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Reversal effect of FW-04-806, a macrolide dilactone compound, on multidrug resistance mediated by ABCB1 and ABCG2 in vitro and in vivo

BACKGROUND: Overexpression of ATP-binding cassette (ABC) transporters, such as ABCB1 and ABCG2, has been proved to be a major trigger for multidrug resistance (MDR) in certain types of cancer. A promising approach to reverse MDR is the combined use of nontoxic and potent ABC transporters inhibitor w...

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Autores principales: Zhang, Zhiqiang, Ma, Chunling, Li, Peng, Wu, Min, Ye, Shengnan, Fu, Liwu, Xu, Jianhua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717650/
https://www.ncbi.nlm.nih.gov/pubmed/31472682
http://dx.doi.org/10.1186/s12964-019-0408-5
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author Zhang, Zhiqiang
Ma, Chunling
Li, Peng
Wu, Min
Ye, Shengnan
Fu, Liwu
Xu, Jianhua
author_facet Zhang, Zhiqiang
Ma, Chunling
Li, Peng
Wu, Min
Ye, Shengnan
Fu, Liwu
Xu, Jianhua
author_sort Zhang, Zhiqiang
collection PubMed
description BACKGROUND: Overexpression of ATP-binding cassette (ABC) transporters, such as ABCB1 and ABCG2, has been proved to be a major trigger for multidrug resistance (MDR) in certain types of cancer. A promising approach to reverse MDR is the combined use of nontoxic and potent ABC transporters inhibitor with conventional anticancer drugs. We previously reported that FW-04-806 (conglobatin) as a novel Hsp90 inhibitor with low toxicity, capable of attenuating Hsp90/Cdc37 /clients interactions and producing antitumor action in vitro and in vivo. Our early activity screening found that FW-04-806 at non-cytotoxic concentration was able to enhance the cytotoxicity of chemotherapeutic agents on the ABCB1 overexpressing cells. Therefore, we speculated that FW-04-806 might be a promising MDR reversal agent. In the present study we further investigated its reversal effect of MDR induced by ABC transporters in vitro and in vivo. METHODS: MTT assay in vitro and xenograftes in vivo were used to investigate reversal effect of FW-04-806 on MDR in ABCB1 or ABCG2 overexpressing cancer cells. To understand the mechanisms for the MDR reversal, we examined the effects of FW-04-806 on intracellular accumulation of doxorubicin (DOX, adriamycin, adr)/Rhodamine 123 (Rho 123), efflux of doxorubicin, expression levels of gene and protein of ABCB1 or ABCG2 and ATPase activity of ABCB1, and carried out molecular docking between FW-04-806 and human ABCB1. RESULTS: The results indicated that FW-04-806 significantly enhanced the cytotoxicity of substrate chemotherapeutic agents on the ABCB1 or ABCG2 overexpressing cells in vitro and in vivo suggesting its reversal MDR effects. FW-04-806 increased the intracellular accumulation of DOX or Rho123 by inhibiting the efflux function of ABC transporters in MDR cells rather than in their parental sensitive cells. However, unlike other ABC transporter inhibitors, FW-04-806 had no effect on the ATPase activity nor on the expression of ABCB1 or ABCG2 on either mRNA or protein level. Molecular docking suggested that FW-04-806 may have lower affinity to the ATPase site, which was consistent with its no significant effect on the ATPase activity of ABCB1; However FW-04-806 may bind to substrate binding site in TMDs more stably than substrate anticancer drugs therefore obstruct the anticancer drugs pumped out of the cell. CONCLUSIONS: FW-04-806 is a compound that has both anti-tumor and reversal MDR effects, and its antitumor clinical application is worth further study. GRAPHICAL ABSTRACT: [Image: see text]
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spelling pubmed-67176502019-09-06 Reversal effect of FW-04-806, a macrolide dilactone compound, on multidrug resistance mediated by ABCB1 and ABCG2 in vitro and in vivo Zhang, Zhiqiang Ma, Chunling Li, Peng Wu, Min Ye, Shengnan Fu, Liwu Xu, Jianhua Cell Commun Signal Research BACKGROUND: Overexpression of ATP-binding cassette (ABC) transporters, such as ABCB1 and ABCG2, has been proved to be a major trigger for multidrug resistance (MDR) in certain types of cancer. A promising approach to reverse MDR is the combined use of nontoxic and potent ABC transporters inhibitor with conventional anticancer drugs. We previously reported that FW-04-806 (conglobatin) as a novel Hsp90 inhibitor with low toxicity, capable of attenuating Hsp90/Cdc37 /clients interactions and producing antitumor action in vitro and in vivo. Our early activity screening found that FW-04-806 at non-cytotoxic concentration was able to enhance the cytotoxicity of chemotherapeutic agents on the ABCB1 overexpressing cells. Therefore, we speculated that FW-04-806 might be a promising MDR reversal agent. In the present study we further investigated its reversal effect of MDR induced by ABC transporters in vitro and in vivo. METHODS: MTT assay in vitro and xenograftes in vivo were used to investigate reversal effect of FW-04-806 on MDR in ABCB1 or ABCG2 overexpressing cancer cells. To understand the mechanisms for the MDR reversal, we examined the effects of FW-04-806 on intracellular accumulation of doxorubicin (DOX, adriamycin, adr)/Rhodamine 123 (Rho 123), efflux of doxorubicin, expression levels of gene and protein of ABCB1 or ABCG2 and ATPase activity of ABCB1, and carried out molecular docking between FW-04-806 and human ABCB1. RESULTS: The results indicated that FW-04-806 significantly enhanced the cytotoxicity of substrate chemotherapeutic agents on the ABCB1 or ABCG2 overexpressing cells in vitro and in vivo suggesting its reversal MDR effects. FW-04-806 increased the intracellular accumulation of DOX or Rho123 by inhibiting the efflux function of ABC transporters in MDR cells rather than in their parental sensitive cells. However, unlike other ABC transporter inhibitors, FW-04-806 had no effect on the ATPase activity nor on the expression of ABCB1 or ABCG2 on either mRNA or protein level. Molecular docking suggested that FW-04-806 may have lower affinity to the ATPase site, which was consistent with its no significant effect on the ATPase activity of ABCB1; However FW-04-806 may bind to substrate binding site in TMDs more stably than substrate anticancer drugs therefore obstruct the anticancer drugs pumped out of the cell. CONCLUSIONS: FW-04-806 is a compound that has both anti-tumor and reversal MDR effects, and its antitumor clinical application is worth further study. GRAPHICAL ABSTRACT: [Image: see text] BioMed Central 2019-09-01 /pmc/articles/PMC6717650/ /pubmed/31472682 http://dx.doi.org/10.1186/s12964-019-0408-5 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Zhang, Zhiqiang
Ma, Chunling
Li, Peng
Wu, Min
Ye, Shengnan
Fu, Liwu
Xu, Jianhua
Reversal effect of FW-04-806, a macrolide dilactone compound, on multidrug resistance mediated by ABCB1 and ABCG2 in vitro and in vivo
title Reversal effect of FW-04-806, a macrolide dilactone compound, on multidrug resistance mediated by ABCB1 and ABCG2 in vitro and in vivo
title_full Reversal effect of FW-04-806, a macrolide dilactone compound, on multidrug resistance mediated by ABCB1 and ABCG2 in vitro and in vivo
title_fullStr Reversal effect of FW-04-806, a macrolide dilactone compound, on multidrug resistance mediated by ABCB1 and ABCG2 in vitro and in vivo
title_full_unstemmed Reversal effect of FW-04-806, a macrolide dilactone compound, on multidrug resistance mediated by ABCB1 and ABCG2 in vitro and in vivo
title_short Reversal effect of FW-04-806, a macrolide dilactone compound, on multidrug resistance mediated by ABCB1 and ABCG2 in vitro and in vivo
title_sort reversal effect of fw-04-806, a macrolide dilactone compound, on multidrug resistance mediated by abcb1 and abcg2 in vitro and in vivo
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717650/
https://www.ncbi.nlm.nih.gov/pubmed/31472682
http://dx.doi.org/10.1186/s12964-019-0408-5
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