Stabilizing versus destabilizing the microtubules: a double-edge sword for an effective cancer treatment option?
Stabilizing versus destabilizing the microtubules: a double-edge sword for an effective cancer treatment option?
复制标题
DOI：
10.1155/2015/690916
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Bazan V
中科院分区：
文献类型：
--
作者：
Fanale D;Bronte G;Passiglia F;Calò V;Castiglia M;Di Piazza F;Barraco N;Cangemi A;Catarella MT;Insalaco L;Listì A;Maragliano R;Massihnia D;Perez A;Toia F;Cicero G;Bazan V
微管是参与多种细胞功能的动态和结构性细胞组分，包括细胞形状、运动性和细胞内运输。在增殖细胞中，它们是通过形成有丝分裂纺锤体的分裂过程中的重要组分。由于这些功能，微管蛋白和微管是抗癌剂的靶标。微管靶向剂可分为两组：微管稳定剂和微管去稳定剂。前者与微管蛋白聚合物结合并稳定微管，而后者与微管蛋白二聚体结合并使微管不稳定。微管蛋白-微管平衡的改变决定了有丝分裂纺锤体的破坏，使细胞周期在中期-后期过渡期停止，最终导致细胞死亡。然而，早期微管抑制剂的临床应用不幸地显示出一些限制，例如神经和骨髓毒性以及耐药肿瘤细胞的出现。在这里，我们回顾了几种天然和合成的微管靶向药物，这些药物在各种临床前和临床研究中显示出抗肿瘤活性，并与传统药物相比具有更高的疗效。在临床试验中使用了念珠藻素类、考布他汀类、奥布布林、soblidotin、D-24851、埃博霉素和discodermolide。他们中的一些人表现出抗血管生成和抗血管活性和其他人表现出克服多药耐药性的能力，支持他们可能用于化疗。
Microtubules are dynamic and structural cellular components involved in several cell functions, including cell shape, motility, and intracellular trafficking. In proliferating cells, they are essential components in the division process through the formation of the mitotic spindle. As a result of these functions, tubulin and microtubules are targets for anticancer agents. Microtubule-targeting agents can be divided into two groups: microtubule-stabilizing, and microtubule-destabilizing agents. The former bind to the tubulin polymer and stabilize microtubules, while the latter bind to the tubulin dimers and destabilize microtubules. Alteration of tubulin-microtubule equilibrium determines the disruption of the mitotic spindle, halting the cell cycle at the metaphase-anaphase transition and, eventually, resulting in cell death. Clinical application of earlier microtubule inhibitors, however, unfortunately showed several limits, such as neurological and bone marrow toxicity and the emergence of drug-resistant tumor cells. Here we review several natural and synthetic microtubule-targeting agents, which showed antitumor activity and increased efficacy in comparison to traditional drugs in various preclinical and clinical studies. Cryptophycins, combretastatins, ombrabulin, soblidotin, D-24851, epothilones and discodermolide were used in clinical trials. Some of them showed antiangiogenic and antivascular activity and others showed the ability to overcome multidrug resistance, supporting their possible use in chemotherapy.