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.
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.
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DOI：
10.1016/j.canlet.2018.10.020
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发表时间：
2019-02-01
期刊：
影响因子：
9.7
通讯作者：
Chen ZS
中科院分区：
文献类型：
--
作者：
De Vera AA;Gupta P;Lei Z;Liao D;Narayanan S;Teng Q;Reznik SE;Chen ZS
磷酸肌肽3-激酶γ亚型（PI3Kγ）在免疫抑制肿瘤微环境的髓源性细胞中起关键作用。IPI-549是最近发现的一种小分子选择性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联合进行免疫肿瘤学临床试验。本研究的目的是探讨IPI-549与p -糖蛋白（P-gp）化疗底物联用后是否能逆转p -糖蛋白（P-gp）介导的MDR。细胞毒性实验显示IPI-549能逆转p- gp介导的SW620/Ad300和LLC-PK-MDR1细胞的MDR。IPI-549增加细胞内紫杉醇的量，抑制紫杉醇向SW620/Ad300细胞外排。ABCB1-ATPase实验显示IPI-549能刺激ABCB1-ATPase的活性。IPI-549不改变P-gp在SW620/Ad300细胞中的表达，也不影响P-gp的亚细胞定位。IPI-549与紫杉醇联合应用表明IPI-549可增强紫杉醇对p- gp过表达MDR SW620/Ad300异种移植肿瘤的抗肿瘤作用。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标准治疗的免疫原性化疗中以改善患者的预后，我们的研究结果支持将IPI-549添加到癌症联合治疗策略的化疗和免疫治疗方面的基本原理。
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.
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影响因子：
11.2
作者：
Dai CL;Tiwari AK;Wu CP;Su XD;Wang SR;Liu DG;Ashby CR Jr;Huang Y;Robey RW;Liang YJ;Chen LM;Shi CJ;Ambudkar SV;Chen ZS;Fu LW
通讯作者：
Fu LW
影响因子：
64.8
作者：
De Henau O;Rausch M;Winkler D;Campesato LF;Liu C;Cymerman DH;Budhu S;Ghosh A;Pink M;Tchaicha J;Douglas M;Tibbitts T;Sharma S;Proctor J;Kosmider N;White K;Stern H;Soglia J;Adams J;Palombella VJ;McGovern K;Kutok JL;Wolchok JD;Merghoub T
通讯作者：
Merghoub T
影响因子：
2.9
作者：
Jones, Peter M.;George, Anthony M.
通讯作者：
George, Anthony M.
影响因子：
--
作者：
Gebremeskel S;Johnston B
通讯作者：
Johnston B
DOI：
10.1126/science.1168750
发表时间：
2009-03-27
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Aller SG;Yu J;Ward A;Weng Y;Chittaboina S;Zhuo R;Harrell PM;Trinh YT;Zhang Q;Urbatsch IL;Chang G
通讯作者：
Chang G