Over-expression of P-glycoprotein and glutathione S-transferase pi in MCF-7 cells selected for vincristine resistance in vitro.
This study has provided evidence that exposure of the wild-type MCF-7 human breast carcinoma cell line to the mutagen ethyl methane sulphonate (EMS), followed by selection in vincristine (VCR), resulted in a stably-resistant subline, designated VCREMS, which expressed an approximately 14-fold level of resistance to VCR. This VCREMS subline showed cross-resistance (3-fold) to adriamycin (ADR) and to etoposide (3-fold), but not to cisplatin. The addition of a non-toxic concentration of verapamil (6.6 microM) significantly enhanced VCR cytotoxicity only in the resistant subline. This resistance was associated with over-expression of P-glycoprotein (Pgp), but without a concomitant increase in Pgp mRNA or gene amplification. In addition, activities of total glutathione S-transferases (GST) and glutathione peroxidase were elevated in this resistant subline, with over-expression of the GST-pi isozyme and its associated mRNA being identified, without gene amplification. This VCR-selected resistant MCF-7 cell line therefore provides another example of a breast carcinoma subline in which there is co-ordinate over-expression of both Pgp and GST-pi, without attributing a causal relationship to either event, and extends the range of anti-tumour drugs known to elicit modifications in glutathione metabolism.
Laboratory of Cellular Chemotherapy, Imperial Cancer Research Fund, London, England.
R D
RD
Whelan
C J
CJ
Waring
C R
CR
Wolf
J D
JD
Hayes
L K
LK
Hosking
B T
BT
Hill
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D001943:Breast Neoplasms / Q000737:chemistry* / Q000188:drug therapy / Q000378:metabolism; D004351:Drug Resistance; D005978:Glutathione / Q000032:analysis; D005980:Glutathione Reductase / Q000032:analysis; D005982:Glutathione Transferase / Q000032:analysis*; D008562:Membrane Glycoproteins / Q000032:analysis*; D012333:RNA, Messenger / Q000032:analysis; D014407:Tumor Cells, Cultured; D014750:Vincristine / Q000378:metabolism*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; D014750:Vincristine; D005980:Glutathione Reductase; D005982:Glutathione Transferase; D005978:Glutathione