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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.
The Fight Against Cancer
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Another strategy to battle cancer is to target the structural elements of the cell division process. Disruption of mitosis will obviously impede cell proliferation. Tubulin is a structural protein that is crucial for cell division, involved in polymerisation and depolymerisation of microtubules, where it is used as protein building blocks. As the cells divide, mitotic spindle fibres link the two daughter cells. The spindle fibres are made from microtubule polymers formed from tubulin proteins. Drugs designed to bind to tubulin prevent its polymerisation to from the microtubules, and thus cell division is arrested.
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 evaluation of dihydro-1H-indene derivatives as novel tubulin polymerisation inhibitors with anti-angiogenic and antitumor potency
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2023
Shengtao Xu, Yijun Sun, Peng Wang, Yuchen Tan, Lei Shi, Jian Chen
Tubulin plays an important role in a variety of cellular processes including cell proliferation, cell signalling and cell morphology, which is one of the attractive targets for new antitumor drugs discovery1–3. Microtubule-targeting agents (MTAs) could inhibit the polymerisation or destabilisation of microtubules by altering its dynamics in cells4. Up to date, six major binding sites have been identified on tubulin, including colchicine binding site (CBS), pironetin binding site, laulimalide binding site, vinca binding site, maytansine binding site, and taxane binding site5,6. Taxanes and vinblastine were examples as MTAs approved by FDA and used for the treatment of solid tumours7,8. However, the application of these drugs in clinic was limited due to their multidrug resistance (MDR)9–11.
Mirvetuximab soravtansine for platinum-resistant epithelial ovarian cancer
Published in Expert Review of Anticancer Therapy, 2023
Rebecca L. Porter, Ursula A. Matulonis
One important consideration as mirvetuximab becomes part of the standard treatment of EOC is the likely development of treatment resistance. Drug resistance is known to occur with ADCs at several different points in their mechanism of acting, including: i) premature release of payload, ii) downregulation of antigen target, iii) reduced lysosomal proteolytic activity, iv) development of mutations in genes encoding tubulin composition, v) increased drug clearance from the cell and the vi) generation of antidrug antibodies that can target the various components of ADCs (reviewed in [30]. The continued incorporation of translational research within trials of mirvetuximab will be imperative to understanding the specific mechanisms of primary and acquired resistance to this ADC. In addition, while the concordance rate of FRα expression between archival tissue and fresh biopsies has been tested [56], whether FRα expression varies between primary and metastatic sites and if this influences the efficacy of mirvetuximab in HGSOC remains unknown. Moreover, distribution of FRα expression within tumors and across multiple metastatic sites, and the possible correlation with response to therapy, remains to be explored and may serve as a future predictive biomarker. In addition, the possible penetration of mirvetuximab into the central nervous system is also not known and will need to be studied. There is now increasing evidence to support CNS penetration of other ADCs and CNS responses in patients with brain metastases [26,90,91].
Design and synthesis of new trimethoxylphenyl-linked combretastatin analogues loaded on diamond nanoparticles as a panel for ameliorated solubility and antiproliferative activity
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Islam Zaki, Amal M. Y. Moustafa, Botros Y. Beshay, Reham E. Masoud, Mohammed A. I. Elbastawesy, Mohammed A. S. Abourehab, Mohamed Y. Zakaria
Microtubules are contemplated like a validated goal for the elaboration of new chemotherapeutic entities1,2. Tubulin is the building block of microtubules which are important in cellular functions, such as separation of chromosomes, motility regulation, cell signalling as well as the maintenance of cell shape3–5. Combretastatin-A4 (CA-4) and its analogues bind to the colchicine binding site of tubulin to inhibit microtubule assembly, leading to rapid vascular shutdown and apoptosis in solid tumour6–9. Unfortunately, the inferior pharmacokinetics of CA-4 due to its poor solubility confined its clinical development and emboldened the researchers to develop a more water-soluble prodrug form (Combretastatin A-4 phosphate, CA-4P)10. Nevertheless, significant adverse effects, such as neurotoxicity and cardiovascular toxicity impinged the clinical progress of CA-4P11. For this purpose, it is crucial to discover other CA-candidates with enhanced pharmacokinetic and pharmacological characteristics.