XXII. BIOCHEMICKÝ ZJAZD - Jesseniova lekárska fakulta

Posters
123.
THE MECHANISM OF CYTOTOXIC EffECT OF NOVEL ACRIDINE
INTERCALATORS
Zuzana Vantová 1 , Helena Paulíková 1 , Mária Kožurková 1 , Danica Sabolová 1 ,
Ima Dovinová 1 , Pavol Kristián 2 , Ján Imrich 2 , Ján Ungvarský 2 and Ladislav Janovec 2
1
Department of Biochemistry and Microbiology, STU Bratislava,
2
Department of Biochemistry, UPJŠ Košice
Acridines are well-known chemotherapeutic agents in cancer therapy. New class of acridine
derivatives were synthesized – 2´,2´´-[(acridin-3,6-diyl)]-3´,3´´-dialkyl-1,3-diimidazolidin-4-
on hydrochloride (AcrDIMs). These compounds bearing imidazolidinone rings, are capable
to interact with DNA, mainly by intercalation and to inhibit activity of topoisomerase I.
Their biological activity to inhibit cell proliferation of leukaemia cells (HL-60 a L1210 cells)
and adherent ovarian cancer cell line A2780 was confirmed. Despite the lowest affinity
to DNA (K = 1.9×10 5 M -1 ), 2´,2´´-[(acridin-3,6-diyl)]-3´,3´´-dihexyl-1,3-diimidazolidin-4-on
was the most active derivative with an IC 50
of 4.61±2.08 µM on a HL 60 cell line, with IC 50
of 5.52±1.08 µM on a L1210 cell line and with IC 50
of 30,83 ± 2,63 µM on a A-2780 cells
after 48h of incubation.. It has been discovered that the cytotoxicity of AcrDIMs correlates
with their hydrophobicity (uptake into cells was monitored). Although apoptosis
of treated cells has not been confirmed it has been shown that dihexyl-AcrDIM arrested
cell cycle, and HL-60 cells were accumulated in G 1
phase after 48 h incubation. Together,
our results support the hypothesis that AcrDIMs exert cytostatic properties by interaction
with DNA inducing arrest of cell cycle and oxidative stress in cancer cells.
Acknowledgement: This work has been supported by VEGA grant 1/0097/10 and 1/0053/08.
248 XXII. Biochemistry Congress, Martin