Leiodermatolide, a novel marine natural product, has potent cytotoxic and antimitotic activity against cancer cells, appears to affect microtubule dynamics, and exhibits antitumor activity.
Leiodermatolide, a novel marine natural product, has potent cytotoxic and antimitotic activity against cancer cells, appears to affect microtubule dynamics, and exhibits antitumor activity.
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DOI：
10.1002/ijc.30253
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发表时间：
2016-11-01
影响因子：
6.4
通讯作者：
Wright, Amy E.
中科院分区：
文献类型：
--
作者：
Guzman, Esther A.;Xu, Qunli;Pitts, Tara P.;Mitsuhashi, Kaoru Ogawa;Baker, Cheryl;Linley, Patricia A.;Oestreicher, Judy;Tendyke, Karen;Winder, Priscilla L.;Suh, Edward M.;Wright, Amy E.
胰腺癌是美国癌症死亡的第四大原因，预后不良，因为转移发生在症状出现之前。Leiodermatium是一种从Leiodermatium属的深水海绵中分离的具有抗有丝分裂活性的聚酮大环内酯，对胰腺癌细胞系AsPC-1、PANC-1、BxPC-3和MIA PaCa-2表现出强效和选择性细胞毒性，对皮肤癌、乳腺癌和结肠癌细胞系表现出强效细胞毒性。在AsPC-1、BxPC-3和MIA PaCa-2细胞中证实了leiodermatitis诱导的细胞凋亡。皮肤松质骨诱导细胞周期停滞，但对单独的微管蛋白的体外聚合或解聚没有影响，而它增强含有微管相关蛋白（MAP）的微管蛋白的聚合。通过共聚焦显微镜观察表明，leiodermatitis，在低浓度下，导致最小的影响聚合或解聚的微管网络在间期细胞，但在有丝分裂细胞纺锤体的形成中断。在较高浓度下，观察到微管网络的解聚。在表达GFP标记的正末端结合蛋白EB-1的HeLa细胞中生长的微管的可视化表明，leiodermatitis停止微管蛋白的聚合。这些结果表明，leiodermatitis可能会影响微管蛋白的动力学，而不直接与微管蛋白相互作用，并暗示在一个独特的作用机制。在转移性胰腺癌的小鼠模型中，与吉西他滨和对照相比，真皮层显示出显著的肿瘤减少。leiodermatitis的抗肿瘤活性，以及抗有丝分裂化合物对癌症的已证实效用，使leiodermatitis成为具有潜在化疗作用的有趣化合物，可能值得进一步研究。
Pancreatic cancer, the fourth leading cause of cancer death in the United States, has a negative prognosis because metastasis occurs before symptoms manifest. Leiodermatolide, a polyketide macrolide with antimitotic activity isolated from a deep water sponge of the genus Leiodermatium, exhibits potent and selective cytotoxicity towards the pancreatic cancer cell lines AsPC-1, PANC-1, BxPC-3, and MIA PaCa-2, and potent cytotoxicity against skin, breast and colon cancer cell lines. Induction of apoptosis by leiodermatolide was confirmed in the AsPC-1, BxPC-3 and MIA PaCa-2 cells. Leiodermatolide induces cell cycle arrest but has no effects on in vitro polymerization or depolymerization of tubulin alone, while it enhances polymerization of tubulin containing microtubule associated proteins (MAPs). Observations through confocal microscopy show that leiodermatolide, at low concentrations, causes minimal effects on polymerization or depolymerization of the microtubule network in interphase cells, but disruption of spindle formation in mitotic cells. At higher concentrations, depolymerization of the microtubule network is observed. Visualization of the growing microtubule in HeLa cells expressing GFP-tagged plus end binding protein EB-1 showed that leiodermatolide stopped the polymerization of tubulin. These results suggest that leiodermatolide may affect tubulin dynamics without directly interacting with tubulin and hint at a unique mechanism of action. In a mouse model of metastatic pancreatic cancer, leiodermatolide exhibited significant tumor reduction when compared to gemcitabine and controls. The anti-tumor activities of leiodermatolide, as well as the proven utility of anti-mitotic compounds against cancer, make leiodermatolide an interesting compound with potential chemotherapeutic effects that may merit further research.
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DOI：
10.1083/jcb.200405094
发表时间：
2005-01-03
期刊：
The Journal of cell biology
影响因子：
--
作者：
Mimori-Kiyosue Y;Grigoriev I;Lansbergen G;Sasaki H;Matsui C;Severin F;Galjart N;Grosveld F;Vorobjev I;Tsukita S;Akhmanova A
通讯作者：
Akhmanova A
影响因子：
16.6
作者：
Paterson, Ian;Dalby, Stephen M.;Roberts, Jill C.;Naylor, Guy J.;Guzman, Esther A.;Isbrucker, Richard;Pitts, Tara P.;Linley, Pat;Divlianska, Daniela;Reed, John K.;Wright, Amy E.
通讯作者：
Wright, Amy E.
DOI：
10.1083/jcb.91.2.479
发表时间：
1981-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Parness J;Horwitz SB
通讯作者：
Horwitz SB
影响因子：
15
作者：
Mailhol, Damien;Willwacher, Jens;Fuerstner, Alois
通讯作者：
Fuerstner, Alois
影响因子：
6.7
作者：
Driowya, Mohsine;Leclercq, Julien;Lebegue, Nicolas
通讯作者：
Lebegue, Nicolas