Vitamine und Mineralien

Cytotoxicity and Apoptogenic Activity of A Novel Synthetic Iron Chelator 1-(N-Acetyl-6-Aminohexyl)-3-Hydroxy-2-Methylpyridin-4-One (CM1) In Human Leukemic Cells

Abstract

Nittaya Chansiw, Kanjana Pangjit,Wirote Tuntiwechapikul, Chada Phisalaphong, Suthat Fucharoen, John B. Porter

An interruption of the iron metabolism with chelators can lead to a significant inhibition of cancer cell growth. 1-(N-acetyl-6-aminohexyl)-3-hydroxy-2-methylpyridin-4-one or CM1, is a novel synthetic bidentate iron chelator which was successfully synthesized by our group. We have studied the characteristics and iron-chelating activity of this compound. Nevertheless, the anti-cancer activity of the chelator is largely unknown. In this study, we demonstrated the cytotoxicity and apoptogenic activity of CM1 against human leukemic cell lines-HL-60 and U937. 3-(4,5-Dimethylthiazol- 2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed for the cytotoxicity study. The results showed that CM1 inhibited the cell growth and metabolic activity of the leukemic cells. Flow cytometric analysis clearly demonstrated the dose and time-response of CM1-induced apoptosis in these two cells. CM1 arrested the cell populations in the sub G1 phase after 24 hours of exposure. The cancer cells induced by the compound significantly decreased mitochondria membrane potential (Δψm), and increased the activation of caspase-2,-3,-8 and caspase-9 activities. Possibly, CM1 would interact with nonheme iron-containing enzymes, such as ribonucleotide reductase and depleting intracellular iron essential for fast dividing cancer cells, leading to cell apoptosis. The CM1 may act as a reducing agent and help to maintain the CM1-Fe2+ complex which can generate radicals.