Research Article
Thiol - Dependent Sensitization of Mitochondria and Tumor Cells to Doxorubicin
Nadezhda I Fedotcheva1*, Valeri A Bykov2, Viktor V Banin2, Tatyana A Fedotcheva3, Vladimir M. Rzheznikov4 and Nikolai L Shimanovskii3
1Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow region, Russia
2All-Russian Research Institute of Medicinal and Aromatic Plants, Moscow, Russia
3Russian State Medical University, Moscow, Russia
4Institute of Experimental Endocrinology, Endocrinology Research Center, Russian Academy of Medical Sciences, Moscow, Russia
- *Corresponding Author:
- Nadezhda I Fedotcheva
Institute of Theoretical and Experimental Biophysics
Russian Academy of Sciences, Institutskaya 3
Pushchino, Moscow region, 142290 Russia
E-mail: [email protected]
Received date: April 09, 2012; Accepted date: June 05, 2012; Published date: June 11, 2012
Citation: Fedotcheva NI, Bykov VA, Banin VV, Fedotcheva TA, Rzheznikov VM, et al. (2012) Thiol - Dependent Sensitization of Mitochondria and Tumor Cells to Doxorubicin. J Clinic Toxicol S7:002. doi: 10.4172/2161-0495.S7-002
Copyright: © 2012 Fedotcheva NI, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Abstract
The problem of multidrug resistance has been intensively studied during the last decade. It is known that some synthetic progestins can chemosensitize tumor cells to cytostatic drugs; however, the mechanisms of the sensitization are not clearly understood. In this study, the effect of synthetic analogue of progesterone (17α-acetoxy- 3b-butanoyloxy-6-methyl-pregna-4, 6-diene-20-on, buterol) on the survival of doxorubicin-resistant MCF-7 cells and the coupling of isolated mitochondria was investigated in comparison with the thiol reagent N-ethylmaleimide (NEM). Both compounds increased the doxorubicin-induced cell death and decreased the oxidative phosphorylation and the coupling in mitochondria; their presence was necessary for the direct action of doxorubicin on the mitochondrial membrane potential. Possible specific targets for NEM and buterol are the SH-groups of mitochondrial ATPase and the nucleotide-binding domain of MDR proteins, owing to which they inhibit the activity of both ATPase and MDR proteins and increase the accumulation of drugs in the cell. In addition, buterol can form hydrogen bonds between its ether carbonyl at carbon C3 and some other thiols, thereby inducing oxidative stress. By contrast to NEM, which irreversibly blocks thiol groups, buterol binds thiols non-covalently, which provides a new useful approach to the enhancement of the anticancer activity of cytostatics in tumor cells.
