Analogues of tetramethylrosamine as transport molecules for and inhibitors of P-glycoprotein-mediated multidrug resistance

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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 × 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 × 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 × 10 −6 M verapamil exposure for 2 h, irradiation of cultures with 5.0 J 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 2 h in the dark resulted in no significant change in the intracellular accumulation of CAM. However, 1 h of light exposure after incubation of cells with TMR- S or TMR- Se resulted in an up to 2-fold increase in CAM uptake.