Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.6.3.44 (P-glycoprotein)
 13,344 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Yoshida rat ascites hepatoma (AH) has several cell lines with a characteristic sensitivity to antitumor drugs. AH66 cells overexpressed 160-170 kDa P-glycoprotein (P-gp) in the membrane and glutathione-S-transferase placental form (GST-P) in the cytosol. AH44 cells did not express P-gp but contained GST-P isozyme, while normal rat liver had GST-(1,2) and-(3,4) classes. AH44 and AH66 cells were more resistant to chlorambucil (CLB) than AH66F cells, which are a variant cell line derived from AH66 cells and lacked both proteins. CLB-resistant AH44 and AH66 cells contained a high amount of glutathione (GSH) and higher GST activity than AH66F cells. Ethacrynic acid, a GST-P inhibitor, and buthionine sulfoximine, a GSH biosynthesis inhibitor, significantly decreased the CBL resistance of AH44 and AH66 cells without influencing the sensitivity of AH66F cells. The CLB resistance of these cell lines were hardly influenced by verapamil, a calcium channel blocker with P-gp antagonistic action, which significantly decreased the vinblastine resistance of AH66 cells. This study indicates that AH66 cells showed multiple drug resistance dependent on P-gp and GST-P isozyme and that the AH44 cell line was CLB resistant through the GSH/GST-P detoxification system. These hepatomas are useful for investigation of the drug resistance of hepatic carcinomas and development of counteracting drugs.
 ...
PMID:Glutathione-S-transferase P-form dependent chlorambucil resistance in Yoshida rat ascites hepatoma cell lines. 791 Jan 11

The ability of physical and pharmacological modulators to increase the cytotoxicity of melphalan was investigated in Chinese hamster ovary cells using a clonogenic cell survival assay. Hyperthermia has potential for use in cancer treatment, particularly as an adjuvant to chemotherapy or radiotherapy. Ethacrynic acid is a glutathione S-transferase inhibitor and also undergoes conjugation with glutathione. Interactions between hyperthermia (41-43 degrees C), ethacrynic acid and melphalan were evaluated in multidrug-resistant (CH(R)C5) cells with overexpression of P-glycoprotein (33.69-fold), and in drug-sensitive (AuxB1) cells. GST alpha was expressed at a higher level (3.65-fold) in CH(R)C5 cells than in sensitive cells, whereas levels of isoforms pi and mu were the same. GST pi was the most highly expressed isoform in the two cell populations. Ethacrynic acid was cytotoxic at elevated temperatures, while it caused little or no cytotoxicity at 37 degrees C. This effect occurred in drug-resistant and drug-sensitive cells, and attributes thermosensitizing properties to ethacrynic acid. Ethacrynic acid (20 microM) alone did not alter the cytotoxicity of melphalan at 37 degrees C. Hyperthermia potentiated drug cytotoxicity in cells, both with and without ethacrynic acid treatment. Ethacrynic acid could be useful in cancer treatment by acting as a thermosensitizer when combined with heat and by enhancing the cytotoxicity of melphalan at elevated temperatures. A major advantage arising from the use of regional hyperthermia is the ability to target drug cytotoxicity to the tumor volume. A useful finding is that ethacrynic acid, heat and/or melphalan are also effective against multidrug-resistant cells with overexpression of P-glycoprotein.
 ...
PMID:Sensitization to the cytotoxicity of melphalan by ethacrynic acid and hyperthermia in drug-sensitive and multidrug-resistant Chinese hamster ovary cells. 1150 Jan 36

Glutathione S-transferases (GSTs) are involved in the detoxification of xenobiotics, such as several cytostatic drugs, through conjugation with glutathione (GSH). Pi class GST (GST P) liver expression is associated with preneoplastic and neoplastic development and contributes with the drug-resistance phenotype. Ethacrynic acid (EA) is an inhibitor of rat and human GSTs. In addition, causes lipid peroxidation in isolated rat hepatocytes. Therefore, we decided to evaluate the role of the GST/GSH system in isolated hepatocytes from preneoplastic rat livers (IP) in the presence of EA and determine the cytotoxicity of the drug. Our results showed a resistance to the toxic effects of EA since viability and cellular integrity values were significantly higher than control. Initial levels of thiobarbituric acid reactive substances (TBARS) in IP hepatocytes were significantly higher than control and the presence of EA did not change TBARS levels. A diminution in intracellular total GSH was observed by treating with EA isolated hepatocytes from both groups. However, the initial total GSH levels were higher in IP hepatocytes than in control. Immunoblotting analysis showed the presence of GST P in IP animals only. Although alpha and mu class isoenzymes levels were decreased in IP hepatocytes, total GST activity was 1.5-fold higher than in control. In addition, multidrug-resistance protein 2 (Mrp2) showed fivefold decreased levels in IP hepatocytes. In conclusion, increased total GSH, decreased Mrp2 levels and the presence of GST P could be critical factors involved in the resistance of IP hepatocytes to the toxicity of EA.
 ...
PMID:Hepatocytes isolated from preneoplastic rat livers are resistant to ethacrynic acid cytotoxicity. 1734 Jan 22