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首页> 美国卫生研究院文献>other >Pluronic block copolymers alter apoptotic signal transduction of doxorubicin in drug-resistant cancer cells
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Pluronic block copolymers alter apoptotic signal transduction of doxorubicin in drug-resistant cancer cells

机译：Pluronic嵌段共聚物改变阿霉素在耐药癌细胞中的凋亡信号转导

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Pluronic block copolymer P85 (P85) sensitizes multidrug resistant (MDR) cancer cells resulting in the increase of cytotoxic activity of antineoplastic agents. This effect is attributed to the inhibition of the most clinically relevant drug efflux transporter, P-glycoprotein (Pgp), through the combined ATP depletion and inhibition of Pgp ATPase activity. The present study elucidates effects of an anticancer agent, doxorubicin (Dox), formulated with P85 on drug-induced apoptosis in MDR cancer cells. Early and late stages of apoptosis were detected by Annexin V and TUNEL methods, respectively. In parallel experiments, the expression of genes related to apoptosis, BCL2, BCLXL, BAX, P53, APAF1, Caspase 3, and Caspase 9, was determined by RT-PCR. The obtained data suggest that Dox/P85 formulation induces apoptosis in the resistant cancer cells more efficiently than free Dox. The treatment of the cells with Dox alone simultaneously activated a proapoptotic signal and an antiapoptotic cellular defense. Therefore, the apoptosis induction by Dox was substantially limited. In contrast, the treatment of the cells with Dox/P85 formulation significantly enhanced the proapoptotic activity of the drug and prevented the activation of the antiapoptotic cellular defense. This is likely to result in the stronger cytotoxic response of the resistant cells to the Dox/P85 formulation compared to the free drug.
机译：Pluronic嵌段共聚物P85（P85）使多药耐药（MDR）癌细胞敏感，导致抗肿瘤药的细胞毒活性增加。这种作用归因于通过结合的ATP耗竭和Pgp ATPase活性的抑制，抑制了临床上最相关的药物外排转运蛋白P-糖蛋白（Pgp）。本研究阐明了用P85配制的抗癌药阿霉素（Dox）对药物诱导的MDR癌细胞凋亡的作用。凋亡的早期和晚期分别通过Annexin V和TUNEL方法检测。在平行实验中，通过RT-PCR确定与凋亡，BCL2，BCLXL，BAX，P53，APAF1，Caspase 3和Caspase 9相关的基因的表达。获得的数据表明Dox / P85制剂比游离Dox更有效地诱导耐药性癌细胞的凋亡。用Dox单独处理细胞会同时激活促凋亡信号和抗凋亡细胞防御。因此，Dox诱导的细胞凋亡受到很大限制。相反，用Dox / P85制剂处理细胞可显着增强药物的促凋亡活性，并阻止抗凋亡细胞防御的激活。与游离药物相比，这可能导致耐药细胞对Dox / P85制剂的较强细胞毒性反应。

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