Analogues of tetramethylrosamine as transport molecules for and inhibitors of P-glycoprotein-mediated multidrug resistance.
Tetramethylrosamine and its thio- and seleno- analogues (TMR-O, TMR-S, and TMR-Se, respectively) were examined for their ability to be transported by Pgp into chemo-resistant CR1R12 cells. Verapamil (7 x 10(-6)M) enhanced the uptake of TMR-O and TMR-S into CR1R12 cells compared to those cultures not previously exposed to verapamil. The uptake of TMR-O and TMR-S in CR1R12 cells in the presence of 7 x 10(-6)M verapamil was equivalent to its uptake in the chemo-sensitive parent cell line AUXB1 in the absence or presence of verapamil. None of the TMR analogues were effective alone as photosensitizers of CR1R12 cells. However, when either TMR-S or TMR-Se was added to CR1R12 cells after 7 x 10(-6)M verapamil exposure for 2h, irradiation of cultures with 5.0J cm(-2) of 350-750 nm light caused significant phototoxicity. TMR-O showed no significant phototoxicity in the presence of verapamil. Chemo-sensitive AUXB1 cells are equally susceptible to phototoxicity using TMR-Se with or without previous exposure to verapamil. The Pgp modulators verapamil and CsA increased the uptake of CAM into CR1R12. Exposure of CR1R12 cells to TMR-S or TMR-Se for 2h in the dark resulted in no significant change in the intracellular accumulation of CAM. However, 1h of light exposure after incubation of cells with TMR-S or TMR-Se resulted in an up to 2-fold increase in CAM uptake.
Gibson
Scott L
SL
Department of Biochemistry and Biophysics, University of Rochester Medical Center, 601 Elmwood Avenue, PO Box 607, Rochester, NY 14642, USA.
Hilf
Russell
R
Donnelly
David J
DJ
Detty
Michael R
MR
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D017484:Dermatitis, Phototoxic; D019008:Drug Resistance, Neoplasm; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology*; D008027:Light; D012235:Rhodamines; D018036:Selenium Compounds / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D014407:Tumor Cells, Cultured; D014700:Verapamil / Q000494:pharmacology
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D006575:Heterocyclic Compounds, 3-Ring; D012235:Rhodamines; D018036:Selenium Compounds; D013438:Sulfhydryl Compounds; C412715:tetramethylrosamine; D014700:Verapamil