Cytotoxic effects of novel 2-methylthio dihydropyrimidines on human acute myeloid leukemia cell lines

Abstract

Abstract Dihydropyrimidines (DPs), one of the six-membered heterocyclic compounds, are well known to have a wide range of pharmacological activities including anticancer. Recently, our previous studies have demonstrated that 6-unsubstituted 2-thioxo-, 2-oxo-, and 2-amino DPs, and 4,4-disubstituted 3,4-dihydropyrimidin-2(1H)-ones and -thiones induced cytotoxicity against human promyelocytic leukemia cell line, HL-60, suggesting that DPs can serve as promising candidates for anticancer treatment. In the current study, the effects of novel 2-methylthio DPs, benzyl 4,4,6-trimethyl-2-methylthio-1,4-dihydropyrimidine-5-carboxylate (DP03) and ethyl 6-methyl-2-methylthio-1,4-dihydropyrimidine-5-carboxylate (DP09) were investigated by focusing on cell viability in human leukemia cell lines, NB4 and HL-60 cells together with other seventeen types of novel 2-methylthio DPs. Our study demonstrated treatment with DP03 at the low concentration for 96 h resulted in a significant decrease in cell viability of NB4 rather than HL-60 cells, whereas treatment with DP09 under the same condition was diametrically opposed to NB4 and HL-60 cells. Whether cell differentiation, cell cycle arrest, and cell death are involved in the DP03-induced cytotoxicity of NB4 cells was further investigated. Instead of necrosis, differentiation, and cell cycle arrest, apoptosis induction was observed in DP03-treated NB4 cells. DP03-triggered apoptosis was accompanied by the activation of caspase-8, -9, and − 3 but not caspase-12, and DP03-induced apoptosis was significantly inhibited by a pan-caspase inhibitor, but not the specific inhibitors of mitogen-activated protein kinase, phosphatidylinositol 3-kinase, janus kinase/signal transducer and activator of transcription. Their finding suggests that induction of apoptosis associated with the activation of caspase-8, -9, and − 3 contributed to the cytotoxicity of DP03 against NB4 cells.