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ABCB1 and ABCG2 Overexpression Mediates Resistance to the Phosphatidylinositol 3-Kinase Inhibitor HS-173 in Cancer Cell Lines

Constitutive activation of the phosphoinositide-3-kinase (PI3K)/Akt signaling pathway is crucial for tumor growth and progression. As such, this pathway has been an enticing target for drug discovery. Although HS-173 is a potent PI3K inhibitor that halts cancer cell proliferation via G2/M cell cycle...

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Autores principales: Wu, Chung-Pu, Hung, Cheng-Yu, Hsieh, Ya-Ju, Murakami, Megumi, Huang, Yang-Hui, Su, Tsung-Yao, Hung, Tai-Ho, Yu, Jau-Song, Wu, Yu-Shan, Ambudkar, Suresh V.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093605/
https://www.ncbi.nlm.nih.gov/pubmed/37048130
http://dx.doi.org/10.3390/cells12071056
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author Wu, Chung-Pu
Hung, Cheng-Yu
Hsieh, Ya-Ju
Murakami, Megumi
Huang, Yang-Hui
Su, Tsung-Yao
Hung, Tai-Ho
Yu, Jau-Song
Wu, Yu-Shan
Ambudkar, Suresh V.
author_facet Wu, Chung-Pu
Hung, Cheng-Yu
Hsieh, Ya-Ju
Murakami, Megumi
Huang, Yang-Hui
Su, Tsung-Yao
Hung, Tai-Ho
Yu, Jau-Song
Wu, Yu-Shan
Ambudkar, Suresh V.
author_sort Wu, Chung-Pu
collection PubMed
description Constitutive activation of the phosphoinositide-3-kinase (PI3K)/Akt signaling pathway is crucial for tumor growth and progression. As such, this pathway has been an enticing target for drug discovery. Although HS-173 is a potent PI3K inhibitor that halts cancer cell proliferation via G2/M cell cycle arrest, the resistance mechanisms to HS-173 have not been investigated. In this study, we investigated the susceptibility of HS-173 to efflux mediated by the multidrug efflux transporters ABCB1 and ABCG2, which are two of the most well-known ATP-binding cassette (ABC) transporters associated with the development of cancer multidrug resistance (MDR). We found that the overexpression of ABCB1 or ABCG2 significantly reduced the efficacy of HS-173 in human cancer cells. Our data show that the intracellular accumulation of HS-173 was substantially reduced by ABCB1 and ABCG2, affecting G2/M arrest and apoptosis induced by HS-173. More importantly, the efficacy of HS-173 in multidrug-resistant cancer cells could be recovered by inhibiting the drug-efflux function of ABCB1 and ABCG2. Taken together, our study has demonstrated that HS-173 is a substrate for both ABCB1 and ABCG2, resulting in decreased intracellular concentration of this drug, which may have implications for its clinical use.
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spelling pubmed-100936052023-04-13 ABCB1 and ABCG2 Overexpression Mediates Resistance to the Phosphatidylinositol 3-Kinase Inhibitor HS-173 in Cancer Cell Lines Wu, Chung-Pu Hung, Cheng-Yu Hsieh, Ya-Ju Murakami, Megumi Huang, Yang-Hui Su, Tsung-Yao Hung, Tai-Ho Yu, Jau-Song Wu, Yu-Shan Ambudkar, Suresh V. Cells Article Constitutive activation of the phosphoinositide-3-kinase (PI3K)/Akt signaling pathway is crucial for tumor growth and progression. As such, this pathway has been an enticing target for drug discovery. Although HS-173 is a potent PI3K inhibitor that halts cancer cell proliferation via G2/M cell cycle arrest, the resistance mechanisms to HS-173 have not been investigated. In this study, we investigated the susceptibility of HS-173 to efflux mediated by the multidrug efflux transporters ABCB1 and ABCG2, which are two of the most well-known ATP-binding cassette (ABC) transporters associated with the development of cancer multidrug resistance (MDR). We found that the overexpression of ABCB1 or ABCG2 significantly reduced the efficacy of HS-173 in human cancer cells. Our data show that the intracellular accumulation of HS-173 was substantially reduced by ABCB1 and ABCG2, affecting G2/M arrest and apoptosis induced by HS-173. More importantly, the efficacy of HS-173 in multidrug-resistant cancer cells could be recovered by inhibiting the drug-efflux function of ABCB1 and ABCG2. Taken together, our study has demonstrated that HS-173 is a substrate for both ABCB1 and ABCG2, resulting in decreased intracellular concentration of this drug, which may have implications for its clinical use. MDPI 2023-03-30 /pmc/articles/PMC10093605/ /pubmed/37048130 http://dx.doi.org/10.3390/cells12071056 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Wu, Chung-Pu
Hung, Cheng-Yu
Hsieh, Ya-Ju
Murakami, Megumi
Huang, Yang-Hui
Su, Tsung-Yao
Hung, Tai-Ho
Yu, Jau-Song
Wu, Yu-Shan
Ambudkar, Suresh V.
ABCB1 and ABCG2 Overexpression Mediates Resistance to the Phosphatidylinositol 3-Kinase Inhibitor HS-173 in Cancer Cell Lines
title ABCB1 and ABCG2 Overexpression Mediates Resistance to the Phosphatidylinositol 3-Kinase Inhibitor HS-173 in Cancer Cell Lines
title_full ABCB1 and ABCG2 Overexpression Mediates Resistance to the Phosphatidylinositol 3-Kinase Inhibitor HS-173 in Cancer Cell Lines
title_fullStr ABCB1 and ABCG2 Overexpression Mediates Resistance to the Phosphatidylinositol 3-Kinase Inhibitor HS-173 in Cancer Cell Lines
title_full_unstemmed ABCB1 and ABCG2 Overexpression Mediates Resistance to the Phosphatidylinositol 3-Kinase Inhibitor HS-173 in Cancer Cell Lines
title_short ABCB1 and ABCG2 Overexpression Mediates Resistance to the Phosphatidylinositol 3-Kinase Inhibitor HS-173 in Cancer Cell Lines
title_sort abcb1 and abcg2 overexpression mediates resistance to the phosphatidylinositol 3-kinase inhibitor hs-173 in cancer cell lines
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10093605/
https://www.ncbi.nlm.nih.gov/pubmed/37048130
http://dx.doi.org/10.3390/cells12071056
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