吖啶橙
化学
细胞周期
细胞凋亡
拓扑异构酶
癌症研究
细胞毒性T细胞
体内
流式细胞术
药理学
癌细胞
癌症
体外
分子生物学
生物
医学
生物化学
内科学
生物技术
作者
Tina Mahieu,Tatjana Mijatovic,Patrick Dumont,Eric Van Quaquebeke,Florence Lefranc,Bo Nilsson,Frank Van Vynckt,Francis Darro,Róbert Kiss
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2007-05-01
卷期号:67: 4831-4831
被引量:1
摘要
4831 UNBS5162 (N-{2-[2-(dimethylamino)ethyl]-1,3-dioxo-2,3-dihydro-1H-benzo[de]isoquinolin-5-yl}urea) is a novel naphthalimide with in vitro cytotoxic activity (IC50 range of 0.5-5µM) against a range of human cancer cell lines including glioblastoma (Hs683 and U373MG), colorectal (HCT-15 and LoVo), non-small-cell lung (A549) and breast (MCF-7). UNBS5162 also displays significant anti-tumor activity in mouse leukaemia and human cancer xenograft models in vivo. The compound has been designed to avoid the metabolism which provokes the clinical hematotoxicity of a large number of naphthalimide derivatives such as amonafide. Accordingly in mice, UNBS5162 was found to have a 3-4 fold higher maximum tolerated dose than that of amonafide irrespective of administration route. Additionally, UNBS5162 preclinically was found not to provoke marked hematotoxicity unlike amonafide. The mechanism of action of UNBS5162 is different to that of other naphthalimide derivatives, which exert their anti-tumor activity as DNA intercalating agents poisoning topoisomerase II. UNBS5162 displays no anti-topoisomerase II activity. However, it markedly impairs the cell cycle progression of human prostate cancer PC3 and glioblastoma U373 cells by increasing very significantly the duration of their G2 phase, as revealed by flow cytometry (FCM) analyses. This UNBS5162-induced increase in G2 phase duration is provoked by marked pro-autophagic effects (but not pro-apoptotic ones) as also revealed by FCM analyses of acridine orange staining. This pro-autophagic effect has been confirmed by the fact that UNBS5162 also markedly increased the levels of expression (as revealed by western blotting analyses) of LC3-I and LC3-II in human cancer cells. LC3 is a specific marker for autophagy. All the data observed here for UNBS5162 with doses ranging between 1 an 10 µM were also observed with respect to the pro-autophagic drug temozolomide, but at doses of 100 µM or even higher. UNBS5162 also induced cancer cell death through lysosomal membrane permeabilization (LMP) in PC3 prostate cancer cells but not in U373 glioblastoma cells, with this LMP process occurring as an UNBS5162-induced decrease in Hsp70 expression. UNBS5162 was also found to markedly decrease the expression of HERP, a gene involved in cancer cell chemoresistance, in several types of human cancer cells. Finally, computer-assisted cellular imaging revealed that pre-treatment of human cancer cells with non-cytotoxic doses of UNBS5162 promoted the anti-tumor effects of other pro-apoptotic cytotoxic drugs.
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