Chemotherapy in pregnancy
Hung N. Winn, Frank A. Chervenak, Roberto Romero in 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).
Phytotherapeutic Potential For the Treatment of Alzheimer’s Disease
Atanu Bhattacharjee, Akula Ramakrishna, Magisetty Obulesu in Phytomedicine and Alzheimer’s Disease, 2020
β-APP is encoded by a gene present on the 21q chromosome arm. Due to gene mutations, structural rearrangements, or even deletions, an increase in the number of genetically altered mRNAs encoding βAPP are produced in some specific tissues or cells. The abnormal βAPP polypeptides are formed which, when presented for proteolytic processing, are cleaved, mostly at residue 687 of the βAPP, thus preventing the formation of AβP. This is what normally happens but, sometimes, overuse of alternate proteolytic pathways leads to the production of large amounts of AβP contained in C-terminal fragments. This AβP is then accumulated in several brain regions, forming the amyloid plaques. The microglia and astrocytes at the site of these abnormal plaques are activated and some AβP-associated proteins are also attracted to accumulate in said plaques. These plaques cause degeneration of the in-contact neurons of cortical and subcortical regions of the brain. Many neurons are affected but studies have associated the clinical signs and symptoms of AD with the loss of cholinergic neurons in the cerebral cortex and hippocampus. The degenerative changes in the neurons start by the formation of the neurofibrillary tangles, that are formed by the hyperphosphorylation of the tau proteins that are normally involved in the formation of microtubules inside neurons. As a result, microtubule formation is disturbed, leading to impaired communication and loss of neuronic function. All these changes occur over several years, to ultimately result in the clinical manifestation of AD (Selkoe, 1991).
Manipulating the Intracellular Trafficking of Nucleic Acids
Kenneth L. Brigham in Gene Therapy for Diseases of the Lung, 2020
Microtubules and actin filaments are believed to maintain intracellular distribution of organelles and to facilitate trafficking between organelles (for review see Ref. 62). Microtubules can be viewed as tracks for the movement of organelles and their cargo, where movement is driven by protein motors fueled by ATP (63,64). Microtubules radiate out from the microtubule organizing center (MTOC) into the peripheral regions of the cytoplasm, thus forming an extensive network of fibers throughout the cell (Fig. 2). The fast-growing ends (plus ends) of the microtubule are located at the cell periphery while the slow-growing ends (minus ends) are found at the MTOC. Differential distribution of organelles and transport vesicles are observed in the microtubule network with endosomes found near the plus ends at the cell periphery, whereas Golgi, late endosomes, and lysosomes are clustered near the minus ends near the nucleus.
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
Tubulin is a globular protein mainly in kinetoplastid protozoa, which consisting of the alpha (α), beta (β), gamma (γ), delta (δ), epsilon (ε), and zeta (ζ) tubulin families1. Meanwhile, α-tubulin and β-tubulin form a heterodimer, which in turn forms long-chain fibres2. Then 13 parallel long-chain fibres are interlinked to form a hollow tube, which is called microtubule1,3. Microtubules are key components of the cytoskeleton and are involved in a variety of cellular functions such as cell signalling, intracellular transport, secretion, formation and maintenance of cell shape, motor regulation, and cell division4,5. The heterodimers are bound to each other by non-covalent bonds, so the heterodimers can be continuously bound and separated. And the two heterodimers at the two ends of the microtubule can be continuously added and released so that the microtubule can be continuously polymerised and discrete, so there is a dynamic balance state in this process6. When the microtubule is in dynamic balance, one end of the microtubule will release a set of heterodimers, and the other end will bind a set of heterodimers, which can not only keep the length of the microtubule constant but also enable the microtubule to move from one side to the other, thus completing the necessary physiological function.
Investigation of the toxicological and inhibitory effects of some benzimidazole agents on acetylcholinesterase and butyrylcholinesterase enzymes
Published in Archives of Physiology and Biochemistry, 2021
Benzimidazoles have been used for the last 30 years to control cereal-borne diseases. Some studies have also been reported that benzimidazoles have been used in controlling mycotoxin contamination caused by fungi (Chen et al.2007). GST enzymes are a multifunctional enzyme group that functions in cellular detoxification, and it catalyzes nonpolar compounds that contain electrophilic conjugates containing carbon, nitrogen, and sulfur atoms (Lacey 1990). The anthelmintic activities of the benzimidazoles are fully related to the active site of the coil in the tubulin in helminths of mammals. For this reason, benzimidazoles are selectively toxic to helminths which are parasites. Benzimidazoles drugs inhibit polymerization by affecting the metabolic energy, structure and integrity of the microtubule group of b-tubulinin which is found in parasite cells (Köhler 2001). Microtubules are cellular organs that play a vital role in cellular functions such as transport and mitosis. The degradation in the cell’s cytoplasm leads to impaired glucose uptake. As a result, the amount of stored glycogen is reduced. Thus, organelle deaths may result from the effects of drugs on cellular activities (Türkan et al.2018c, Türkan et al.2018d, Türkan et al.2019c).