A novel areneisonitrile Tc complex inhibits the transport activity of MDR P-glycoprotein.
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.
Rao
V V
VV
Mallinckrodt Institute of Radiology, and Department of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Herman
L W
LW
Kronauge
J F
JF
Piwnica-Worms
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D
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*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000345:Affinity Labels; C113310:hexakis(3,4,5-trimethoxyphenylisonitrile)technetium; D017256:Technetium Tc 99m Sestamibi