High effectiveness of platinum(IV) complex with adamantylamine in overcoming resistance to cisplatin and suppressing proliferation of ovarian cancer cells in vitro

Publikace: BIOCHEMICAL PHARMACOLOGY 69, 373-383 Autoři: Kozubik, A., Horvath, V., Svihalkova-Sindlerova, L., Soucek, K., Hofmanova, J., Sova, P., Kroutil, A., Zak, F., Mistr, A., Turanek, J. Rok: 2005


[(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. IC50 and IC90 concentrations of LA-12 were 6-(A2780) or 18-fold (A2780cis) lower than those for cisplatin (MTT assay). Equitoxic concentrations (IC50 or IC90) 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 IC50 or IC90 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. (C) 2004 Elsevier Inc. All rights reserved.