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Aneuploidy in Human Oocytes and Preimplantation Embryos
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Microtubules are composed of alpha and beta tubulin subunits. Recently, mutations in TUBB8, the major β-tubulin expressed only in oocytes and preimplantation embryos, were shown to be associated with maturation arrest (104) as well as defective divisions in both oocytes and embryos (104–106). TUBB8 is particularly interesting because it evolved in the primate clade and could thus contribute to the substantial differences in spindle dynamics in mouse and human oocytes.
Chemotherapy in pregnancy
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Vinblastine is also a vinca alkaloid derived from the periwinkle plant. It is indicated for the treatment of HL and NHL, breast cancer, Kaposi’s sarcoma, and renal cell carcinoma. It exerts its antitumor effect by inhibiting tubulin polymerization and disrupting microtubules during the M-phase of the cell cycle. As with most agents described here, animal studies in early pregnancy have demonstrated increased resorption, spontaneous abortion, and gross fetal abnormalities. However, some human studies have reported no teratogenic effects from first-trimester exposure (90). At 18 weeks of gestation, a patient was diagnosed with an endodermal sinus tumor of the ovary, and following laparotomy, she received three courses of cisplatin, vinblastine, and bleomycin (69). She delivered a healthy and normal infant at 31 weeks. To date, there have been more than half a dozen other patients who have received vinblastine in combination regimens, followed by the delivery of normal, healthy infants (91,92).
Herbs in Cancer Therapy
Published in Anil K. Sharma, Raj K. Keservani, Surya Prakash Gautam, Herbal Product Development, 2020
Annum Malik, Shahzadi Sidra Saleem, Kifayat Ullah Shah, Learn-Han Lee, Bey Hing Goh, Tahir Mehmood Khan
Two important classes of the tubulin-binding agents include Vinca alkaloids and taxanes. Vinca alkaloids are microtubule-targeting drugs which binds with ɑ/β-tubulin dimers and as a result destabilized the microtubules. (Hassan and MA). Recent evidence indicates that microtubule function is disrupted by both kinds of drugs including taxanes that are known to be microtubule stabilizing drugs and vinca alkaloids that are considered as microtubule destabilizing drugs (Escuin et al. 2005). Hence, they prevent the proper alignment of daughter chromosomes to the microtubules. This disruption in proper alignment of daughter chromosomes on microtubules results in the inhibition of phases of mitotic cell division, particularly metaphase and anaphase. Such inhibition of cell division or particularly called cell cycle arrest may ultimately be followed by apoptosis (Nobili et al. 2009). For example, vinca alkaloids prevents cell cycle progression and induce mitotic block and apoptosis. Whatever the concentration of vinca alkaloids, mitochondria appear to be at the point of convergence for the apoptotic signals (Pourroy et al. 2004). Podophyllotoxin binds to microtubules, thus preventing their formation and destabilizing them (Darwiche et al. 2007).
Design, synthesis and biological evaluation of novel diarylpyridine derivatives as tubulin polymerisation inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Shanbo Yang, Chao Wang, Lingyu Shi, Jing Chang, Yujing Zhang, Jingsen Meng, Wenjing Liu, Jun Zeng, Renshuai Zhang, Yingchun Shao, Dongming Xing
Microtubules are hollow tubular structures composed of heterodimers of α-tubulin and β-tubulin, which have a variety of roles in eukaryotic cells, including maintenance of cell morphology, cell growth, cell motility, material transport, organelle transport, signalling, mitosis, etc.1–3 If the dynamic cycle of microtubule assembly–disassembly is disrupted, the mitotic process of tumour cells is affected, thereby inhibiting their growth and leading to apoptosis.4 Therefore, drugs that interfere with the kinetics of microtubule protein depolymerisation and polymerisation are an important class of antitumor drugs.5 Several clinical agents have been developed (e.g. paclitaxel and vincristine), but there are currently no FDA-approved inhibitors of microtubulin at the colchicine site. The development of microtubulin polymerisation inhibitors targeting the colchicine binding site has, therefore, attracted the interest of many medicinal chemists.6
Design, synthesis, and biological screening of a series of 4′-fluoro-benzotriazole-acrylonitrile derivatives as microtubule-destabilising agents (MDAs)
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Federico Riu, Roberta Ibba, Stefano Zoroddu, Simona Sestito, Michele Lai, Sandra Piras, Luca Sanna, Valentina Bordoni, Luigi Bagella, Antonio Carta
Cancer is one of the main clinical issues worldwide. Anticancer therapy is still a focus of academic and industrial research, which aims to improve the potency and safety of validated anticancer protocols and to create new ones.1 Antitumor compounds targeting the microtubule (MT) structure affect the cell skeleton and the replication process but also act on apoptosis, therefore some of them have been approved for clinical cancer treatment.2 Microtubules (MTs) have a fine-tuned dynamic mechanism of polymerisation and depolymerisation dealing with cell division. A single microtubule is constituted by heterodimers of α- and β-tubulin.3–5 Tubulin polymerisation is crucial for the creation of microtubules. It is regulated by the hydrolysis of GTP (guanosine-5′-triphosphate) in the β-portion of tubulin dimer. GTP caps stabilise the formed microtubule ends.6 The α- and β-hetero-polypeptides of tubulin have about 36–42% similarity to each other and each subunit consists of about 445 amino acids. The 3D structure of the α,β-tubulin heterodimer has been determined by X-ray diffraction (Protein Data Bank Identity [PDB ID]: 4O2B)7 and both monomers were shown to surround a GTP molecule. MT growth occurs at the plus end and the shortening at the minus end.8,9Figure 1 reports a simplified representation of the mitotic cycle and the microtubule depolymerisation at the plus end.
A review on synthetic chalcone derivatives as tubulin polymerisation inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Wenjing Liu, Min He, Yongjun Li, Zhiyun Peng, Guangcheng Wang
In mammalian cells, microtubules are closely related to cell division. Tubulin inhibitors can disturb the dynamic balance of microtubules by inhibiting the kinetic properties of microtubules. Thus, leading to the induction of cell cycle arrest at the G2/M phase and interfering with the mitotic process to inhibit cell proliferation7. Four targets of action have been identified in the study of microtubule proteins, which can be divided into two classes: microtubule-stabilizing binder including taxanes binding site and laurimalide binding sites; and microtubule destabilising binder including vinca alkaloids binding site and colchicine binding site. The former can promote the polymerisation of microtubule proteins, while the latter inhibits the polymerisation of tubulin, both of which can arrest the process of tumour cell growth in the cell division phase8. Many anti-mitotic drugs, such as vinblastine alkaloids, taxanes, and nocodazole, have been used clinically for many years9, while problems such as drug resistance and toxic side effects remain to be solved. Thus, it is of great significance to discover and develop new tubulin polymerisation inhibitors10,11.