The current work investigates the effect of new bifunctional and mononuclear Pt(II) compounds, the cis- and trans-isomers of [PtCl2(NH3)(L)] (L = 1-methyl-7-azaindole, compounds 1 and 2, respectively), on growth and viability of human carcinoma cells as well as their putative mechanism(s) of cytotoxicity. The results show that substitution of 1-methyl-7-azaindole for ammine in cisplatin or transplatin results in an increase of the toxic efficiency, selectivity for tumor cells in cisplatin-resistant cancer cells, and activation of the trans geometry. The differences in the cytotoxic activities of 1 and 2 were suggested to be due to their different DNA binding mode, different capability to induce cell cycle perturbations, and fundamentally different role of transcription factor p53 in their mechanism of action. Interestingly, both isomers make it possible to detect their cellular uptake and distribution in living cells by confocal microscopy without their modification with an optically active tag.
- MeSH
- apoptóza účinky léků MeSH
- buněčný cyklus účinky léků MeSH
- cisplatina analogy a deriváty MeSH
- DNA metabolismus MeSH
- indoly chemie MeSH
- lidé MeSH
- nádorový supresorový protein p53 fyziologie MeSH
- organoplatinové sloučeniny chemická syntéza chemie farmakologie MeSH
- protinádorové látky chemická syntéza chemie farmakologie MeSH
- vazba proteinů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Cytotoxicity and mutagenicity of trans,trans,trans-[PtCl2(CH3COO)2(NH3)(1-adamantylamine)] [trans-adamplatin(IV)] and its reduced analog trans-[PtCl2(NH3)(1-adamantylamine)] [trans-adamplatin(II)] were examined. In addition, the several factors underlying biological effects of these trans-platinum compounds using various biochemical methods were investigated. A notable feature of the growth inhibition studies was the remarkable circumvention of both acquired and intrinsic cisplatin resistance by the two lipophilic trans-compounds. Interestingly, trans-adamplatin(IV) was considerably less mutagenic than cisplatin. Consistent with the lipophilic character of trans-adamplatin complexes, their total accumulation in A2780 cells was considerably greater than that of cisplatin. The results also demonstrate that trans-adamplatin(II) exhibits DNA binding mode markedly different from that of ineffective transplatin. In addition, the reduced deactivation of trans-adamplatin(II) by glutathione seems to be an important determinant of the cytotoxic effects of the complexes tested in the present work. The factors associated with cytotoxic and mutagenic effects of trans-adamplatin complexes in tumor cell lines examined in the present work are likely to play a significant role in the overall antitumor activity of these complexes.
- MeSH
- adukty DNA chemie MeSH
- amantadin analogy a deriváty farmakologie chemie metabolismus MeSH
- cirkulární dichroismus MeSH
- DNA chemie MeSH
- financování organizované MeSH
- hypoxanthinfosforibosyltransferasa genetika účinky léků MeSH
- lidé MeSH
- mutageny farmakologie chemie metabolismus MeSH
- nádorové buněčné linie MeSH
- organoplatinové sloučeniny chemie metabolismus farmakologie MeSH
- protinádorové látky farmakologie chemie metabolismus MeSH
- Check Tag
- lidé MeSH
