In vitro and in vivo growth inhibition of cancer cells by adamantylmaleimide derivatives.

Abstract

We have previously found that adamantylmaleimide derivatives inhibited the growth of several cancer cell lines in vitro. In this study we examined the effect of adamantylmaleimide derivatives on the in vivo and in vitro growth of human gastric cancer cells. Experimental results showed that N-1-adamantylmaleimide (AMI) and N-1-(3,5-dimethyladamantyl)maleimide (DMAMI) exert modest growth inhibitory activities in vitro against five different cancer cell lines. In contrast, N-1-(3,5-dimethyl-adamantyl)maleamic acid (DMAMA), N-1-adamantylmaleamic acid (AMA) and N-1-adamantylsuccinimide (ASI) were virtually inactive. These results suggest that the double bond of N-substituted maleimide plays a prominent role in their antitumor activities. Further analysis with flow cytometry showed an accumulation of apoptotic SC-M1 cells after treatment with 3-10 microM AMI or 5-20 microM DMAMI for up to 72 h. DNA fragmentation by gel electrophoresis confirmed that AMI- and DMAMI- induced cytotoxicity led to cell apoptosis. In addition, scanning electron microscopy (SEM) showed that treating cells with AMI (> or = 10 microM) for 24 h, significantly changed the morphology of SC-M1 cells, i.e. they had an irregular flat shape and the cell membrane was porous. The AMI-induced morphological changes of the cell membrane may lead to apoptosis of SC-M1 cells. AMI-induced growth inhibition was observed in vivo using SCID mice bearing SC-M1 tumors. The AMI-induced growth inhibition of SC-M1 tumor was dose-dependent.