title: Novel tetramethylpiperidine-substituted phenazines are potent inhibitors of P-glycoprotein activity in a multidrug resistant cancer cell line.
abstract: The multidrug resistance (MDR)-neutralizing and cytotoxic properties of 16 novel tetramethylpiperidine (TMP)-substituted phenazines were compared with those of clofazimine and B669 using a P-glycoprotein (P-gp)-expressing undifferentiated, human leukemia cell line (K562/MMB). Unchlorinated TMP-substituted phenazine molecules were more cytotoxic than their chlorinated counterparts, while the halogenated molecules, especially those with chlorine atoms at position 3 on the aniline and phenyl rings, were less cytotoxic but more effective as chemosensitizing, P-gp-neutralizing agents. One of the TMP-substituted phenazines, B4121, increased the sensitivity of K562/MMB cells to vinblastine by 100-fold. TMP-substituted phenazines are a novel class of pharmacologic anti-cancer agents with both direct cytotoxic, as well as MDR-neutralizing anti-tumor properties.
authors.affiliation: Department of Immunology, Faculty of Medicine, University of Pretoria, South Africa.
authors.forename: C E
authors.initials: CE
authors.lastname: Van Rensburg
authors.forename: R
authors.initials: R
authors.lastname: Anderson
authors.forename: G
authors.initials: G
authors.lastname: Jooné
authors.forename: M S
authors.initials: MS
authors.lastname: Myer
authors.forename: J F
authors.initials: JF
authors.lastname: O'Sullivan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000633:toxicity*; D002991:Clofazimine / Q000031:analogs & derivatives* / Q000633:toxicity*; D018432:Drug Resistance, Multiple; D006801:Humans; D007938:Leukemia; D015394:Molecular Structure; D010619:Phenazines / Q000633:toxicity*; D010880:Piperidines / Q000633:toxicity*; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D014747:Vinblastine / Q000493:pharmacokinetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D010619:Phenazines; D010880:Piperidines; D014747:Vinblastine; C030428:B 669; D002991:Clofazimine