Microtubules and Cell Division: Potential Pharmacological Targets in Cancer Therapy.

Microtubules are a well-known target in cancer chemotherapy because of their critical role in cell division. Chromosome segregation during mitosis depends on the establishment of the mitotic spindle apparatus through microtubule dynamics. The disruption of microtubule dynamics through the stabilization or destabilization of microtubules results in the mitotic arrest of the cells.

MD simulation-based screening approach identified tolvaptan as a potential inhibitor of Eg5.

We discovered tolvaptan as a new Eg5 inhibitor using molecular dynamics simulation-based virtual screening. The Eg5-monastrol, Eg5-ispinesib, and Eg5-STLC complexes with "closed" L5 conformation obtained in MD simulation were used to generate a combined pharmacophore model, and this model was used during the process of virtual screening. Further, the MD simulation for 1 µs showed that the binding of tolvaptan to Eg5 was stable due to the closure of the α2/L5/α3 pocket.

Cytotoxic mechanism of tioconazole involves cell cycle arrest at mitosis through inhibition of microtubule assembly.

Unlabelled: Tioconazole is one of the drugs used to treat topical mycotic infections. It exhibited severe toxicity during systemic administration; however, the molecular mechanism behind the cytotoxic effect was not well established. We employed HeLa cells as a model to investigate the molecular mechanism of its toxicity and discovered that tioconazole inhibited HeLa cell growth through mitotic block (37%).

Sertaconazole induced toxicity in HeLa cells through mitotic arrest and inhibition of microtubule assembly.

Econazole, miconazole, and sertaconazole, the structurally related azoles with imidazole moiety, were evaluated for their cytotoxicity and their ability to bind to mammalian tubulin. Our results indicated that sertaconazole and econazole bound to goat brain tubulin with a dissociation constant of 9 and 19 μM respectively, while miconazole did not bind to goat brain tubulin. Econazole, miconazole, and sertaconazole inhibited the proliferation of HeLa cells with an IC of 28, 98, and 38 μM respectively with sertaconazole alone inducing a mitotic block in the treated cells.

Benserazide Perturbs Kif15-kinesin Binding Protein Interaction with Prolonged Metaphase and Defects in Chromosomal Congression: A Study Based on in silico Modeling and Cell Culture.

The interaction of Kif15 with kinesin binding protein (KBP) is critical for its microtubule localization, bundling of kinetochore microtubules and proper alignment of chromosomes at the metaphase plate. The Kif15-KBP structure was prepared from the crystal structure of Kif15 and nonhomologous model of KBP through docking. Benserazide was retrieved when we did a screening of the ZINC Drug Database using the pharmacophore model generated from the potential binding site on Kif15 in an effort to identify molecules for repurposing as Kif15 inhibitors.

Zerumbone, a cyclic sesquiterpene, exerts antimitotic activity in HeLa cells through tubulin binding and exhibits synergistic activity with vinblastine and paclitaxel.

Objectives: The aim of this study was to elucidate the antimitotic mechanism of zerumbone and to investigate its effect on the HeLa cells in combination with other mitotic blockers.

Materials And Methods: HeLa cells and fluorescence microscopy were used to analyse the effect of zerumbone on cancer cell lines. Cellular internalization of zerumbone was investigated using FITC-labelled zerumbone.

Indirubin, a bis-indole alkaloid binds to tubulin and exhibits antimitotic activity against HeLa cells in synergism with vinblastine.

Indirubin, a bis-indole alkaloid used in traditional Chinese medicine has shown remarkable anticancer activity against chronic myelocytic leukemia. The present work was aimed to decipher the underlying molecular mechanisms responsible for its anticancer attributes. Our findings suggest that indirubin inhibited the proliferation of HeLa cells with an IC of 40 μM and induced a mitotic block.

Biochemical and Biophysical characterization of curcumin binding to human mitotic kinesin Eg5: Insights into the inhibitory mechanism of curcumin on Eg5.

In this study we have characterized the biochemical and biophysical interactions of curcumin with the mitotic kinesin Eg5 which plays a pivotal role in the separation of centrosomes during cell division. Curcumin bound to the purified Eg5 (Eg5-437H) with a K value of 7.8μM.

Dihydropyrazole and dihydropyrrole structures based design of Kif15 inhibitors as novel therapeutic agents for cancer.

Mitotic Kinesin motors, Eg5 and Kif15, have recently emerged as good targets for cancer as they play an inevitable role during mitosis. But, most of the Eg5 inhibitors were found ineffective when the cancer cells develop resistance to them by escalating the expression of Kif15 as alternative to Eg5. Therefore, the drugs that target Kif15 became necessary to be used either as a single or in combination with Eg5 inhibitors.

Structure-Activity Relationship Study Reveals Benzazepine Derivatives of Luteolin as New Aldose Reductase Inhibitors for Diabetic Cataract.

Hyperglycaemia in diabetic patients causes diverse range of complications and the earliest among them is diabetic cataract. The role of aldose reductase, the key enzyme in polyol pathway, is well known in the genesis of cataract in chronic diabetic patients. Controlling of sorbitol flux into lens epithelial cells through aldose reductase inhibitors is an important treatment strategy.

Parmotrema tinctorum exhibits antioxidant, antiglycation and inhibitory activities against aldose reductase and carbohydrate digestive enzymes: an in vitro study.

This study evaluated the inhibitory potential of ethyl acetate extract of Parmotrema tinctorum (PTEE), an edible lichen, against aldose reductase (AR) and carbohydrate digestive enzymes such as α-glucosidase and α-amylase. It was also screened for antioxidant activities by using DPPH, ABTS, superoxide and hydroxyl radical-scavenging assays. PTEE exhibited α-glucosidase, α-amylase and AR inhibition along with significant antiglycation potential with an estimated IC50 value of 58.