免疫肿瘤学药物IPI-549是体内癌症中P-糖蛋白（P-gp，MDR1，ABCB1）介导的多药耐药性（MDR）的调节剂。,Cancer Letters

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免疫肿瘤学药物IPI-549是体内癌症中P-糖蛋白（P-gp，MDR1，ABCB1）介导的多药耐药性（MDR）的调节剂。
Cancer Letters ( IF 9.1 ) Pub Date : 2018-11-01 , DOI: 10.1016/j.canlet.2018.10.020
Albert A De Vera ₁ , Pranav Gupta ₁ , Zining Lei ₁ , Dan Liao ₁ , Silpa Narayanan ₁ , Qiuxu Teng ₁ , Sandra E Reznik ₂ , Zhe-Sheng Chen ₁

Affiliation

磷酸肌醇3-激酶γ亚型（PI3Kγ）在免疫抑制性肿瘤微环境的髓样来源的细胞中起关键作用。IPI-549是一种最近发现的小分子选择性PI3Kγ抑制剂，目前正在与抗PD-1单克隆抗体免疫检查点阻断剂nivolumab结合进行免疫肿瘤学临床试验。这项研究的目的是调查IPI-549与P-gp的化疗底物结合时是否可以逆转P-糖蛋白（P-gp）介导的MDR。细胞毒性试验表明IPI-549可以逆转SW620 / Ad300和LLC-PK-MDR1细胞中P-gp介导的MDR。IPI-549增加了细胞内紫杉醇的量，并抑制了紫杉醇从SW620 / Ad300细胞中流出。ABCB1-ATPase检测表明IPI-549刺激了ABCB1-ATPase的活性。IPI-549不会改变表达，也不会影响SW620 / Ad300细胞中P-gp的亚细胞定位。IPI-549与紫杉醇的组合显示IPI-549增强了紫杉醇在过表达P-gp的MDR SW620 / Ad300异种移植肿瘤中的抗肿瘤作用。随着临床试验开始将新批准的基于免疫检查点的免疫疗法添加到护理标准的免疫原性化疗中以改善患者的预后，我们的发现支持将IPI-549添加到癌症联合治疗策略的化学治疗和免疫治疗方面的基本原理。IPI-549与紫杉醇的组合显示IPI-549增强了紫杉醇在过表达P-gp的MDR SW620 / Ad300异种移植肿瘤中的抗肿瘤作用。随着临床试验开始将新批准的基于免疫检查点的免疫疗法添加到护理标准的免疫原性化疗中以改善患者的预后，我们的发现支持将IPI-549添加到癌症联合治疗策略的化学治疗和免疫治疗方面的基本原理。IPI-549与紫杉醇的组合显示IPI-549增强了紫杉醇在过表达P-gp的MDR SW620 / Ad300异种移植肿瘤中的抗肿瘤作用。随着临床试验开始将新批准的基于免疫检查点的免疫疗法添加到护理标准的免疫原性化疗中以改善患者的预后，我们的发现支持将IPI-549添加到癌症联合治疗策略的化学治疗和免疫治疗方面的基本原理。

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Immuno-oncology agent IPI-549 is a modulator of P-glycoprotein (P-gp, MDR1, ABCB1)-mediated multidrug resistance (MDR) in cancer: In vitro and in vivo.

Phosphoinositide 3-kinase gamma isoform (PI3Kγ) plays a critical role in myeloid-derived cells of the immunosuppressive tumor microenvironment. IPI-549, a recently discovered small molecule selective PI3Kγ inhibitor, is currently under immuno-oncology clinical trials in combination with nivolumab, an anti-PD-1 monoclonal antibody immune checkpoint blocker. The purpose of this study is to investigate whether IPI-549 could reverse P-glycoprotein (P-gp)-mediated MDR when combined with chemotherapeutic substrates of P-gp. Cytotoxicity assays showed that IPI-549 reverses P-gp-mediated MDR in SW620/Ad300 and LLC-PK-MDR1 cells. IPI-549 increases the amount of intracellular paclitaxel and inhibits the efflux of paclitaxel out of SW620/Ad300 cells. ABCB1-ATPase assay showed that IPI-549 stimulates the activity of ABCB1-ATPase. IPI-549 does not alter the expression and does not affect the subcellular localization of P-gp in SW620/Ad300 cells. The combination of IPI-549 with paclitaxel showed that IPI-549 potentiates the anti-tumor effects of paclitaxel in P-gp-overexpressing MDR SW620/Ad300 xenograft tumors. With clinical trials beginning to add newly approved immune checkpoint-based immunotherapy into standard-of-care immunogenic chemotherapy to improve patient outcomes, our findings support the rationale of adding IPI-549 to both the chemotherapeutic and immunotherapeutic aspects of cancer combination treatment strategies.

更新日期：2018-11-01

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