REGULATION OF MULTIDRUG-RESISTANCE THROUGH THE CAMP AND EGF SIGNALING 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.