Novel analogue of colchicine induces selective pro-death autophagy and necrosis in human cancer cells.
Novel analogue of colchicine induces selective pro-death autophagy and necrosis in human cancer cells.
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DOI：
10.1371/journal.pone.0087064
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Pandey S
中科院分区：
文献类型：
--
作者：
Larocque K;Ovadje P;Djurdjevic S;Mehdi M;Green J;Pandey S
秋水仙碱是秋水仙的天然产物，目前用于痛风治疗，是一种微管蛋白靶向化合物，通过靶向快速分裂的细胞来抑制微管的形成。这种微管蛋白靶向特性促使研究人员研究秋水仙碱及其类似物作为可能的癌症治疗方法的潜力。一项针对异秋水仙碱类似物zd6126的大型研究因与治疗相关的严重心脏毒性而停止了2期临床试验。本研究涉及开发和测试具有无毒抗癌特性的新型异秋水仙碱类似物。目前我们已经合成并评价了两种类似物的抗癌活性；n -乙酰基- o -甲基秋水仙醇（NSC 51046或NCME），其结构类似于zd6126，以及(S)-3,8,9,10-四甲基异秋水仙碱（Green 1），它是异秋水仙碱的一个新的衍生物，在a环上是异构体。NSC 51046在BxPC-3和PANC-1胰腺癌细胞以及正常人成纤维细胞中均具有诱导凋亡的非选择性。有趣的是，我们发现Green 1能够在这些胰腺癌细胞和E6-1白血病细胞中适度诱导死亡前自噬，但在正常的人成纤维细胞中却没有。与秋水仙碱和NSC 51046不同，Green 1似乎不影响微管蛋白聚合，这表明它具有不同的分子靶标。绿色1也引起从胰腺癌细胞分离的线粒体中活性氧（ROS）的产生增加。此外，体内研究表明，小鼠对Green 1具有良好的耐受性。我们的研究结果表明，秋水仙碱结构的微小变化明显改变了作用机制，并导致选择性提高。这可能会导致癌症治疗中更好的选择性治疗。
Colchicine, a natural product of Colchicum autumnae currently used for gout treatment, is a tubulin targeting compound which inhibits microtubule formation by targeting fast dividing cells. This tubulin-targeting property has lead researchers to investigate the potential of colchicine and analogs as possible cancer therapies. One major study conducted on an analogue of allocolchicine, ZD 6126, was halted in phase 2 clinical trials due to severe cardio-toxicity associated with treatment. This study involves the development and testing of novel allocolchicine analogues that hold non-toxic anti-cancer properties. Currently we have synthesized and evaluated the anti-cancer activities of two analogues; N-acetyl-O-methylcolchinol (NSC 51046 or NCME), which is structurally similar to ZD 6126, and (S)-3,8,9,10-tetramethoxyallocolchicine (Green 1), which is a novel derivative of allocolchicine that is isomeric in the A ring. NSC 51046 was found to be non-selective as it induced apoptosis in both BxPC-3 and PANC-1 pancreatic cancer cells and in normal human fibroblasts. Interestingly, we found that Green 1 was able to modestly induce pro-death autophagy in these pancreatic cancer cells and E6-1 leukemia cells but not in normal human fibroblasts. Unlike colchicine and NSC 51046, Green 1 does not appear to affect tubulin polymerization indicating that it has a different molecular target. Green 1 also caused increased reactive oxygen species (ROS) production in mitochondria isolated from pancreatic cancer cells. Furthermore, in vivo studies revealed that Green 1 was well tolerated in mice. Our findings suggest that a small change in the structure of colchicine has apparently changed the mechanism of action and lead to improved selectivity. This may lead to better selective treatments in cancer therapy.
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DOI：
10.1016/0006-291x(78)91014-8
发表时间：
1978-01-01
影响因子：
3.1
作者：
MARGULIS, TN;LESSINGER, L
通讯作者：
LESSINGER, L
影响因子：
13.3
作者：
Dalby KN;Tekedereli I;Lopez-Berestein G;Ozpolat B
通讯作者：
Ozpolat B
影响因子：
158.5
作者：
KERSHENOBICH, D;VARGAS, F;ROJKIND, M
通讯作者：
ROJKIND, M
影响因子：
3.4
作者：
LoRusso, Patricia M.;Gadgeel, Shirish M.;Wheeler, Catherine
通讯作者：
Wheeler, Catherine
影响因子：
11.5
作者：
Goto, H;Yano, S;Sone, S
通讯作者：
Sone, S