Glazer R I, Rohlff C
Georgetown University Medical Center, Department of Pharmacology, Washington, DC 20007.
Breast Cancer Res Treat. 1994;31(2-3):263-71. doi: 10.1007/BF00666159.
The development of cross-resistance to many natural product anticancer drugs, termed multidrug resistance (MDR), is one of the major reasons why cancer chemotherapy ultimately fails. This type of MDR is often associated with over-expression of the MDR1 gene product, P-glycoprotein (Pgp), a multifunctional drug transporter. The expression of MDR in breast tumors is related to their origination from a tissue that constitutively expresses Pgp as well as to the development of resistance during successive courses of chemotherapy. Therefore, 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), opening up the possibility of modulating MDR by selectively down-regulating the activity of PKA-dependent transcription factors which upregulate MDR1 expression. High levels of type I PKA occurs in primary breast carcinomas and patients exhibiting this phenotype show decreased survival. The selective type I cAMP-dependent protein kinase (PKA) inhibitors, 8-Cl-cAMP and Rp8-Cl-cAMP[S] may be particularly useful for downregulating PKA-dependent MDR-associated transcription factors, and we have found these compounds to downregulate transient expression of a reporter gene under the control of several MDR1 promoter elements. Thus, investigations of this nature should not only lead to a greater understanding of the mechanisms governing the expression of MDR, but also provide a focus for pharmacologic intervention by a new class of inhibitors.
对许多天然产物抗癌药物产生交叉耐药性，即多药耐药性（MDR），是癌症化疗最终失败的主要原因之一。这种类型的MDR通常与MDR1基因产物P-糖蛋白（Pgp）的过度表达有关，P-糖蛋白是一种多功能药物转运蛋白。乳腺肿瘤中MDR的表达与其起源于组成性表达Pgp的组织以及在连续化疗过程中耐药性的产生有关。因此，了解调节MDR1转录激活的机制可能提供一种减少或消除MDR的方法。我们发现MDR1的表达可以被I型环磷酸腺苷依赖性蛋白激酶（PKA）调节，这为通过选择性下调上调MDR1表达的PKA依赖性转录因子的活性来调节MDR开辟了可能性。I型PKA在原发性乳腺癌中水平较高，表现出这种表型的患者生存率降低。选择性I型环磷酸腺苷依赖性蛋白激酶（PKA）抑制剂8-Cl-cAMP和Rp8-Cl-cAMP[S]可能对下调PKA依赖性MDR相关转录因子特别有用，并且我们发现这些化合物可以下调几种MDR1启动子元件控制下的报告基因的瞬时表达。因此，这种性质的研究不仅应该导致对MDR表达调控机制的更深入理解，而且还为一类新型抑制剂的药理干预提供了重点。
