[(OC-6-43)-bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV)], coded as LA-12, is an octahedral platinum(IV) complex containing a bulky hydrophobic ligand - adamantylamine. The use of bulky hydrophobic amines as non-leaving ligands, may increase uptake of the compound by the cancer cells. Therefore, the effects of LA-12 on sensitive (A2780) and cisplatin resistant (A2780cis) ovarian cancer cell lines were investigated and compared to those of cisplatin. IC(50) and IC(90) concentrations of LA-12 were 6- (A2780) or 18-fold (A2780cis) lower than those for cisplatin (MTT assay). Equitoxic concentrations (IC(50) or IC(90)) of both compounds caused a significant and similar time- and dose-dependent inhibition of cell proliferation and an increase in the number of floating cells which corresponded to the decrease of total cell viability. A different type and dynamics of cell cycle perturbation after cisplatin and LA-12 treatment were detected. Exposure to LA-12 resulted in transient accumulation of A2780 and A2780cis cells in S phase, while cisplatin caused G(2)/M arrest in sensitive and S phase arrest in resistant cells. A relatively low rate of apoptosis after exposure to IC(50) or IC(90) of both complexes was observed, markedly higher in resistant A2780cis cells. Western blot analysis indicated a concentration-dependent p53 level increase in both lines (higher after cisplatin treatment). PARP cleavage was observed only in A2780cis cells. In conclusion, LA-12 was found to be significantly more efficient than cisplatin, and it was able to overcome the acquired cisplatin resistance (showing resistance factor 2.84-fold lower than those for cisplatin). In spite of the low rate of apoptosis, LA-12 caused increase of p53 level and cell cycle perturbations in the ovarian cancer cell lines studied.
- MeSH
- amantadin analogy a deriváty farmakologie MeSH
- buněčný cyklus účinky léků MeSH
- chemorezistence MeSH
- cisplatina farmakologie MeSH
- fragmentace DNA účinky léků MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádorový supresorový protein p53 analýza MeSH
- nádory vaječníků farmakoterapie patologie MeSH
- organoplatinové sloučeniny farmakologie MeSH
- poly(ADP-ribosa)polymerasy analýza MeSH
- proliferace buněk účinky léků MeSH
- protinádorové látky farmakologie MeSH
- Check Tag
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- amantadin MeSH
- bis(acetato)(1-adamantylamine)amminedichloroplatinum(IV) MeSH Prohlížeč
- cisplatina MeSH
- nádorový supresorový protein p53 MeSH
- organoplatinové sloučeniny MeSH
- poly(ADP-ribosa)polymerasy MeSH
- protinádorové látky MeSH
