Sensitization of drug resistant human ovarian cancer cells to cyanomorpholino doxorubicin (MRA-CN) by modulation of glutathione metabolism.

Abstract

MRA-CN, the alkylating cyanomorpholino derivative of doxorubicin (DOX), is extremely potent (100 to 1000 fold increase in cytotoxicity in vitro and in vivo), more lipophilic, non-cardiotoxic, and non-cross-resistant in multidrug resistant cells compared to DOX. We have developed an ovarian carcinoma cell line ES-2R that is 4-fold resistant to MRA-CN, compared to the parental ES-2 cells. This resistant cell line exhibits cross-resistance to alkylators and ionizing radiation. Glutathione (GSH) and GSH-dependent enzymes were found to be altered in the resistant cells with 1.5-fold increase in GSH, and 2- to 3-fold increase in the pi-class glutathione-s-transferase (GST) protein. Both D,L buthionine-S,R-sulfoximine (BSO) and ethacrynic acid (EA), inhibitors of GSH biosynthesis and pi-class GST activity, respectively, could sensitize the ES-2R cells to MRA-CN. These findings implicate a role for GSH metabolism in resistance of ES-2R cells to MRA-CN. The data also indicates the potential utility of EA to modulate GST activity and sensitize tumor cells toward alkylators.

• Authors: A D Lewis, G E Durán, D H Lau, B I Sikic
• Journal: International journal of radiation oncology, biology, physics (Int J Radiat Oncol Biol Phys) Vol. 22 Issue 4 Pg. 821-4 ( 1992) ISSN: 0360-3016 [Print] United States
• PMID: 1544857 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibiotics, Antineoplastic
• Methionine Sulfoximine
• Buthionine Sulfoximine
• Doxorubicin
• 3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin
• Glutathione
• Ethacrynic Acid

Topics

• Antibiotics, Antineoplastic (therapeutic use)
• Buthionine Sulfoximine
• Cell Survival (drug effects)
• Doxorubicin (analogs & derivatives, therapeutic use)
• Drug Resistance
• Ethacrynic Acid (pharmacology)
• Female
• Glutathione (physiology)
• Humans
• In Vitro Techniques
• Methionine Sulfoximine (analogs & derivatives, pharmacology)
• Ovarian Neoplasms (pathology)
• Tumor Cells, Cultured