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VKNG-1 Antagonizes ABCG2-Mediated Multidrug Resistance via p-AKT and Bcl-2 Pathway in Colon Cancer: In Vitro and In Vivo Study

SIMPLE SUMMARY: 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...

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Detalles Bibliográficos
Autores principales: Narayanan, Silpa, Fan, Ying-Fang, Gujarati, Nehaben A., Teng, Qiu-Xu, Wang, Jing-Quan, Cai, Chao-Yun, Yang, Yuqi, Chintalapati, Anirudh J., Lei, Yixiong, Korlipara, Vijaya L., Chen, Zhe-Sheng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8470077/
https://www.ncbi.nlm.nih.gov/pubmed/34572902
http://dx.doi.org/10.3390/cancers13184675
Descripción
Sumario:SIMPLE SUMMARY: 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. ABSTRACT: 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.