P-glycoprotein-independent cytotoxic effects of 5-aminopyrazole in L1210 leukemia cells
We previously investigated the cytotoxic effects of 5-aminopyrazoles (5-APs) on leukemia cells both negative and positive for P-glycoprotein (P-gp) expression, a common contributor to multidrug resistance. Five derivatives (A1-A5), each containing perfluorinated methylbenzene at the N3 nitrogen of t...
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Elsevier
2025-04-01
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| Series: | European Journal of Medicinal Chemistry Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2772417425000020 |
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| author | Lucia Sofrankova Jana Spaldova Pavol Stefik Branislav Pavilek Dusan Bortnak Lucia Pavlikova Ivana Zidekova Daniel Vegh Viktor Milata Albert Breier Zdena Sulova |
| author_facet | Lucia Sofrankova Jana Spaldova Pavol Stefik Branislav Pavilek Dusan Bortnak Lucia Pavlikova Ivana Zidekova Daniel Vegh Viktor Milata Albert Breier Zdena Sulova |
| author_sort | Lucia Sofrankova |
| collection | DOAJ |
| description | We previously investigated the cytotoxic effects of 5-aminopyrazoles (5-APs) on leukemia cells both negative and positive for P-glycoprotein (P-gp) expression, a common contributor to multidrug resistance. Five derivatives (A1-A5), each containing perfluorinated methylbenzene at the N3 nitrogen of the pyrazole ring, were tested on murine lymphoblastic cell line variants: parental S cells (P-gp positive), R cells (vincristine-resistant and P-gp positive), and T cells (human P-gp transfected). Among these, A1 and A4 exhibited the strongest effects, especially in R cells, with lesser but similar effects observed in S and T cells. Cell death assays revealed both apoptosis and necrosis, with apoptosis confirmed by DNA fragmentation and activation of caspases 3/7, 8, and, to a lesser extent, 9, suggesting a predominance of extrinsic apoptosis. The compounds also induced autophagy, identified by LysoTracker Green and monodansylcadaverine staining. All derivatives, except A5, suppressed P-gp activity, though they did not alter P-gp expression at the mRNA or protein level. Cell cycle analysis showed changes in the G0/G1 and S phases. The heightened sensitivity of R cells to 5-AP, despite P-gp expression, likely results from an altered phenotype due to vincristine-induced stress rather than from P-gp inhibition alone. This conclusion is supported by the fact that T cells expressing P-gp are as sensitive to 5-APs as S cells. |
| format | Article |
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| institution | Kabale University |
| issn | 2772-4174 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
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| series | European Journal of Medicinal Chemistry Reports |
| spelling | doaj-art-bf69d371f88e4bee9ed53481f3a376e92025-01-13T04:19:19ZengElsevierEuropean Journal of Medicinal Chemistry Reports2772-41742025-04-0113100246P-glycoprotein-independent cytotoxic effects of 5-aminopyrazole in L1210 leukemia cellsLucia Sofrankova0Jana Spaldova1Pavol Stefik2Branislav Pavilek3Dusan Bortnak4Lucia Pavlikova5Ivana Zidekova6Daniel Vegh7Viktor Milata8Albert Breier9Zdena Sulova10Department of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 81237 Bratislava, Slovak Republic; Corresponding author.Department of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 81237 Bratislava, Slovak RepublicDepartment of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 81237 Bratislava, Slovak RepublicDepartment of Organic Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 81237, Bratislava Slovak RepublicDepartment of Organic Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 81237, Bratislava Slovak RepublicInstitute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská cesta 9, 8405, Bratislava, Slovak RepublicCentral Laboratories, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 81237, Bratislava Slovak RepublicDepartment of Organic Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 81237, Bratislava Slovak RepublicDepartment of Organic Chemistry, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 81237, Bratislava Slovak RepublicDepartment of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 81237 Bratislava, Slovak Republic; Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská cesta 9, 8405, Bratislava, Slovak Republic; Corresponding author. epartment of Biochemistry and Microbiology, Faculty of Chemical and Food Technology, Slovak University of Technology in Bratislava, Radlinského 9, 81237, Bratislava Slovak Republic.Institute of Molecular Physiology and Genetics, Centre of Bioscience, Slovak Academy of Sciences, Dúbravská cesta 9, 8405, Bratislava, Slovak RepublicWe previously investigated the cytotoxic effects of 5-aminopyrazoles (5-APs) on leukemia cells both negative and positive for P-glycoprotein (P-gp) expression, a common contributor to multidrug resistance. Five derivatives (A1-A5), each containing perfluorinated methylbenzene at the N3 nitrogen of the pyrazole ring, were tested on murine lymphoblastic cell line variants: parental S cells (P-gp positive), R cells (vincristine-resistant and P-gp positive), and T cells (human P-gp transfected). Among these, A1 and A4 exhibited the strongest effects, especially in R cells, with lesser but similar effects observed in S and T cells. Cell death assays revealed both apoptosis and necrosis, with apoptosis confirmed by DNA fragmentation and activation of caspases 3/7, 8, and, to a lesser extent, 9, suggesting a predominance of extrinsic apoptosis. The compounds also induced autophagy, identified by LysoTracker Green and monodansylcadaverine staining. All derivatives, except A5, suppressed P-gp activity, though they did not alter P-gp expression at the mRNA or protein level. Cell cycle analysis showed changes in the G0/G1 and S phases. The heightened sensitivity of R cells to 5-AP, despite P-gp expression, likely results from an altered phenotype due to vincristine-induced stress rather than from P-gp inhibition alone. This conclusion is supported by the fact that T cells expressing P-gp are as sensitive to 5-APs as S cells.http://www.sciencedirect.com/science/article/pii/S27724174250000205-AminopyrazolesCancerCell deathP-glycoprotein |
| spellingShingle | Lucia Sofrankova Jana Spaldova Pavol Stefik Branislav Pavilek Dusan Bortnak Lucia Pavlikova Ivana Zidekova Daniel Vegh Viktor Milata Albert Breier Zdena Sulova P-glycoprotein-independent cytotoxic effects of 5-aminopyrazole in L1210 leukemia cells European Journal of Medicinal Chemistry Reports 5-Aminopyrazoles Cancer Cell death P-glycoprotein |
| title | P-glycoprotein-independent cytotoxic effects of 5-aminopyrazole in L1210 leukemia cells |
| title_full | P-glycoprotein-independent cytotoxic effects of 5-aminopyrazole in L1210 leukemia cells |
| title_fullStr | P-glycoprotein-independent cytotoxic effects of 5-aminopyrazole in L1210 leukemia cells |
| title_full_unstemmed | P-glycoprotein-independent cytotoxic effects of 5-aminopyrazole in L1210 leukemia cells |
| title_short | P-glycoprotein-independent cytotoxic effects of 5-aminopyrazole in L1210 leukemia cells |
| title_sort | p glycoprotein independent cytotoxic effects of 5 aminopyrazole in l1210 leukemia cells |
| topic | 5-Aminopyrazoles Cancer Cell death P-glycoprotein |
| url | http://www.sciencedirect.com/science/article/pii/S2772417425000020 |
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