HZ08 Reverse P-Glycoprotein Mediated Multidrug Resistance In Vitro and In Vivo |
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| Authors: | Zheyi Hu Zaigang Zhou Yahui Hu Jinhui Wu Yunman Li Wenlong Huang |
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| Affiliation: | 1State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, 210009, China;2State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210093, China;3Center of Drug Discovery, China Pharmaceutical University, Nanjing, 210009, China;Columbia University, UNITED STATES |
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| Abstract: | BackgroundMultidrug efflux transporter P-glycoprotein (P-gp) is highly expressed on membrane of tumor cells and is implicated in resistance to tumor chemotherapy. HZ08 is synthesized and studied in order to find a novel P-gp inhibitor.MethodsMDCK-MDR1 monolayer transport, calcein-AM P-gp inhibition and P-gp ATPase assays were used to confirm the P-gp inhibition capability of HZ08. Furthermore, KB-WT and KB-VCR cells were used to evaluate the P-gp inhibitory activity of HZ08 both in vitro and in vivo.ResultsResults showed that HZ08 was more potent than verapamil in MDCK-MDR1 monolayer transportation model. Meanwhile, P-gp ATPase assay and calcein-AM P-gp inhibition assay confirmed that HZ08 inhibited P-gp ATPase with a calcein-AM IC50 of 2.44±0.31μM. In addition, significantly greater in vitro multidrug resistance reversing effects were observed when vincristine or paclitaxel was used in combination with 10μM HZ08 compared with 10μM verapamil. Moreover, HZ08 could significantly enhance the sensitivity of vincristine with a similar effect like verapamil in both KB-WT and KB-VCR tumor xenograft models.ConclusionsThe novel structure HZ08 could be a potent P-gp inhibitor. |
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