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

• Published in: Biochemical pharmacology Vol. 69; no. 3; pp. 373 - 383
• Main Authors: Kozubík, Alois, Horváth, Viktor, Švihálková-Šindlerová, Lenka, Souček, Karel, Hofmanová, Jiřina, Sova, Petr, Kroutil, Aleš, Žák, František, Mistr, Adolf, Turánek, Jaroslav
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.02.2005; Elsevier Science
• Subjects: Amantadine - analogs & derivatives; Amantadine - pharmacology; Antineoplastic Agents - pharmacology; Apoptosis; Biological and medical sciences; Cell Cycle - drug effects; Cell cycle perturbations; Cell Line, Tumor; Cell Proliferation - drug effects; Cisplatin; Cisplatin - pharmacology; Cytotoxicity; DNA Fragmentation - drug effects; Drug Resistance, Neoplasm; Female; Humans; LA-12; Medical sciences; Organoplatinum Compounds - pharmacology; Ovarian cancer; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - pathology; Pharmacology. Drug treatments; Poly(ADP-ribose) Polymerases - analysis; Tumor Suppressor Protein p53 - analysis; Cell cycle perturbations; Pt(IV); JM216; HRP; DAPI; Cytotoxicity; PARP; PAGE; MTT; DABCO; Cisplatin; cis-DDP; Ovarian cancer; LA-12; PI; cisplatin (50 or 90); Pt(II); Apoptosis; Antineoplastic agent; Cell proliferation; Ovary cancer; Malignant tumor; In vitro; Female genital diseases; Resistance; Ovarian diseases; Alkylating agent; Cell death; Cell cycle; Tumor cell; Platinum II Complexes
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2004.09.005

[( 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.