Free radical formation by ansamycin benzoquinone in human breast tumor cells: implications for cytotoxicity and resistance.
The benzoquinonoid ansamycin antibiotics, geldanamycin and herbimycin A, are potent cytotoxins against tumor cells in vitro. We have examined the mechanism of their in vitro cytotoxicity against human breast adenocarcinoma (MCF-7) cells and we have found that multidrug-resistant MCF-7/ADRR cells that exhibit the MDR phenotype and the overexpression of P-170-glycoprotein, were cross-resistant to geldanamycin and herbimycin A. Verapamil, which binds competitively with P-170-glycoprotein, enhanced geldanamycin cytotoxicity 12-fold only in resistant cells, suggesting that geldanamycin may interact with the drug efflux protein. Geldanamycin and herbimycin A, like adriamycin, were reductively activated by the NADPH-cytochrome P450-reductase and formed reactive .OH. The formation of .OH was significantly lower in resistant cells. In contrast to adriamycin, the formation of .OH was unaffected by the addition of DNA, indicating that a DNA-complexed drug was redoxactive and may, therefore, may be more effective in killing tumor cells at the DNA level. These observations indicate that both the decreased free radical formation and interactions with P170 glycoprotein may be important in geldanamycin and herbimycin A resistance in multidrug resistant human breast tumor cells.
Benchekroun
N M
NM
Biochemical & Molecular Pharmacology Section, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
Myers
C E
CE
Sinha
B K
BK
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000378:metabolism* / Q000627:therapeutic use; D016227:Benzoquinones; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D004317:Doxorubicin / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D005609:Free Radicals; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism; D047029:Lactams, Macrocyclic; D009251:NADPH-Ferrihemoprotein Reductase / Q000378:metabolism; D011809:Quinones / Q000378:metabolism* / Q000627:therapeutic use; D017828:Rifabutin / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D005609:Free Radicals; D047029:Lactams, Macrocyclic; D011809:Quinones; D017828:Rifabutin; D017665:Hydroxyl Radical; C020754:herbimycin; D004317:Doxorubicin; D014700:Verapamil; D009251:NADPH-Ferrihemoprotein Reductase; C001277:geldanamycin