay, based on the transport of calcein across the cell membrane as performed for two of the cell lines. Further studies should prove whether other pump mechanisms or DNA repair are involved in the cisplatin accumulation and the subsequent HNSCC cell growth inhibition.