程序性细胞死亡
迪考马洛
细胞凋亡
NAD+激酶
癌细胞
细胞培养
合成致死
DNA损伤
癌症研究
生物
DNA修复
癌症
化学
药理学
生物化学
DNA
酶
遗传学
作者
Arthur B. Pardee,You Zhi Li,Chiang J. Li
出处
期刊:Current Cancer Drug Targets
[Bentham Science]
日期:2002-09-01
卷期号:2 (3): 227-242
被引量:205
标识
DOI:10.2174/1568009023333854
摘要
ß-Lapachone is an ortho naphthoquinone, originally isolated from a tree whose extract has been used medicinally for centuries. Recent investigations suggest its potential application against numerous diseases. Its lethality at micromolar (μm) concentrations against a variety of cancer cells in culture indicates its potential against tumor growth. A few experiments with positive results have been performed that apply the compound to tumors growing in animals. Particularly promising is the remarkably powerful synergistic lethality between ß-lapachone and taxol against several tumor cell lines implanted into mice; the mice did not appear to be adversely affected. Enhanced lethality of X-rays and alkylating agents to tumor cells in culture was reported when ß-lapachone was applied during the recovery period, because of inhibition of DNA lesion repair. Clinical trials are still to be initiated. The detailed mechanism of cell death induced by ß-lapachone remains for investigation. DNA topoisomerase I was the first biochemical target of ß-lapachone to be discovered, although its role in cell death is not clear. A proposed mechanism of cell death is via activation of a futile cycling of the drug by the cytoplasmic two-electron reductase NAD(P) H: quinone oxidoreductase, also known as NQO1, DTdiaphorase and Xip3. Death of NQO1 expressing cells is prevented by the NQO1 inhibitor dicoumarol, and cells with low NQO1 are resistant. At higher drug concentrations the production of reactive oxygen species (ROS) appears to be responsible. Furthermore, this process is p53- and caspase- independent. Either apoptotic or necrotic cell death can result, as reported in various studies performed under differing conditions. ß-Lapachone is one of a few novel anticancer drugs currently under active investigation, and it shows promise for chemotherapy alone and especially in combinations. Keywords: cancer therapy, lapachone, cytoplasmic two-electron reductase, prostate tumor cells, dna-related enzymes, proteases, isolated mitochondria
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