Anomalous expression of P-glycoprotein in highly drug-resistant human KB cells

Int J Cancer. 1993 May 8;54(2):302-8. doi: 10.1002/ijc.2910540223.

Abstract

KB-A1 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 1 gene copy number, an increase in mdr 1 mRNA expression, a corresponding increase in transcription rate and a consequent over-expression of P-glycoprotein. However, the more highly resistant KB-A10 cells have a lower gene copy number, express less mdr 1 mRNA and contain less P-glycoprotein than the A1 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-A1 and KB-A10 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-A10 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Blotting, Western
  • DNA Topoisomerases, Type II / metabolism
  • Doxorubicin / pharmacology
  • Drug Resistance*
  • Gene Expression
  • Glutathione Transferase / metabolism
  • Humans
  • In Vitro Techniques
  • KB Cells / drug effects*
  • KB Cells / metabolism
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism*
  • Membrane Proteins / metabolism
  • Phosphoproteins / metabolism
  • Phosphorylation
  • Protein Kinase C / metabolism

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Membrane Glycoproteins
  • Membrane Proteins
  • Phosphoproteins
  • Doxorubicin
  • Glutathione Transferase
  • Protein Kinase C
  • DNA Topoisomerases, Type II