Regulation of multidrug resistance through the cAMP and EGF signalling pathways

Cell Signal. 1995 Jul;7(5):431-43. doi: 10.1016/0898-6568(95)00018-k.

Abstract

The development of cross-resistance to many natural product anticancer drugs, termed multidrug resistance (MDR), is a serious limitation to cancer chemotherapy. MDR is often associated with overexpression of the MDR1 gene product, P-glycoprotein, a multifunctional drug transporter. Understanding the mechanisms that regulate the transcriptional activation of MDR1 may afford a means of reducing or eliminating MDR. We have found that MDR1 expression can be modulated by type I cAMP-dependent protein kinase (PKA). This suggests that MDR may be modulated by selectively downregulating PKA activity to effect inhibition of PKA-dependent trans-activating factors which may be involved in MDR1 transcription. High levels of type I PKA occur in primary breast carcinomas and patients exhibiting this phenotype show decreased survival. The selective type I PKA inhibitors, 8-Cl-cAMP and Rp8-Cl-cAMP[S], may be particularly useful for downregulating PKA, and inhibit transient expression of a reporter gene under the control of MDR1 promoter elements. Thus, investigations of the signalling pathways involved in transcriptional regulation of MDR1 may lead to a greater understanding of the mechanisms governing the expression of MDR and provide a focus for pharmacological intervention.

Publication types

  • Review

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / biosynthesis*
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • Antineoplastic Agents / pharmacology
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Cyclic AMP / analogs & derivatives
  • Cyclic AMP / metabolism*
  • Cyclic AMP-Dependent Protein Kinases / antagonists & inhibitors
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Down-Regulation
  • Drug Resistance, Multiple / physiology*
  • Epidermal Growth Factor / metabolism*
  • Female
  • Humans
  • Signal Transduction*
  • Transcription Factors / genetics
  • Tumor Cells, Cultured

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Antineoplastic Agents
  • Transcription Factors
  • Epidermal Growth Factor
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases