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Anomalous expression of P‐glycoprotein in highly drug‐resistant human KB cells
Author(s) -
Dolci Elizabeth D.,
Abramson Robin,
Xuan Yongzhi,
Siegfried Jennifer,
Yuenger Kristin A.,
Yassa David S.,
Tritton Thomas R.
Publication year - 1993
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910540223
Subject(s) - p glycoprotein , cell culture , biology , gene , multiple drug resistance , gene expression , glycoprotein , microbiology and biotechnology , phenotype , drug resistance , transcription (linguistics) , orosomucoid , genetics , philosophy , linguistics
Abstract KB‐AI and KB‐A10 are 2 multi‐drug‐resistant cell lines which are 100‐ and 1,000‐fold resistant to Adriamycin, respectively. We have examined the expression of P‐glycoprotein at the molecular and cellular levels in these human carcinoma cells. Both MDR cell lines, when compared to the parental KB‐3–1, show characteristic increases in mdr l gene copy number, an increase in mdr l mRNA expression, a corresponding increase in transcription rate and a consequent over‐expression of P‐glycoprotein. However, the more highly resistant KB‐A 10 cells have a lower gene copy number, express less mdr l mRNA and contain less P‐glycoprotein than the AI cell line. To determine whether higher levels of cellular resistance were attributable to enhanced efficacy of P‐glycoprotein or to other cellular regulatory mechanisms, we examined other major cellular properties known to be associated with the mdr phenotype. Both the KB‐AI and KB‐A 10 lines exhibit similar increases in protein kinase C activity as compared to the drug‐sensitive parent. In addition, neither glutathione‐S‐transferase nor topoisomerase II activities account for enhanced resistance of the KB‐A 10 cells. The above observations are contrary to the premise that the level of drug resistance is necessarily proportional to expression of P‐glycoprotein or to other common factors thought to participate in drug insensitivity; consequently, new mechanisms of resistance must be in operation in these cells.