Reversal effect of FW-04-806, a macrolide dilactone compound, on multidrug resistance mediated by ABCB1 and ABCG2 in vitro and in vivo
Abstract 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 inh...
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| Format: | Article |
| Language: | English |
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BMC
2019-09-01
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| Series: | Cell Communication and Signaling |
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| Online Access: | http://link.springer.com/article/10.1186/s12964-019-0408-5 |
| _version_ | 1818967168917700608 |
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| author | Zhiqiang Zhang Chunling Ma Peng Li Min Wu Shengnan Ye Liwu Fu Jianhua Xu |
| author_facet | Zhiqiang Zhang Chunling Ma Peng Li Min Wu Shengnan Ye Liwu Fu Jianhua Xu |
| author_sort | Zhiqiang Zhang |
| collection | DOAJ |
| description | Abstract 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 |
| first_indexed | 2024-12-20T13:44:31Z |
| format | Article |
| id | doaj.art-7f24695948e24f4c98b638b6dc7747db |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-12-20T13:44:31Z |
| publishDate | 2019-09-01 |
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| series | Cell Communication and Signaling |
| spelling | doaj.art-7f24695948e24f4c98b638b6dc7747db2022-12-21T19:38:43ZengBMCCell Communication and Signaling1478-811X2019-09-0117111610.1186/s12964-019-0408-5Reversal effect of FW-04-806, a macrolide dilactone compound, on multidrug resistance mediated by ABCB1 and ABCG2 in vitro and in vivoZhiqiang Zhang0Chunling Ma1Peng Li2Min Wu3Shengnan Ye4Liwu Fu5Jianhua Xu6Department of Pharmacology, School of Pharmacy, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical UniversityDepartment of Pharmacology, School of Pharmacy, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical UniversityDepartment of Pharmacology, School of Pharmacy, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical UniversityDepartment of Pharmacology, School of Pharmacy, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical UniversityThe First Affiliated Hospital of Fujian Medical UniversityState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Esophageal Cancer Institute, Sun Yat-sen University Cancer CenterDepartment of Pharmacology, School of Pharmacy, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical UniversityAbstract 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 abstracthttp://link.springer.com/article/10.1186/s12964-019-0408-5FW-04-806ABCB1 transporterABCG2 transporterMultiple drug resistanceMolecular docking |
| spellingShingle | Zhiqiang Zhang Chunling Ma Peng Li Min Wu Shengnan Ye Liwu Fu Jianhua Xu Reversal effect of FW-04-806, a macrolide dilactone compound, on multidrug resistance mediated by ABCB1 and ABCG2 in vitro and in vivo Cell Communication and Signaling FW-04-806 ABCB1 transporter ABCG2 transporter Multiple drug resistance Molecular docking |
| 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 | FW-04-806 ABCB1 transporter ABCG2 transporter Multiple drug resistance Molecular docking |
| url | http://link.springer.com/article/10.1186/s12964-019-0408-5 |
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