title: Pharmacological and molecular effects of platinum(II) complexes involving 7-azaindole derivatives.
abstract: The in vitro antitumour activity studies on a panel of human cancer cell lines (A549, HeLa, G-361, A2780, and A2780R) and the combined in vivo and ex vivo antitumour testing on the L1210 lymphocytic leukaemia model were performed on the cis-[PtCl2(naza)2] complexes (1-3) involving the 7-azaindole derivatives (naza). The platinum(II) complexes showed significantly higher in vitro cytotoxic effects on cell-based models, as compared with cisplatin, and showed the ability to avoid the acquired resistance of the A2780R cell line to cisplatin. The in vivo testing of the complexes (applied at the same dose as cisplatin) revealed their positive effect on the reduction of cancerous tissues volume, even if it is lower than that of cisplatin, however, they also showed less serious adverse effects on the healthy tissues and the health status of the treated mice. The results of ex vivo assays revealed that the complexes 1-3 were able to modulate the levels of active forms of caspases 3 and 8, and the transcription factor p53, and thus activate the intrinsic (mitochondrial) pathway of apoptosis. The pharmacological observations were supported by both the histological and immunohistochemical evaluation of isolated cancerous tissues. The applicability of the prepared complexes and their fate in biological systems, characterized by the hydrolytic stability and the thermodynamic aspects of the interactions with cysteine, reduced glutathione, and human serum albumin were studied by the mass spectrometry and isothermal titration calorimetric experiments.
authors.affiliation: Department of Inorganic Chemistry, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacký University, Olomouc, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Starha
authors.affiliation: Department of Inorganic Chemistry, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacký University, Olomouc, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Hošek
authors.affiliation: Department of Inorganic Chemistry, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacký University, Olomouc, Czech Republic.
authors.forename: Ján
authors.initials: J
authors.lastname: Vančo
authors.affiliation: Department of Cell Biology and Genetics, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacký University, Olomouc, Czech Republic.
authors.forename: Zdeněk
authors.initials: Z
authors.lastname: Dvořák
authors.affiliation: Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Brno, Czech Republic.
authors.forename: Pavel
authors.initials: P
authors.lastname: Suchý
authors.affiliation: Department of Inorganic Chemistry, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacký University, Olomouc, Czech Republic.
authors.forename: Igor
authors.initials: I
authors.lastname: Popa
authors.affiliation: Department of Human Pharmacology and Toxicology, Faculty of Pharmacy, University of Veterinary and Pharmaceutical Sciences Brno, Brno, Czech Republic.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Pražanová
authors.affiliation: Department of Inorganic Chemistry, Regional Centre of Advanced Technologies and Materials, Faculty of Science, Palacký University, Olomouc, Czech Republic.
authors.forename: Zdeněk
authors.initials: Z
authors.lastname: Trávníček
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D015153:Blotting, Western; D053148:Caspase 3 / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D004355:Drug Stability; D005260:Female; D006367:HeLa Cells; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles / Q000737:chemistry*; D053208:Kaplan-Meier Estimate; D007945:Leukemia, Lymphoid / Q000188:drug therapy* / Q000473:pathology; D061986:MCF-7 Cells; D009682:Magnetic Resonance Spectroscopy; D008811:Mice, Inbred DBA; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013816:Thermodynamics; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: C023422:7-azaindole dimer; D000970:Antineoplastic Agents; D007211:Indoles; D009944:Organoplatinum Compounds; D016159:Tumor Suppressor Protein p53; D053148:Caspase 3; D053181:Caspase 8; D002945:Cisplatin