Center for Drug Delivery and Nanomedicine and Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198-5830, United States.
J Control Release. 2010 Feb 25;142(1):89-100. doi: 10.1016/j.jconrel.2009.09.026. Epub 2009 Oct 6.
A synthetic amphiphilic block copolymer, Pluronic, is a potent chemosensitizer of multidrug resistant (MDR) cancers that has shown promise in clinical trials. It has unique activities in MDR cells, which include a decrease in ATP pools and inhibition of P-glycoprotein (Pgp) resulting in increased drug accumulation in cells. This work demonstrates that Pluronic rapidly (15min) translocates into MDR cells and co-localizes with the mitochondria. It inhibits complex I and complex IV of the mitochondria respiratory chain, decreases oxygen consumption and causes ATP depletion in MDR cells. These effects are selective and pronounced for MDR cells compared to non-MDR counterparts and demonstrated for both drug-selected and Pgp-transfected cell models. Furthermore, inhibition of Pgp functional activity also abolishes the effects of Pluronic on intracellular ATP levels in MDR cells suggesting that Pgp contributes to increased responsiveness of molecular "targets" of Pluronic in the mitochondria of MDR cells. The Pluronic-caused impairment of respiration in mitochondria of MDR cells is accompanied with a decrease in mitochondria membrane potential, production of ROS, and release of cytochrome c. Altogether these effects eventually enhance drug-induced apoptosis and contribute to potent chemosensitization of MDR tumors by Pluronic.
一种合成的两亲性嵌段共聚物普朗尼克（Pluronic）是一种有效的多药耐药（MDR）癌症化学增敏剂，已在临床试验中显示出前景。它在 MDR 细胞中具有独特的活性，包括降低 ATP 池和抑制 P 糖蛋白（Pgp），从而导致细胞内药物积累增加。这项工作表明，普朗尼克（Pluronic）能迅速（15 分钟）转运到 MDR 细胞中，并与线粒体共定位。它抑制线粒体呼吸链的复合物 I 和复合物 IV，降低耗氧量并导致 MDR 细胞中 ATP 耗竭。与非 MDR 细胞相比，这些作用对 MDR 细胞具有选择性和明显性，并且在药物选择和 Pgp 转染的细胞模型中都得到了证明。此外，抑制 Pgp 的功能活性也会消除普朗尼克（Pluronic）对 MDR 细胞内 ATP 水平的影响，表明 Pgp 有助于增加 MDR 细胞线粒体中普朗尼克（Pluronic）分子“靶标”的反应性。普朗尼克（Pluronic）引起的 MDR 细胞线粒体呼吸损伤伴随着线粒体膜电位降低、ROS 产生和细胞色素 c 的释放。总之，这些作用最终增强了药物诱导的细胞凋亡，并有助于普朗尼克（Pluronic）对 MDR 肿瘤的有效化学增敏作用。
