title: A novel areneisonitrile Tc complex inhibits the transport activity of MDR P-glycoprotein.
abstract: P-glycoprotein (Pgp), the product of the multidrug resistance (MDR1) gene, has been an important cancer target for development of MDR modulators that act to inhibit Pgp efflux transport activity. From a series of novel substituted areneisonitrile analogues of Tc-sestamibi, a known Pgp transport substrate, emerged the hexakis(3,4,5-trimethoxyphenylisonitrile)Tc(I) complex (Tc-TMPI) as a potential modulator of Pgp. Tracer 99mTc-TMPI showed net cellular accumulation in inverse proportion to expression of Pgp and enhancement upon addition of classic MDR modulators. At pharmacological concentrations, the carrier-added 94Tc-TMPI complex showed potent inhibition of Pgp-mediated 99mTc-sestamibi transport (EC50, 1.1 +/- 0.2 microM) and displacement of a Pgp-specific photolabel in a concentration-dependent manner. We conclude that 99Tc-TMPI directly inhibited Pgp transport activity and serves as a convenient template for development of nonradioactive Re(I) analogues as novel MDR modulators.
authors.affiliation: Mallinckrodt Institute of Radiology, and Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: V V
authors.initials: VV
authors.lastname: Rao
authors.forename: L W
authors.initials: LW
authors.lastname: Herman
authors.forename: J F
authors.initials: JF
authors.lastname: Kronauge
authors.forename: D
authors.initials: D
authors.lastname: Piwnica-Worms
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D000345:Affinity Labels; D000818:Animals; D001692:Biological Transport; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D018432:Drug Resistance, Multiple; D006801:Humans; D007700:Kinetics; D008168:Lung; D015394:Molecular Structure; D017256:Technetium Tc 99m Sestamibi / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; C113310:hexakis(3,4,5-trimethoxyphenylisonitrile)technetium; D017256:Technetium Tc 99m Sestamibi