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Molecules. 2018 May 1;23(5). pii: E1053. doi: 10.3390/molecules23051053.

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

Author information

1
Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dubravska Cesta 9, 84005 Bratislava, Slovakia. viera.bohacova@savba.sk.
2
Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dubravska Cesta 9, 84005 Bratislava, Slovakia. mario.seres@savba.sk.
3
Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dubravska Cesta 9, 84005 Bratislava, Slovakia. lucia.pavlikova@savba.sk.
4
Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dubravska Cesta 9, 84005 Bratislava, Slovakia. szilvia.kontar@savba.sk.
5
Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dubravska Cesta 9, 84005 Bratislava, Slovakia. martin.cagala@savba.sk.
6
Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Palackeho 1946/1, 61242 Brno, Czech Republic. bobalp@vfu.cz.
7
Department of Chemical Drugs, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences, Brno, Palackeho 1946/1, 61242 Brno, Czech Republic. otevrelj@vfu.cz.
8
Institute of Experimental Endocrinology, Biomedical Research Center SAS, Dubravska Cesta 9, 84505 Bratislava, Slovakia. julius.brtko@savba.sk.
9
Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dubravska Cesta 9, 84005 Bratislava, Slovakia. zdena.sulova@savba.sk.
10
Institute of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology, Radlinskeho 9, 81237 Bratislava, Slovakia. albert.breier@stuba.sk.

Abstract

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.

KEYWORDS:

L1210 cells; P-glycoprotein; apoptosis; calcein cell retention; multidrug resistance; triorganotin derivatives

PMID:
29723984
PMCID:
PMC6100532
DOI:
10.3390/molecules23051053
[Indexed for MEDLINE]
Free PMC Article

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