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Triorganotin Derivatives Induce Cell Death Effects on L1210 Leukemia Cells at Submicromolar Concentrations Independently of P-glycoprotein Expression

1
Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dubravska Cesta 9, 84005 Bratislava, Slovakia
2
Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Palackeho 1946/1, 61242 Brno, Czech Republic
3
Institute of Experimental Endocrinology, Biomedical Research Center SAS, Dubravska Cesta 9, 84505 Bratislava, Slovakia
4
Institute of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinskeho 9, 81237 Bratislava, Slovakia
*
Authors to whom correspondence should be addressed.
Molecules 2018, 23(5), 1053; https://doi.org/10.3390/molecules23051053
Received: 12 April 2018 / Revised: 25 April 2018 / Accepted: 26 April 2018 / Published: 1 May 2018
(This article belongs to the Section Medicinal Chemistry)
The acceleration of drug efflux activity realized by plasma membrane transporters in neoplastic cells, particularly by P-glycoprotein (P-gp, ABCB1 member of the ABC transporter family), represents a frequently observed molecular cause of multidrug resistance (MDR). This multiple resistance represents a real obstacle in the effective chemotherapy of neoplastic diseases. Therefore, identifying cytotoxic substances that are also effective in P-gp overexpressing cells may be useful for the rational design of substances for the treatment of malignancies with developed MDR. Here, we showed that triorganotin derivatives—tributyltin-chloride (TBT-Cl), tributyltin-bromide (TBT-Br), tributyltin-iodide (TBT-I) and tributyltin-isothiocyanate (TBT-NCS) or triphenyltin-chloride (TPT-Cl) and triphenyltin-isothiocyanate (TPT-NCS)—could induce the death of L1210 mice leukemia cells at a submicromolar concentration independently of P-gp overexpression. The median lethal concentration obtained for triorganotin derivatives did not exceed 0.5 µM in the induction of cell death of either P-gp negative or P-gp positive L1210 cells. Apoptosis related to regulatory pathway of Bcl-2 family proteins seems to be the predominant mode of cell death in either P-gp negative or P-gp positive L1210 cells. TBT-Cl and TBT-Br were more efficient with L1210 cells overexpressing P-gp than with their counterpart P-gp negative cells. In contrast, TBT-I and TPT-NCS induced a more pronounced cell death effect on P-gp negative cells than on P-gp positive cells. Triorganotin derivatives did not affect P-gp efflux in native cells measured by calcein retention within the cells. Taken together, we assumed that triorganotin derivatives represent substances suitable for suppressing the viability of P-gp positive malignant cells. View Full-Text
Keywords: L1210 cells; P-glycoprotein; multidrug resistance; triorganotin derivatives; apoptosis; calcein cell retention L1210 cells; P-glycoprotein; multidrug resistance; triorganotin derivatives; apoptosis; calcein cell retention
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Bohacova, V.; Seres, M.; Pavlikova, L.; Kontar, S.; Cagala, M.; Bobal, P.; Otevrel, J.; Brtko, J.; Sulova, Z.; Breier, A. Triorganotin Derivatives Induce Cell Death Effects on L1210 Leukemia Cells at Submicromolar Concentrations Independently of P-glycoprotein Expression. Molecules 2018, 23, 1053.

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