VKNG-1 Antagonizes ABCG2-Mediated Multidrug Resistance via p-AKT and Bcl-2 Pathway in Colon Cancer: In Vitro and In Vivo Study.
VKNG-1 Antagonizes ABCG2-Mediated Multidrug Resistance via p-AKT and Bcl-2 Pathway in Colon Cancer: In Vitro and In Vivo Study.
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DOI：
10.3390/cancers13184675
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发表时间：
2021-09-17
期刊：
影响因子：
5.2
通讯作者：
Chen ZS
中科院分区：
文献类型：
--
作者：
Narayanan S;Fan YF;Gujarati NA;Teng QX;Wang JQ;Cai CY;Yang Y;Chintalapati AJ;Lei Y;Korlipara VL;Chen ZS
多药耐药性或化学耐药性是一种现象，其中细胞表现出对药物的耐药性，这些药物在结构上是不同的。ABCG 2是ABC转运蛋白超家族的成员之一，它通过泵出多种化疗药物而成为多种肿瘤多药耐药的主要原因。VKNG-1，一种苯基四唑类似物，在ABCG 2过表达的结肠癌中选择性地抑制ABCG 2转运蛋白并逆转体外和体内对标准抗癌药物的耐药性。这项研究提出了VKNG-1作为ABCG 2转运蛋白调节剂的重要性。在癌症患者中，VKNG-1和ABCG 2底物药物的组合可能是ABCG 2高表达细胞的有益治疗选择。化疗药物的多药耐药（MDR）是肿瘤治疗中的一个主要问题。了解癌症耐药性的机制对于开发有效的治疗方法是必要的。ATP结合盒（ABC）转运蛋白是跨膜蛋白，其将化疗药物从癌细胞外排，从而产生MDR。我们的研究工作导致了VKNG-1的发现，VKNG-1是一种选择性抑制ABCG 2转运蛋白并逆转体外和体内对标准抗癌药物的耐药性的化合物。6 µM的VKNG-1选择性抑制ABCG 2转运蛋白，并使ABCG 2过表达的耐药癌细胞对ABCG 2底物抗癌药物米托蒽醌、SN-38和阿霉素在ABCG 2过表达的结肠癌中敏感。VKNG- 1通过阻断ABCG 2外排活性并在mRNA和蛋白水平下调ABCG 2表达来逆转ABCG 2介导的MDR。此外，VKNG-1抑制磷酸化蛋白激酶B（PKB/p-AKT）和B细胞淋巴瘤-2（Bcl-2）蛋白的水平，这可以克服对抗癌药物的抗性。然而，在存在6 µM VKNG-1的情况下，ABCG 2蛋白的体外易位未发生。此外，VKNG-1增强了伊立替康在ABCG 2过表达小鼠肿瘤异种移植物中的抗癌疗效。总体而言，我们的研究结果表明，VKNG-1可能与某些抗癌药物组合，代表了克服ABCG 2介导的MDR结肠癌的治疗。
Multidrug resistance or chemoresistance is a phenomenon where cells exhibit resistance to drugs that are pharmacologically and structurally distinct. ABCG2, a member of ABC transporter superfamily has been widely reported to be a principal cause of MDR in various cancers via pumping out various antineoplastic drugs. VKNG-1, a phenyltetrazole analogue selectively inhibits the ABCG2 transporter and reverses resistance to standard anticancer drugs both in vitro and in vivo in ABCG2-overexpressing colon cancers. This study presents the importance of VKNG-1 as a modulator of the ABCG2 transporter. In cancer patients, a combination of VKNG-1 and ABCG2 substrate drugs could be a beneficial treatment option for cells with high ABCG2 expression. The emergence of multidrug resistance (MDR) to chemotherapeutic drugs is a major problem in the therapy of cancer. Knowledge of the mechanisms of drug resistance in cancer is necessary for developing efficacious therapies. ATP-binding cassette (ABC) transporters are transmembrane proteins that efflux chemotherapeutic drugs from cancer cells, thereby producing MDR. Our research efforts have led to the discovery of VKNG-1, a compound that selectively inhibits the ABCG2 transporter and reverses resistanctabe to standard anticancer drugs both in vitro and in vivo. VKNG-1, at 6 µM, selectively inhibited ABCG2 transporter and sensitized ABCG2-overexpressing drug-resistant cancer cells to the ABCG2 substrate anticancer drugs mitoxantrone, SN-38, and doxorubicin in ABCG2-overexpressing colon cancers. VKNG- 1 reverses ABCG2-mediated MDR by blocking ABCG2 efflux activity and downregulating ABCG2 expression at the mRNA and protein levels. Moreover, VKNG-1 inhibits the level of phosphorylated protein kinase B (PKB/p-AKT), and B-cell lymphoma-2 (Bcl-2) protein which may overcome resistance to anticancer drugs. However, the in vitro translocation of ABCG2 protein did not occur in the presence of 6 µM of VKNG-1. In addition, VKNG-1 enhanced the anticancer efficacy of irinotecan in ABCG2- overexpressing mouse tumor xenografts. Overall, our results suggest that VKNG-1 may, in combination with certain anticancer drugs, represent a treatment to overcome ABCG2-mediated MDR colon cancers.
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影响因子：
9.7
作者：
De Vera AA;Gupta P;Lei Z;Liao D;Narayanan S;Teng Q;Reznik SE;Chen ZS
通讯作者：
Chen ZS
影响因子：
16.8
作者：
Jackson, Scott M.;Manolaridis, Ioannis;Locher, Kaspar P.
通讯作者：
Locher, Kaspar P.
影响因子：
3.6
作者：
Chen, ZS;Hopper-Borge, E;Kruh, GD
通讯作者：
Kruh, GD
影响因子：
3.1
作者：
Kosztyu, Petr;Dolezel, Petr;Mlejnek, Petr
通讯作者：
Mlejnek, Petr
色瑞替尼（LDK378）对 ABCB1 和 ABCG2 过表达细胞体内外增强化疗药物的作用
影响因子：
--
作者：
Hu J;Zhang X;Wang F;Wang X;Yang K;Xu M;To KK;Li Q;Fu L
通讯作者：
Fu L