Grunicke H, Hofmann J, Utz I, Uberall F
Institut für Medizinische Chemie und Biochemie, Universität Innsbruck, Austria.
Ann Hematol. 1994;69 Suppl 1:S1-6. doi: 10.1007/BF01757347.
The activity of several proteins involved in the development of antitumor drug resistance is regulated by protein phosphorylation. These proteins include the mdr-1-encoded P-glycoprotein (Pgp) and topoisomerase II (topo II). The corresponding evidence is reviewed and attempts to modulate multidrug resistance (MDR) by protein kinase C inhibitors are described. The expression of several proteins which are essential in drug resistance is regulated at the transcriptional level, involving protein phosphorylation by members of the protein kinase C (PKC) family, casein kinase II (CKII), and others. These proteins include mdr-1-encoded P-glycoprotein, metallothionein, glutathione S-transferase (GST), dTMP synthase, and the proteins Fos and Jun. The corresponding genes are under positive regulation of ras, which in turn requires the activation of a protein kinase cascade for its function. Protein kinases are therefore potentially useful targets in reducing the expression of proteins involved in the development of multifactorial drug resistance caused by the expression of transforming ras-genes. Attempts to inhibit the ras-induced fos expression by an inhibitor of protein kinase C (ilmofosine) are described. Protein kinase inhibitors are also able to synergistically enhance the cytotoxicity of cis-platinum, which is discussed as resulting from a reduction of PKC-dependent fos expression.
几种参与抗肿瘤耐药性发展的蛋白质的活性受蛋白质磷酸化调节。这些蛋白质包括多药耐药基因1（mdr-1）编码的P-糖蛋白（Pgp）和拓扑异构酶II（topo II）。本文综述了相应证据，并描述了用蛋白激酶C抑制剂调节多药耐药性（MDR）的尝试。几种对耐药性至关重要的蛋白质的表达在转录水平受到调节，涉及蛋白激酶C（PKC）家族成员、酪蛋白激酶II（CKII）等的蛋白磷酸化。这些蛋白质包括mdr-1编码的P-糖蛋白、金属硫蛋白、谷胱甘肽S-转移酶（GST）、胸苷酸合成酶以及Fos和Jun蛋白。相应的基因受ras的正向调控，而ras反过来又需要激活蛋白激酶级联反应才能发挥其功能。因此，蛋白激酶可能是减少因转化型ras基因表达导致的多因素耐药性发展过程中涉及的蛋白质表达的潜在有用靶点。本文描述了用蛋白激酶C抑制剂（ ilmofosine）抑制ras诱导的fos表达的尝试。蛋白激酶抑制剂还能够协同增强顺铂的细胞毒性，这被认为是由于减少了PKC依赖的fos表达所致。
