School of Pharmaceutical Sciences, Faculty of Sciences, University of Geneva, Rue Michel-Servet 1, CMU, 1211, Geneva 4, Switzerland.
Institute of Pharmaceutical Sciences of Western Switzerland, University of Geneva, Rue Michel-Servet 1, CMU, 1211, Geneva 4, Switzerland.
Apoptosis. 2021 Jun;26(5-6):248-252. doi: 10.1007/s10495-021-01671-3. Epub 2021 Apr 19.
Mitosis, under the control of the microtubule-based mitotic spindle, is an attractive target for anti-cancer treatments, as cancer cells undergo frequent and uncontrolled cell divisions. Microtubule targeting agents that disrupt mitosis or single molecule inhibitors of mitotic kinases or microtubule motors kill cancer cells with a high efficacy. These treatments have, nevertheless, severe disadvantages: they also target frequently dividing healthy tissues, such as the haematopoietic system, and they often lose their efficacy due to primary or acquired resistance mechanisms. An alternative target that has emerged in dividing cancer cells is their ability to "cluster" the poles of the mitotic spindle into a bipolar configuration. This mechanism is necessary for the specific survival of cancer cells that tend to form multipolar spindles due to the frequent presence of abnormal centrosome numbers or other spindle defects. Here we discuss the recent development of combinatorial treatments targeting spindle pole clustering that specifically target cancer cells bearing aberrant centrosome numbers and that have the potential to avoid resistance mechanism due their combinatorial nature.
有丝分裂是在基于微管的有丝分裂纺锤体的控制下进行的，是抗癌治疗的一个有吸引力的靶点，因为癌细胞经常经历不受控制的细胞分裂。有丝分裂的微管靶向药物或有丝分裂激酶或微管马达的单分子抑制剂会高效杀死癌细胞。然而，这些治疗方法有严重的缺点：它们也针对经常分裂的健康组织，如造血系统，而且由于原发性或获得性耐药机制，它们经常失去疗效。在分裂的癌细胞中出现的另一个靶点是它们将有丝分裂纺锤体的两极“聚类”成双极结构的能力。由于异常中心体数量或其他纺锤体缺陷的频繁存在，导致癌细胞倾向于形成多极纺锤体，这种机制对于癌细胞的特定存活是必要的。在这里，我们讨论了针对纺锤体极聚类的组合治疗的最新进展，这些治疗方法专门针对具有异常中心体数量的癌细胞，并且由于其组合性质，有可能避免耐药机制。
