1,4-Diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126) Enhances the Cytotoxicity of Combretastatin A4 Independently of Mitogen-Activated Protein Kinase Kinase

doi:10.1124/jpet.109.153320

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	1,4-Diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126) Enhances the Cytotoxicity of Combretastatin A4 Independently of Mitogen-Activated Protein Kinase Kinase
	Quan, Haitian2 ; Liu, Houfu 1; Li, Chuan1 ; Lou, Liguang2
刊名	JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS
	2009-07
卷号	330 期号:1 页码:326-333
ISSN号	0022-3565
DOI	10.1124/jpet.109.153320
文献子类	Article
英文摘要	Combretastatin A4 (CA4) is a novel vascular-disrupting agent that has shown promising anticancer effects through its inhibition of microtubule assembly and subsequent disruption of tumor blood flow. In this report, we demonstrate that 1,4-diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126), a selective inhibitor of mitogen-activated protein kinase kinase (MEK), significantly enhances the cytotoxicity of CA4 in BEL-7402 cells, independently of MEK inhibition. This independence is evidenced by the fact that another, more specific MEK inhibitor, PD0325901 [N-[(R)-2,3-dihydroxy-propoxy]-3,4-difluoro-2-[2-fluoro-4-iodo-phenylamino]-benzamide], does not have the same effect as U0126. The disassembled microtubules are able to reassemble in the later stages of CA4 treatment, because of the inactivating glucuronidation of CA4. U0126, but not PD0325901, inhibits CA4 glucuronidation, thereby blocking microtubule reassembly and enhancing CA4-induced G(2)/M cell-cycle arrest. Consistent with this, U0126 significantly enhances CA4-induced cytotoxicity for cells in which CA4 glucuronidation occurs, but not for cells in which such glucuronidation does not occur. These results suggest that great caution should be exercised when interpreting data obtained using U0126 or when CA4 is combined with inhibitors of glucuronidation in clinical practice. It is most important to note that these findings indicate that the combination of CA4 with inhibitors of glucuronidation may be a novel and rational strategy for cancer therapy.
资助项目	National Natural Science Foundation of China[0901041042] ; Chinese Academy of Sciences[KSCX2-YW-R-25]
WOS关键词	SOLID TUMOR-THERAPY ; PHASE-I TRIAL ; A-4 PHOSPHATE ; CANCER CELLS ; DRUG GLUCURONIDATION ; INHIBITOR U0126 ; AGENT ; APOPTOSIS ; ERK ; IDENTIFICATION
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
WOS记录号	WOS:000267280300036
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279202]
专题	药理学第一研究室
通讯作者	Lou, Liguang
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Metab & Pharmacokinet Res, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Pharmacol, Shanghai 201203, Peoples R China;
推荐引用方式 GB/T 7714	Quan, Haitian,Liu, Houfu,Li, Chuan,et al. 1,4-Diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126) Enhances the Cytotoxicity of Combretastatin A4 Independently of Mitogen-Activated Protein Kinase Kinase[J]. JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,2009,330(1):326-333.
APA	Quan, Haitian,Liu, Houfu,Li, Chuan,&Lou, Liguang.(2009).1,4-Diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126) Enhances the Cytotoxicity of Combretastatin A4 Independently of Mitogen-Activated Protein Kinase Kinase.JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS,330(1),326-333.
MLA	Quan, Haitian,et al."1,4-Diamino-2,3-dicyano-1,4-bis(methylthio)butadiene (U0126) Enhances the Cytotoxicity of Combretastatin A4 Independently of Mitogen-Activated Protein Kinase Kinase".JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS 330.1(2009):326-333.