Naslov
Antitumor effect of novel small molecules targeting AT-rich DNA regions

Autori
Marjanović, Marko ; Kralj, Marijeta ; Radić Stojković, Marijana ; Piantanida, Ivo ; Pawlica, Dariusz ; Eilmes, Julita

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
FEBS speciall meeting Cellular Signalning, 2006 / Đikić, Ivan ; Husnjak, Koraljka - Zagreb, 2006, 251-252

Skup
FEBS speciall meeting Cellular Signalning

Mjesto i datum
Cavtat, Hrvatska, 26.05.2006. - 01.06.2006

Vrsta sudjelovanja
Poster

Vrsta recenzije
Nije recenziran

Ključne riječi
antitumor compounds; AT-rich regions; DNA active drugs

Sažetak
Cancer biochemistry and biology has been of a great interest for many years, as well as the anticancer drugs. Although chemotherapeutics interfere with many cellular functions, their pivotal target is genomic DNA. Current focus in anticancer drug design is to mimic uniqueness of the disease's characteristics with an attempt to selectively aim at transformed cells. The classical antitumor DNA-reactive drugs currently in the clinic display low sequence specificity, binding virtually indiscriminately to cellular DNA, but also to other macromolecules. Therefore, they are considered as non-specific cytotoxic agents building its strength on a cytokinetic difference between normal and cancer cells. More recently, special DNA interacting agents are being designed to affect specific nuclear functions through interaction at designated primary DNA sequences, genomic sites, secondary structures and DNA associated proteins. For example, certain minor groove-binding agents combine high sequence specificity for AT motifs with a lack of reactivity with non-DNA targets. We have tested three novel small DNA binding molecules (dibenzotetraaza[14]annulenes, DBTA), that show structural similarity to porphyrins and are known for their ability to accommodate various substituents and adopt various conformations. Besides, metal complexes of DBTA system are offering a range of coordination modes, thus being of huge interest regarding the interactions with DNA/RNA. Spectroscopic studies revealed that all molecules interacted preferentially with DNA, and all show pronounced poly dT – poly dA selectivity pointing to minor groove binding, but with different affinities, which correlated perfectly with their antiproliferative properties on several different human tumor cell lines (HEp-2, HeLa, MiaPaCa-2, SW620, MCF-7), showing that two compounds with higher affinities toward AT-rich regions showed much stronger cell-growth inhibition. To shed more light on the mechanism of antiprolifertive activity, we assessed their influence on cell cycle and activation of apoptosis. Again, the results confirmed good correlation of diverse DNA-interaction/affinity with the cell-response. Moreover, since both active compounds bind well to AT-rich regions, different outcome on different tumor cell lines is very likely due to the different abundance of AT-rich regions. Following the lead that AT-rich islands in genomic DNA can be considered as a target for AT-specific DNA-reactive antitumor drugs, the elucidation of mechanisms and importance of specific AT sequence targeting and their applicability to rational drug design is of utmost importance, just as designing molecules with even greater selectivity.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Biologija, Temeljne medicinske znanosti

POVEZANOST RADA