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Effect of multidrug-resistant P-glycoprotein gene expression on chloroaluminum tetrasulfonate phthalocyanine
D L Frazier1, M A Barnhill, X Lu
1University of Tennessee College of Veterinary Medicine, Knoxville 37901.
Abstract:
The effect of multidrug-resistant P-glycoprotein gene expression (MDR1) in 3T3 cells on cellular concentrations and cytotoxicity induced by the photodynamic agent chloroaluminum tetrasulfonate phthalocyanine (AlSPc) was evaluated. 3T3 cells transfected with a retroviral vector expressing human MDR1 cDNA were resistant to colchicine. Resistant cells incubated with daunomycin accumulated only 40-50% of the quantity of daunomycin accumulated in control cells. Resistant cells incubated with daunomycin in the presence of verapamil had intracellular daunomycin concentrations approximately equal to control cells without verapamil. When these MDR1 3T3 cells were incubated with AlSPc, cellular concentrations of AlSPc did not differ between cells resistant to colchicine and those that were not. Similarly, there was little difference in cytotoxicity demonstrated by 51Cromium release in the two cell lines exposed to AlSPc and light (675 nm; 6 J/cm2). This study suggests photodynamic therapy using AlSPc may be a useful treatment modality for tumors in which the MDR1 P-glycoprotein confers resistance to cancer chemotherapeutics.
Insights
Multidrug-resistant P-glycoprotein (MDR1) expression did not affect chloroaluminum tetrasulfonate phthalocyanine (AlSPc) cellular uptake or photodynamic therapy (PDT) cytotoxicity. AlSPc may be effective against MDR1-expressing tumors resistant to chemotherapy.
Area of Science:
- Biochemistry
- Cell Biology
- Pharmacology
Background:
- Multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) is a major challenge in cancer chemotherapy.
- Photodynamic therapy (PDT) is an alternative cancer treatment modality.
Purpose of the Study:
- To investigate the effect of MDR1 gene expression on the cellular concentration and phototoxicity of chloroaluminum tetrasulfonate phthalocyanine (AlSPc).
- To assess the potential of AlSPc-mediated PDT as a treatment for MDR1-overexpressing tumors.
Main Methods:
- 3T3 cells were transfected with a retroviral vector expressing human MDR1 cDNA to establish resistant cell lines.
- Cellular accumulation of daunomycin and AlSPc was measured in resistant and control cells.
- Cytotoxicity of AlSPc-mediated PDT was evaluated using 51Cr release assay.
Main Results:
- MDR1-expressing cells showed reduced daunomycin accumulation, confirming P-gp mediated drug efflux.
- Cellular concentrations of AlSPc were similar in both MDR1-resistant and control cells.
- AlSPc-mediated phototoxicity was comparable between MDR1-resistant and control cells.
Conclusions:
- The MDR1 P-glycoprotein does not significantly impact AlSPc cellular uptake or its photodynamic cytotoxicity.
- AlSPc-based photodynamic therapy could be a viable treatment option for tumors exhibiting MDR1-mediated resistance to conventional chemotherapeutics.