title: HZ08 inhibits the multi-drug resistance on multiple sites as the substrate of p-glycoprotein.
abstract: Overexpression of p-glycoprotein (p-gp) leads to the production of multi-drug resistance (MDR) which could discharge various anti-tumor chemicals with structural heterogeneity. HZ08, a novel tetrahydroisoquinoline derivate, was discovered to modulate the MDR. What was confirmed is its definite inhibition of multi-drug resistance caused by p-gp and its promotion for the intracellular cytotoxins accumulation in the previous study. In order to explore whether HZ08 is the substrate of p-gp and on which sites it exerts its function, RNAi to mdr1 was introduced and the interaction between HZ08 and some classic agents (verapamil, rhodamine 123) with clearly binding sites was also investigated. Experimental results revealed that HZ08 is the most probable substrate of p-gp and may share the same modulation sites located at the p-gp with verapamil. Data obtained also indicated that there is a common binding site shared by rhodamine 123 and HZ08, but negative competition showed between HZ08 and adriamycin. In conclusion, HZ08 may be the substrate of p-gp and acts as a multiple target modulator to invert the efflux function of p-gp.
authors.affiliation: Department of Physiology, China Pharmaceutical University, Mailbox 207, 24 TongJiaXiang, Nanjing 210009, PR China.
authors.forename: Yidong
authors.initials: Y
authors.lastname: Feng
authors.forename: Yahui
authors.initials: Y
authors.lastname: Hu
authors.forename: Juan
authors.initials: J
authors.lastname: Cen
authors.forename: Kodithuwakku Nandani
authors.initials: KN
authors.lastname: Darshika
authors.forename: Weirong
authors.initials: W
authors.lastname: Fang
authors.forename: Yunman
authors.initials: Y
authors.lastname: Li
authors.forename: Wenlong
authors.initials: W
authors.lastname: Huang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D001665:Binding Sites; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000378:metabolism; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D006801:Humans; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D007546:Isoquinolines / Q000378:metabolism* / Q000494:pharmacology*; D020014:K562 Cells; D020112:Rhodamine 123 / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D007546:Isoquinolines; C524509:N-cyano-1-((3,4-dimethoxyphenyl)methyl)-3,4-dihydro-6,7-dimethoxy-N'-octyl-2(1H)-isoquinoline-carboximidamide; D020112:Rhodamine 123; D004317:Doxorubicin; D014700:Verapamil