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.

Platinum(II) Iodido Complexes of 7-Azaindoles with Significant Antiproliferative Effects: An Old Story Revisited with Unexpected Outcomes

“…The obtained survival time results expressed as the percentage of mean survival time (T/C; %) were 100%, 99% and 109% for complexes 5 , 6 and 8 , respectively, and 108% for cisplatin . In comparison with the dichlorido analogues of herein tested diiodido complexes, complex 8 exceeded significantly the average T/C values previously reported for the mentioned dichlorido complexes applied at 2 mg/kg dose, lying in the range between 97.1 and 100.0% [17]. The similar results, as for the survival times, were also reported for cis -[PtCl 2 { E -N(H) = C(OMe)CH 2 Ph} 2 ] complex applied at 2.5 mg/kg dosage in similar experimental model [50].…”

“…Lowering of levels and/or dysfunction of p53 is one of the best known mechanisms of the cancerogenesis and it is also connected with chemotherapy resistance [51]. Our previously published work showed that cisplatin was able to increase the p53 level in the L1210 cell-induced murine cancer model, but cis -[PtCl 2 ( n aza) 2 ] complexes, that are previously reported dichlorido-analogues of the herein presented complexes, had lower effect or even decreased its level [17]. Similarly, complex 8 attenuated the amount of p53 but complexes 5 and 6 did not affect the p53 level at all.…”

Potentiating Effect of UVA Irradiation on Anticancer Activity of Carboplatin Derivatives Involving 7-Azaindoles

“…In this work, the second approach was applied to yield a series of cyclobutane-1,1'-dicarboxylatoplatinum(II) complexes where both the NH 3 ligands are substituted by various 7-azaindoles ( n aza). 7-Azaindole was recently used as a suitable N -donor carrier ligand of various types of antitumor active platinum(II) complexes, and a number of dichlorido [ 11 – 13 ], mixed-ligand [ 14 , 15 ] and oxalato [ 11 ] complexes have been reported to date. The herein presented complexes represent a logical step towards the extension of the group of dichlorido and oxalato platinum(II) complexes, involving the analogical halogeno-derivatives of 7-azaindole, recently developed by our research group [ 11 – 13 ].…”

“…7-Azaindole was recently used as a suitable N -donor carrier ligand of various types of antitumor active platinum(II) complexes, and a number of dichlorido [ 11 – 13 ], mixed-ligand [ 14 , 15 ] and oxalato [ 11 ] complexes have been reported to date. The herein presented complexes represent a logical step towards the extension of the group of dichlorido and oxalato platinum(II) complexes, involving the analogical halogeno-derivatives of 7-azaindole, recently developed by our research group [ 11 – 13 ]. In the case of dichlorido complexes, considerably high in vitro cytotoxicity (with IC 50 values up to 0.6 μM) was found against various human cancer cell lines (ovarian A2780, breast MCF7, osteosarcoma HOS, lung A549, cervical HeLa, malignant melanoma G361 and prostate LNCaP).…”

Anti-growth effect of a novel trans-dichloridobis[2-(2-hydroxyethyl)pyridine]platinum (II) complex via induction of apoptosis on breast cancer cell lines

“…Platinum therapy associated inadequacies such as acquired resistance [3] and toxic side effects [4] emphasizes the need for new anticancer drugs with new mechanisms of action. Several research groups showed that platinum (II) complexes have significant anti-tumor activities against different types of cancers in vitro and in vivo [5][6][7][8][9][10][11].…”