DENSpm通过激活多胺分解代谢机制克服了Bcl-2介导的MCF-7乳腺癌细胞对紫杉醇治疗的耐药性。,Biomedicine & Pharmacotherapy

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DENSpm通过激活多胺分解代谢机制克服了Bcl-2介导的MCF-7乳腺癌细胞对紫杉醇治疗的耐药性。
Biomedicine & Pharmacotherapy ( IF 6.9 ) Pub Date : 2016-11-25 , DOI: 10.1016/j.biopha.2016.11.016
Zeynep Akyol ₁ , Ajda Çoker-Gürkan ₁ , Elif Damla Arisan ₁ , Pınar Obakan-Yerlikaya ₁ , Narçin Palavan-Ünsal ₁

Affiliation

目的Bcl-2介导的耐药性是癌症治疗中最关键的障碍之一。常规化学疗法，例如紫杉醇，通常用于治疗转移性乳腺癌，不足以克服Bcl-2介导的耐药机制。因此，研究人员倾向于采用联合用药方案来克服对药物的耐药表型。N1，N11-二乙基去甲精胺（DENSpm），一种多胺类似物，通过活化的多胺分解代谢和活性氧生成，是一种有前途的候选药物，可诱导各种癌细胞（例如前列腺癌，黑素瘤，结肠癌和乳腺癌）中的细胞周期阻滞和凋亡。最近的研究表明，DENSpm在乳腺癌病例的I和II期试验中具有潜在的治疗作用。尽管已充分证明了紫杉醇在凋亡细胞死亡机制中的分子靶标，但尚未研究DENSpm和紫杉醇在乳腺癌细胞中的治疗作用。在这项研究中，我们的目标是通过确定过表达wt和Bcl-2的MCF-7乳腺癌细胞中多胺代谢相关的靶标来确定DENSpm和紫杉醇对凋亡细胞死亡的时间依赖性作用。结果在我们的实验研究中，紫杉醇在24小时内以剂量依赖性方式降低了细胞活力。在MCF-7 Bcl-2 +乳腺癌细胞中，与单独的紫杉醇（30nM）治疗相比，紫杉醇（30nM）与DENSpm（20μM）的共同治疗进一步增加了紫杉醇（30nM）的细胞毒性。此外，我们确定，由于多胺分解代谢途径的激活（导致多胺耗竭），可以克服Bcl-2过表达的MCF-7细胞对紫杉醇诱导的凋亡细胞死亡的抗性。结论DENSpm联合治疗可能增加低细胞毒性紫杉醇在耐药性乳腺癌患者中的作用。

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DENSpm overcame Bcl-2 mediated resistance against Paclitaxel treatment in MCF-7 breast cancer cells via activating polyamine catabolic machinery.

PURPOSE The Bcl-2 mediated resistance is one of the most critical obstacle in cancer therapy. Conventional chemotherapeutics such as Paclitaxel, a commonly used in the treatment of metastatic breast cancer, is not sufficient to overcome Bcl-2 mediated drug resistance mechanism. Thus, combinational drug regimes are favored by researchers to overcome resistance phenotype against drugs. N1,N11-diethylnorspermine (DENSpm), a polyamine analogue, which is a promising drug candidate induced-cell cycle arrest and apoptosis in various cancer cells such as prostate, melanoma, colon and breast cancer cells via activated polyamine catabolism and reactive oxygen generation. Recent studies indicated the potential therapeutic role of DENSpm in phase I and II trials in breast cancer cases. Although the molecular targets of Paclitaxel in apoptotic cell death mechanism is well documented, the therapeutic effect of DENSpm and Paclitaxel in breast cancer cells has not been investigated yet. In this study, our aim was to determine the time dependent effect of DENSpm and Paclitaxel on apoptotic cell death via determination of polyamine metabolism related targets in wt and Bcl-2 overexpressing MCF-7 breast cancer cells. RESULTS In our experimental study, Paclitaxel decreased cell viability in dose-dependent manner within 24h. Co-treatment of Paclitaxel (30nM) with DENSpm (20μM) further increased the cytoxicity of Paclitaxel (30nM) compared to alone Paclitaxel (30nM) treatment in MCF-7 Bcl-2+ breast cancer cells. In addition, we determined that resistance against Paclitaxel-induced apoptotic cell death in Bcl-2 overexpressed MCF-7 cells was overcome due to activation of polyamine catabolic pathway, which caused depletion of polyamines. CONCLUSIONS DENSpm combinational treatment might increase the effect of low cytotoxic paclitaxel in drug-resistant breast cancer cases.

更新日期：2019-11-01

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