Vascular disrupting agent drug classes differ in effects on the cytoskeleton.
Vascular disrupting agent drug classes differ in effects on the cytoskeleton.
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DOI：
10.1371/journal.pone.0040177
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Mitchison TJ
中科院分区：
文献类型：
--
作者：
Kim S;Peshkin L;Mitchison TJ
血管破坏剂（VDAs）是针对已建立的肿瘤血管的抗癌药物，主要分为两类：微管靶向药物，如combretastatin A4 (CA4)；类黄酮，如5,6-二甲基黄酮-4-乙酸（DMXAA）。在小鼠模型中，这两类药物都增加了肿瘤血管的通透性，特别是DMXAA可引起肿瘤大量坏死。CA4的分子靶点显然是微管。DMXAA的分子靶点尚不清楚。它被认为可以促进白细胞中的炎症信号，并且被认为不以微管为目标，尽管从文献中尚不清楚这种假设是否得到了仔细的验证。一种早期的黄酮类似物，黄酮乙酸，据报道可以促进有丝分裂停止，这表明黄酮可能具有抗微管活性，内皮细胞对微管的轻微破坏也很敏感。通过比较CA4和DMXAA对人脐静脉内皮细胞（HUVEC）的影响，我们仔细研究了DMXAA是否直接影响内皮细胞的微管或肌动蛋白细胞骨架，使用时间推移成像和细胞骨架完整性测定。CA4引起细胞边缘收缩、有丝分裂阻滞和微管解聚，而DMXAA浓度达到500µM时，则没有这些影响。与CA4不同，DMXAA对纯微管蛋白的成核和聚合也没有影响。我们得出结论，DMXAA没有直接的抗微管作用，因此在分子水平上与CA4的作用机制明显不同。
Vascular disrupting agents (VDAs), anti-cancer drugs that target established tumor blood vessels, fall into two main classes: microtubule targeting drugs, exemplified by combretastatin A4 (CA4), and flavonoids, exemplified by 5,6-dimethylxanthenone-4-acetic acid (DMXAA). Both classes increase permeability of tumor vasculature in mouse models, and DMXAA in particular can cause massive tumor necrosis. The molecular target of CA4 is clearly microtubules. The molecular target(s) of DMXAA remains unclear. It is thought to promote inflammatory signaling in leukocytes, and has been assumed to not target microtubules, though it is not clear from the literature how carefully this assumption has been tested. An earlier flavone analog, flavone acetic acid, was reported to promote mitotic arrest suggesting flavones might possess anti-microtubule activity, and endothelial cells are sensitive to even mild disruption of microtubules. We carefully investigated whether DMXAA directly affects the microtubule or actin cytoskeletons of endothelial cells by comparing effects of CA4 and DMXAA on human umbilical vein endothelial cells (HUVEC) using time-lapse imaging and assays for cytoskeleton integrity. CA4 caused retraction of the cell margin, mitotic arrest and microtubule depolymerization, while DMXAA, up to 500 µM, showed none of these effects. DMXAA also had no effect on pure tubulin nucleation and polymerization, unlike CA4. We conclude that DMXAA exhibits no direct anti-microtubule action and thus cleanly differs from CA4 in its mechanism of action at the molecular level.
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DOI：
10.1158/1078-0432.ccr-08-2710
发表时间：
2009-04-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Schwartz EL
通讯作者：
Schwartz EL
通过预防新血管形成，体内肿瘤休眠。
影响因子：
15.3
作者：
Gimbrone, M A Jr;Leapman, S B;Cotran, R S;Folkman, J
通讯作者：
Folkman, J
抗血管剂5,6-二甲基苯乙烯-4-乙酸诱导内皮细胞凋亡。
影响因子：
8.8
作者：
Ching, LM;Cao, Z;Kieda, C;Zwain, S;Jameson, MB;Baguley, BC
通讯作者：
Baguley, BC
影响因子：
5.7
作者：
Orth JD;Tang Y;Shi J;Loy CT;Amendt C;Wilm C;Zenke FT;Mitchison TJ
通讯作者：
Mitchison TJ
影响因子：
64.5
作者：
BELMONT, LD;HYMAN, AA;MITCHISON, TJ
通讯作者：
MITCHISON, TJ