In silico identified targeted inhibitors of P-glycoprotein overcome multidrug resistance in human cancer cells in culture.
In silico identified targeted inhibitors of P-glycoprotein overcome multidrug resistance in human cancer cells in culture.
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DOI：
10.1002/prp2.170
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发表时间：
2015-10
影响因子：
2.6
通讯作者：
Vogel PD
中科院分区：
文献类型：
--
作者：
Follit CA;Brewer FK;Wise JG;Vogel PD
癌症化疗的失败通常与ABC外排转运蛋白（如多药耐药P-糖蛋白（P-gp））的过度表达有关。P-gp在细胞中的表达导致各种化学上不相关的、主要是细胞毒性化合物的消除。在治疗期间施用化学治疗剂经常选择过表达P-gp的细胞，因此能够从细胞稳健地输出不同的化合物，包括化学治疗剂。因此，P-gp赋予目前用于治疗癌症和艾滋病毒/艾滋病等疾病的大多数药物多药耐药性。迄今为止，寻找P-gp抑制剂用作对抗多药耐药性的共同治疗剂几乎没有成功。在先前的研究中（Brewer等人，第86章：一个女人716-726，2014），我们描述了在体外如何通过PCR通量计算搜索鉴定特异性干扰底物转运的能量收集步骤并抑制P-gp催化的ATP水解的四种药物样分子。在本研究中，我们证明了这些化合物中的三种逆转了培养的前列腺癌细胞的P-gp介导的多药耐药性，恢复了与幼稚前列腺癌细胞对化疗药物紫杉醇的敏感性。抑制剂的增强浓度均<3 μmol/L。在逆转癌细胞多药耐药性的浓度下，这些抑制剂对非癌细胞没有表现出显着的毒性。我们的研究结果表明，这些化合物与P-gp抑制的新机制是很好的领导共同治疗多药耐药的治疗发展。
Failure of cancer chemotherapies is often linked to the over expression of ABC efflux transporters like the multidrug resistance P-glycoprotein (P-gp). P-gp expression in cells leads to the elimination of a variety of chemically unrelated, mostly cytotoxic compounds. Administration of chemotherapeutics during therapy frequently selects for cells that over express P-gp and are therefore capable of robustly exporting diverse compounds, including chemotherapeutics, from the cells. P-gp thus confers multidrug resistance to a majority of drugs currently available for the treatment of cancers and diseases like HIV/AIDS. The search for P-gp inhibitors for use as co-therapeutics to combat multidrug resistances has had little success to date. In a previous study (Brewer et al., Mol Pharmacol 86: 716–726, 2014), we described how ultrahigh throughput computational searches led to the identification of four drug-like molecules that specifically interfere with the energy harvesting steps of substrate transport and inhibit P-gp catalyzed ATP hydrolysis in vitro. In the present study, we demonstrate that three of these compounds reversed P-gp-mediated multidrug resistance of cultured prostate cancer cells to restore sensitivity comparable to naïve prostate cancer cells to the chemotherapeutic drug, paclitaxel. Potentiation concentrations of the inhibitors were <3 μmol/L. The inhibitors did not exhibit significant toxicity to noncancerous cells at concentrations where they reversed multidrug resistance in cancerous cells. Our results indicate that these compounds with novel mechanisms of P-gp inhibition are excellent leads for the development of co-therapeutics for the treatment of multidrug resistances.