HZ08 reverse P-glycoprotein mediated multidrug resistance in vitro and in vivo

Zheyi Hu; Zaigang Zhou; Yahui Hu; Jinhui Wu; Yunman Li; Wenlong Huang

doi:10.1371/journal.pone.0116886

HZ08 reverse P-glycoprotein mediated multidrug resistance in vitro and in vivo

PLoS One. 2015 Feb 17;10(2):e0116886. doi: 10.1371/journal.pone.0116886. eCollection 2015.

Authors

Zheyi Hu¹, Zaigang Zhou², Yahui Hu¹, Jinhui Wu², Yunman Li¹, Wenlong Huang³

Affiliations

¹ State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing, 210009, China.
² State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210093, China.
³ Center of Drug Discovery, China Pharmaceutical University, Nanjing, 210009, China.

Abstract

Background: Multidrug 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.

Methods: MDCK-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.

Results: Results 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.

Conclusions: The novel structure HZ08 could be a potent P-gp inhibitor.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors
ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
Acridines / pharmacology
Animals
Biological Transport / drug effects
Dogs
Drug Resistance, Multiple / drug effects*
Humans
Isoquinolines / chemistry
Isoquinolines / pharmacology*
Isoquinolines / therapeutic use
KB Cells
Madin Darby Canine Kidney Cells
Mice
Neoplasms / drug therapy
Tetrahydroisoquinolines / pharmacology
Transplantation, Heterologous
Verapamil / pharmacology
Verapamil / therapeutic use

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Acridines
Isoquinolines
N-cyano-1-((3,4-dimethoxyphenyl)methyl)-3,4-dihydro-6,7-dimethoxy-N'-octyl-2(1H)-isoquinoline-carboximidamide
Tetrahydroisoquinolines
Verapamil
Elacridar

Grants and funding

This work was supported by the National Nature Science Foundation of P.R. China (No. 81173088), National Science and Technology Major Project (No. 2002AA233071), Scientific Research and Innovation Project of College Students of Jiangsu Province (No. CXLX13_317). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.