Julie Dartier1, Elsa Lemaitre2, Igor Chourpa3, Caroline Goupille4, Stéphane Servais5, Stéphan Chevalier6, Karine Mahéo7, Jean-François Dumas8. 1. INSERM UMR1069, "Nutrition, Croissance et Cancer", Tours, France; Université François Rabelais, Tours, France. 2. INSERM UMR1069, "Nutrition, Croissance et Cancer", Tours, France. 3. Université François Rabelais, Tours, France; EA 6295 "Nanomédicaments et Nanosondes", Tours, France; UFR Sciences Pharmaceutiques, Tours, France. 4. INSERM UMR1069, "Nutrition, Croissance et Cancer", Tours, France; CHRU Bretonneau, Tours, France. 5. INSERM UMR1069, "Nutrition, Croissance et Cancer", Tours, France; Université François Rabelais, Tours, France; IUT, Tours, France. 6. INSERM UMR1069, "Nutrition, Croissance et Cancer", Tours, France; Université François Rabelais, Tours, France; UFR Sciences Pharmaceutiques, Tours, France. 7. INSERM UMR1069, "Nutrition, Croissance et Cancer", Tours, France; Université François Rabelais, Tours, France; UFR Sciences Pharmaceutiques, Tours, France. Electronic address: karine.maheo@univ-tours.fr. 8. INSERM UMR1069, "Nutrition, Croissance et Cancer", Tours, France; Université François Rabelais, Tours, France; UFR Sciences Pharmaceutiques, Tours, France. Electronic address: jean-francois.dumas@univ-tours.fr.
Abstract
BACKGROUND: We hypothesized that, among the mechanisms of drug-resistance acquired by doxorubicin (DOX)-resistant breast cancer cells to maintain cell survival, ATP-dependent drug efflux pumps could be expressed in their mitochondrial membranes and this might limit the accumulation of DOX in this subcellular compartment in relation to mitochondrial ATP production. METHODS/ RESULTS: Mitochondrial DOX accumulation: the presence and the activity of mitochondrial efflux pumps and their relationship with mitochondrial ATP synthesis were analyzed in DOX-resistant (MCF-7doxR) and -sensitive (MCF-7S) breast cancer cells. Mitochondrial accumulation of DOX (autofluorescence) was decreased when ATP was produced, but only in MCF-7doxR. In these DOX-resistant cells, breast cancer resistance protein (BCRP) and multidrug resistance-associated protein (MRP1) were expressed and localized in mitochondria (confocal microscopy and confocal spectral imaging studies). In addition, mitochondrial accumulation of DOX was increased by BCRP and MRP1 inhibitors and, to a lower extent, by the mitochondrial ATP synthase inhibitor, oligomycin, in MCF-7doxR. CONCLUSIONS: Both BCRP and MRP1 were localized in mitochondria and participated to the reduction of mitochondrial accumulation of DOX in MCF-7doxR. This process was partly dependent of mitochondrial ATP synthesis. GENERAL SIGNIFICANCE: The present study provides novel insights in the involvement of mitochondria in the underlying mechanisms of DOX-resistance in breast cancer cells.
BACKGROUND: We hypothesized that, among the mechanisms of drug-resistance acquired by doxorubicin (DOX)-resistant breast cancer cells to maintain cell survival, ATP-dependent drug efflux pumps could be expressed in their mitochondrial membranes and this might limit the accumulation of DOX in this subcellular compartment in relation to mitochondrial ATP production. METHODS/ RESULTS: Mitochondrial DOX accumulation: the presence and the activity of mitochondrial efflux pumps and their relationship with mitochondrial ATP synthesis were analyzed in DOX-resistant (MCF-7doxR) and -sensitive (MCF-7S) breast cancer cells. Mitochondrial accumulation of DOX (autofluorescence) was decreased when ATP was produced, but only in MCF-7doxR. In these DOX-resistant cells, breast cancer resistance protein (BCRP) and multidrug resistance-associated protein (MRP1) were expressed and localized in mitochondria (confocal microscopy and confocal spectral imaging studies). In addition, mitochondrial accumulation of DOX was increased by BCRP and MRP1 inhibitors and, to a lower extent, by the mitochondrial ATP synthase inhibitor, oligomycin, in MCF-7doxR. CONCLUSIONS: Both BCRP and MRP1 were localized in mitochondria and participated to the reduction of mitochondrial accumulation of DOX in MCF-7doxR. This process was partly dependent of mitochondrial ATP synthesis. GENERAL SIGNIFICANCE: The present study provides novel insights in the involvement of mitochondria in the underlying mechanisms of DOX-resistance in breast cancer cells.
Authors: Mariam A Fouad; Mohamed M Sayed-Ahmed; Etimad A Huwait; Hafez F Hafez; Abdel-Moneim M Osman Journal: BMC Pharmacol Toxicol Date: 2021-01-28 Impact factor: 2.483
Authors: Saloni S Andhari; Ravindra D Wavhale; Kshama D Dhobale; Bhausaheb V Tawade; Govind P Chate; Yuvraj N Patil; Jayant J Khandare; Shashwat S Banerjee Journal: Sci Rep Date: 2020-03-13 Impact factor: 4.379