Thio and Seleno Rhodamine Derivatives as Reversal Agents of Multidrug Resistance in Breast Cancer
Abstract
The overall objective of this proposal is to identify rhodamine analogues that photosensitize the inhibition of Pgp function in the presence or absence of modulators and/or chemotherapeutic agents. The specific aims are: the synthesis of a series of rhodamine analogues and the determination of their photophysical properties using standard methods; the measurement of uptake and/or efflux of these analogues in the presence or absence of Pgp modulators in chemo-sensitive and Pgp-expressing cell lines; the determination of doxorubicin or Calcein AM uptake in chemo-sensitive and resistant cell lines in the presence or absence of rhodamine analogues with or without light exposure; and the determination of whether rhodamine-induced photosensitized inhibition of Pgp results in greater chemo-sensitivity and/or enhanced phototoxicity. The completed work demonstrates that substituent effects among the various rhodamine analogues impact their phototoxicity towards either chemosensitive AUXB1 cells or multidrug resistant CR1R12 cells. The substituent effects for the rhodamine analogues were realized in drug resistant CR1R12 cells only when the Pgp modulator verapamil was present indicating that the substituent effects extend to the interaction between the chemical structure of the analogues and binding/transport function of Pgp. The presence of vanadate, oligomycin, or verapamil increased the level of uptake of three dyes into CR1R12 cells. Presumably, the additives impair the ability of Pgp to remove the rhodamine analogues from the cells. Following treatment with verapamil, the mitochondria are targets for the photosensitizers in the multidrug-resistant CR1R12 cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2005
- Accession Number
- ADA448247
Entities
People
- Michael R. Detty
- Scott L. Gibson
Organizations
- State University of New York at Albany