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.
Highlights
Cisplatin is a simple platinum(II) coordination compound that is used world-wide for the treatment of various types of cancer [1,2]
The set of new signals was detected at the spectra of the complexes heated in the mentioned DMF-d7/ H2O mixture to 50uC or 100uC
These changes are most probably connected with the hydrolysis of the studied complexes in the mentioned watercontaining system, since the chemical shifts of the new signals do not correspond to either cis
Summary
Cisplatin is a simple platinum(II) coordination compound that is used world-wide for the treatment of various types of cancer [1,2]. Two basic approaches focused either on the substitution of the leaving groups, i.e. two chlorides (e.g. in carboplatin [5] or nedaplatin [6]), or on the substitution of two NH3 molecules within the cisplatin molecule by different N-donor ligands (e.g. in oxaliplatin [7] or lobaplatin [8]) represent the most promising ways leading towards clinically useful platinum(II) compounds None of these compounds avoided completely both of the main disadvantages related with the platinum-based drugs application, i.e. the resistance (acquired or intrinsic), and negative and dose-limiting side effects (nephrotoxicity, neurotoxicity, myelosuppression etc.) [1,2,9]. Picoplatin failed in the clinical trials on non-small-cell lung carcinoma due to the continued progression of the disease and showing several drawbacks (e.g. neutropenia, thrombocytopenia or vomiting), it is currently undergoing clinical trials as therapeutic for colorectal and prostate cancer [14]
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