Sensitization of drug resistant human ovarian cancer cells to cyanomorpholino doxorubicin (MRA-CN) by modulation of glutathione metabolism.
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.
Lewis
A D
AD
Stanford University Medical Center, Department of Medicine/Oncology, CA 94305.
Durán
G E
GE
Lau
D H
DH
Sikic
B I
BI
D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D019328:Buthionine Sulfoximine; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004351:Drug Resistance; D004976:Ethacrynic Acid / Q000494:pharmacology; D005260:Female; D005978:Glutathione / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D008717:Methionine Sulfoximine / Q000031:analogs & derivatives / Q000494:pharmacology; D010051:Ovarian Neoplasms / Q000473:pathology; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D008717:Methionine Sulfoximine; D019328:Buthionine Sulfoximine; D004317:Doxorubicin; C038555:3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin; D005978:Glutathione; D004976:Ethacrynic Acid