Docetaxel-based combination chemotherapy remains the predominant treatment for castration-resistant prostate cancer. However, taxane-related drug resistance and neurotoxicity have prompted us to develop substitute tre...Docetaxel-based combination chemotherapy remains the predominant treatment for castration-resistant prostate cancer. However, taxane-related drug resistance and neurotoxicity have prompted us to develop substitute treatment strategies. Eg5 （kinesin spindle protein）, which is crucial for bipolar spindle formation and duplicated chromosome separation during the early phase of mitosis, has emerged as an attractive target for cancer chemotherapy. The aim of this study was to investigate the anticancer efficacy of $-（methoxytrityl）-L-cysteine （S（MeO）TLC）, a novel Eg5 inhibitor in prostate cancer. Eg5 expression was examined in human prostate cancer cell lines and tissue microarrays were constructed from clinical specimens. Antiproliferative activity of S（MeO）TLC in prostate cancer cells was assessed by a cell viability assay. The anticancer effect and inhibitory mechanism of S（MeO）TLC in prostate cancer cells was further explored by Hoechst staining, flow cytometry and immunofluorescence. In addition, the antitumor effect of S（MeO）TLC on subcutaneous xenograft models was assessed. Eg5 expression was identified in PC3, DU145 and LNCaP cells. More than half of prostate cancer clinical specimens displayed Eg5 expression. S（Me0）TLC exhibited more powerful anticancer activity in prostate cancer cells compared with the other four Eg5 inhibitors tested. S（MeO）TLC induced cell death after arresting dividing cells at mitosis with distinct monopolar spindle formation. S（MeO）TLC exhibited its significant inhibitory activity （P〈0.05） on subcutaneous xenograft models also through induction of mitotic arrest. We conclude that Eg5 is a good target for prostate cancer chemotherapy, and S（MeO）TLC is a potent promising anticancer agent in prostate cancer.展开更多
Eg5又名Kif11(kinesin family member 11)是驱动蛋白家族成员之一,在增殖组织细胞中高表达,定位于有丝分裂期的微管,主要与细胞分裂中染色体的定位、中心体的分离以及双极纺锤体的形成和分离有关。Eg5是近年来研究较多的一种驱动蛋白分...Eg5又名Kif11(kinesin family member 11)是驱动蛋白家族成员之一,在增殖组织细胞中高表达,定位于有丝分裂期的微管,主要与细胞分裂中染色体的定位、中心体的分离以及双极纺锤体的形成和分离有关。Eg5是近年来研究较多的一种驱动蛋白分子,已开发出抑制其活性的肿瘤靶向治疗药物。该文介绍Eg5生物学特性、其抑制物在肿瘤靶向治疗中作用及与疾病关系等方面的最新研究进展。展开更多
驱动蛋白Eg5(kinesin-5),又名驱动蛋白超家族成员11(kinesin family member 11,KIF11),是一种广泛表达于人体正常组织的蛋白,对纺锤体微管组装、染色体排列和分离具有重要作用。在有丝分裂前期,Eg5蛋白定位于纺锤体微管和中心体,且沿微...驱动蛋白Eg5(kinesin-5),又名驱动蛋白超家族成员11(kinesin family member 11,KIF11),是一种广泛表达于人体正常组织的蛋白,对纺锤体微管组装、染色体排列和分离具有重要作用。在有丝分裂前期,Eg5蛋白定位于纺锤体微管和中心体,且沿微管正向运动。在有丝分裂的前中期,Eg5蛋白协同驱动蛋白-14调控中心体分离,维持纺锤体结构并促进染色体排列。展开更多
Microtubules have been identified as a powerful target for augmenting regeneration of injured adult axons in the central nervous system. Drugs that stabilize microtubules have shown some promise, but there are concern...Microtubules have been identified as a powerful target for augmenting regeneration of injured adult axons in the central nervous system. Drugs that stabilize microtubules have shown some promise, but there are concerns that abnormally stabilizing microtubules may have only limited benefits for regeneration, while at the same time may be detrimental to the normal work that microtubules perform for the axon. Kinesin-5 （also called kifl I or EgS）, a molecular motor protein best known for its crucial role in mitosis, acts as a brake on microtubule movements by other motor proteins in the axon. Drugs that inhibit kinesin-5, originally developed to treat cancer, result in greater mobility of microtubules in the axon and an overall shift in the forces on the microtubule array. As a result, the axon grows faster, retracts less, and more readily enters environments that are inhibitory to axonal regeneration. Thus, drugs that inhibit kinesin-5 offer a novel microtubule-based means to boost axonal regeneration without the concerns that accompany abnormal stabilization of the microtubule array. Even so, inhibiting kinesin-5 is not without its own caveats, such as potential problems with navigation of the regenerating axon to its target, as well as morphological effects on dendrites that could affect learning and memory if the drugs reach the brain.展开更多
Cilia are hair-like organelles that protrude from the surface of many types of eukaryotic cells.Each cilium possesses a microtubule-based central core,known as the axoneme,surrounded by the ciliary membrane.Ciliogenes...Cilia are hair-like organelles that protrude from the surface of many types of eukaryotic cells.Each cilium possesses a microtubule-based central core,known as the axoneme,surrounded by the ciliary membrane.Ciliogenesis is a multi-step process that typically involves vesicle transport to the centrosome,maturation of the mother centriole into a basal body,docking of the basal body onto the plasma membrane,and extension of the axoneme from the basal body[1].展开更多
文摘Docetaxel-based combination chemotherapy remains the predominant treatment for castration-resistant prostate cancer. However, taxane-related drug resistance and neurotoxicity have prompted us to develop substitute treatment strategies. Eg5 （kinesin spindle protein）, which is crucial for bipolar spindle formation and duplicated chromosome separation during the early phase of mitosis, has emerged as an attractive target for cancer chemotherapy. The aim of this study was to investigate the anticancer efficacy of $-（methoxytrityl）-L-cysteine （S（MeO）TLC）, a novel Eg5 inhibitor in prostate cancer. Eg5 expression was examined in human prostate cancer cell lines and tissue microarrays were constructed from clinical specimens. Antiproliferative activity of S（MeO）TLC in prostate cancer cells was assessed by a cell viability assay. The anticancer effect and inhibitory mechanism of S（MeO）TLC in prostate cancer cells was further explored by Hoechst staining, flow cytometry and immunofluorescence. In addition, the antitumor effect of S（MeO）TLC on subcutaneous xenograft models was assessed. Eg5 expression was identified in PC3, DU145 and LNCaP cells. More than half of prostate cancer clinical specimens displayed Eg5 expression. S（Me0）TLC exhibited more powerful anticancer activity in prostate cancer cells compared with the other four Eg5 inhibitors tested. S（MeO）TLC induced cell death after arresting dividing cells at mitosis with distinct monopolar spindle formation. S（MeO）TLC exhibited its significant inhibitory activity （P〈0.05） on subcutaneous xenograft models also through induction of mitotic arrest. We conclude that Eg5 is a good target for prostate cancer chemotherapy, and S（MeO）TLC is a potent promising anticancer agent in prostate cancer.
文摘Eg5又名Kif11(kinesin family member 11)是驱动蛋白家族成员之一,在增殖组织细胞中高表达,定位于有丝分裂期的微管,主要与细胞分裂中染色体的定位、中心体的分离以及双极纺锤体的形成和分离有关。Eg5是近年来研究较多的一种驱动蛋白分子,已开发出抑制其活性的肿瘤靶向治疗药物。该文介绍Eg5生物学特性、其抑制物在肿瘤靶向治疗中作用及与疾病关系等方面的最新研究进展。
文摘驱动蛋白Eg5(kinesin-5),又名驱动蛋白超家族成员11(kinesin family member 11,KIF11),是一种广泛表达于人体正常组织的蛋白,对纺锤体微管组装、染色体排列和分离具有重要作用。在有丝分裂前期,Eg5蛋白定位于纺锤体微管和中心体,且沿微管正向运动。在有丝分裂的前中期,Eg5蛋白协同驱动蛋白-14调控中心体分离,维持纺锤体结构并促进染色体排列。
基金discussed here on kinesin-5 inhibition as a means for augmenting nerve regeneration after injury was supported mainly by grants from the Craig H.Neilsen Foundation
文摘Microtubules have been identified as a powerful target for augmenting regeneration of injured adult axons in the central nervous system. Drugs that stabilize microtubules have shown some promise, but there are concerns that abnormally stabilizing microtubules may have only limited benefits for regeneration, while at the same time may be detrimental to the normal work that microtubules perform for the axon. Kinesin-5 （also called kifl I or EgS）, a molecular motor protein best known for its crucial role in mitosis, acts as a brake on microtubule movements by other motor proteins in the axon. Drugs that inhibit kinesin-5, originally developed to treat cancer, result in greater mobility of microtubules in the axon and an overall shift in the forces on the microtubule array. As a result, the axon grows faster, retracts less, and more readily enters environments that are inhibitory to axonal regeneration. Thus, drugs that inhibit kinesin-5 offer a novel microtubule-based means to boost axonal regeneration without the concerns that accompany abnormal stabilization of the microtubule array. Even so, inhibiting kinesin-5 is not without its own caveats, such as potential problems with navigation of the regenerating axon to its target, as well as morphological effects on dendrites that could affect learning and memory if the drugs reach the brain.
基金National Natural Science Foundation(30772624)Specialized Research Fundfor the Doctoral Program of Higher Educa-tion P.R.C.(No.20030316006)"The Six Top Talents" of Jiangsu Province(No.06-C-023)
基金This work was supported by the National Key R&D Program of China(2018YFA0107001)the National Natural Science Foundation of China(31671403 and 31701169).
文摘Cilia are hair-like organelles that protrude from the surface of many types of eukaryotic cells.Each cilium possesses a microtubule-based central core,known as the axoneme,surrounded by the ciliary membrane.Ciliogenesis is a multi-step process that typically involves vesicle transport to the centrosome,maturation of the mother centriole into a basal body,docking of the basal body onto the plasma membrane,and extension of the axoneme from the basal body[1].
