Synergistic suppression of microtubule dynamics by discodermolide and paclitaxel in non-small cell lung carcinoma cells
Synergistic suppression of microtubule dynamics by discodermolide and paclitaxel in non-small cell lung carcinoma cells
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DOI：
10.1158/0008-5472.can-04-0693
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发表时间：
2004-07-15
期刊：
影响因子：
11.2
通讯作者：
Jordan, MA
中科院分区：
文献类型：
--
作者：
Honore, S;Kamath, K;Jordan, MA
Discodermolide是一种新的微管靶向抗有丝分裂药物，在I期临床试验中，像紫杉醇一样，稳定微管动力学，并在体外和细胞中增加微管聚合物质量。尽管它们在微管上的结合位点明显相似，但discodermolide与紫杉醇协同作用，抑制A549人肺癌细胞的增殖（L. Martello等人，临床癌症研究，6：1978-1987，2000）。为了了解它们的协同作用，我们检查了这两种药物单独和联合在A549细胞中的作用，令人惊讶的是，发现它们的抗增殖协同作用与它们协同抑制微管动态不稳定性和有丝分裂的能力有关。discodermolide和紫杉醇在其抗增殖IC（50）s（discodermolide为7 nm，紫杉醇为2 nm）的组合协同改变了除基于时间的救援频率外的所有动态不稳定参数。例如，药物一起抑制总体微管动力学71%，但每种药物单独抑制动力学仅24%，组合指数（CI）为0.23。Discodermolide和紫杉醇也协同阻断细胞周期进展在G（2）-M（41，9.6，和16%的两种药物一起，单独的discodermolide，和紫杉醇单独，分别; CI = 0.59），他们协同增强细胞凋亡（CI = 0.85）。微管是药物的独特受体。结果表明，与单个微管上的大量结合位点结合的配体可以以一种知之甚少的方式相互作用，以协同抑制微管动态不稳定性并抑制有丝分裂和细胞增殖，这对与微管靶向药物的临床联合治疗具有重要意义。
Discodermolide is a new microtubule-targeted antimitotic drug in Phase I clinical trials that, like paclitaxel, stabilizes microtubule dynamics and enhances microtubule polymer mass in vitro and in cells. Despite their apparently similar binding sites on microtubules, discodermolide acts synergistically with paclitaxel to inhibit proliferation of A549 human lung cancer cells (L. Martello et at., Clin. Cancer Res., 6: 1978-1987, 2000). To understand their synergy, we examined the effects of the two drugs singly and in combination in A549 cells and found that, surprisingly, their antiproliferative synergy is related to their ability to synergistically inhibit microtubule dynamic instability and mitosis. The combination of discodermolide and paclitaxel at their antiproliferative IC(50)s (7 nm for discodermolide and 2 nm for paclitaxel) altered all of the parameters of dynamic instability synergistically except the time-based rescue frequency. For example, together the drugs inhibited overall microtubule dynamicity by 71 %, but each drug individually inhibited dynamicity by only 24%, giving a combination index (CI) of 0.23. Discodermolide and paclitaxel also synergistically blocked cell cycle progression at G(2)-M (41, 9.6, and 16% for both drugs together, for discoderimolide alone, and for paclitaxel alone, respectively; CI = 0.59), and they synergistically enhanced apoptosis (CI = 0.85). Microtubules are unique receptors for drugs. The results suggest that ligands that bind to large numbers of binding sites on an individual microtubule can interact in a poorly understood manner to synergistically suppress microtubule dynamic instability and inhibit both mitosis and cell proliferation, with important consequences for combination clinical therapy with microtubule-targeted drugs.