Regulation of multidrug resistance through the cAMP and EGF signalling pathways.
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.
Rohlff
C
C
Department of Pharmacology, Georgetown University Medical Center, Washington, DC 20007, USA.
Glazer
R I
RI
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D015536:Down-Regulation; D018432:Drug Resistance, Multiple / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000378:metabolism*; D005260:Female; D006801:Humans; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D014157:Transcription Factors; D004815:Epidermal Growth Factor; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases