Ispitivanje citotoksične aktivnosti aminokiselinskih estara vitamina E na ćelijama tumora dojke i pluća

Abstract

U velikom broju studija pokazana je antitumorska aktivnost prirodnih izomera vitamina E, a naročito njihovih polusintetskih derivata. Cilj ove studije je bio ispitivanje citotoksične aktivnosti estara α‐tokoferola sa aminokiselinama lizinom, prolinom, glutaminom, asparaginom i estara γ‐tokotrienola sa lizinom, prolinom i glutaminom na MCF7 i MDA‐MB 231 ćelijskim linijama tumora dojke i A549 ćelijskoj liniji tumora pluća. Sve ćelijske linije tretirane su koncentracijama ispitivanih jedinjenja u opsegu 0,62‐50 μM u toku 48 sati. Preživljavanje ćelija nakon tretmana ispitivanim jedinjenjima je određeno MTT‐testom. Najveći uticaj na preživljavanje malignih ćelija su imali α‐tokoferil lizin, α‐tokoferil asparagin u formi nitrila i γ‐tokotrienil lizin. α‐ Tokoferil lizin je ispoljio snažnu antitumorsku aktivnost na A549 (IC50=10,6 μM) i MCF7 (IC50=8,6 μM) ćelijama, dok je γ‐tokotrienil lizin je jedini od ispitivanih jedinjenja koji je ispoljio aktivnost na sve tri maligne ćelijske linije, sa IC50 vrednostima 20,6 μM (MCF7), 28,6 μM (MDA‐MB‐231) i 19 μM (A549). Asparaginski estar α‐tokoferola u formi nitrila je je doveo do snažne inhibicije preživljavanja MDA‐MB‐231 ćelija (IC50=9,2 μM) koje se odlikuju višestrukom rezistencijom na lekove koji se koriste u terapiji tumora dojke. Ispitivana jedinjenja nisu ispoljila toksičnost ka MRC‐5 zdravoj ćelijskoj liniji fetalnih fibroblasta pluća. Zahvaljujući pokazanoj in vitro citotoksičnoj aktivnosti i selektivnosti za maligne ćelije, aminokiselinski estri α‐tokoferola i γ‐tokotrienola predstavljaju dobre kandidate za buduća in vivo ispitivanja.

In recent studies, the antitumor activity of vitamin E derivatives has been demonstrated. The aim of this study was to investigate the cytotoxic activity of α‐ tocopherol esters with amino acids lysine, proline, glutamine, asparagine and γ‐ tocotrienol esters with lysine, proline and glutamine on MCF7 and MDA‐MB 231 breast cancer cell lines and A549 lung cancer cell line. All cell lines were treated with concentrations of the test compounds in the range of 0.62‐50 μM for 48 hours. Cell survival after treatment with the investigated compounds was determined by MTT test. The greatest influence on the survival of malignant cells was observed with α‐ tocopheryl lysine, α‐tocopheryl asparagine in the form of nitrile and γ‐tocotrienyl lysine. α‐Tocopheryl lysine exhibited strong cytotoxic activity on A549 (IC50 = 10.6 μM) and MCF7 (IC50 = 8.6 μM) cells, while γ‐tocotrienyl lysine is the only compound that exhibited activity on all three cancer cell lines, with IC50 values of 20.6 μM (MCF7), 28.6μM (MDA‐MB‐231) and 19 μM (A549). The α‐tocopheryl asparagine nitrile led to a strong inhibition of the survival of MDA‐MB‐231 cells (IC50 =9.2 μM) that are characterized by multiple resistance to drugs used for treatment of breast cancer. All investigated compounds did not exhibit toxicity to normal MRC‐5 cell line of the fetal fibroblasts of the lungs. Based on the shown in vitro cytotoxic activity and selectivity for tumor cells, α‐ tocopherol and γ‐tocotrienol amino acid esters represent promising candidates for future in vivo studies.