TH588 and Low-Dose Nocodazole Impair Chromosome Congression by Suppressing Microtubule Turnover within the Mitotic Spindle

Rajendraprasad, Girish; Eibes, Susana; Boldú, Clàudia Guasch; Barišić, Marin

doi:10.3390/cancers13235995

Cited by 11 publications

(10 citation statements)

References 61 publications

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“…Given that GSK923295 locks CENP-E on MTs in a rigor-like bound state, we hypothesized that GSK923295-treated cells, in addition to dynein-driven KT-stripping, accumulate CENP-E at the poles via MT poleward flux 40 . To address that, we used low-dose nocodazole to effectively reduce MT-flux 41 in metaphasearrested cells (MT-flux: 0.18 ± 0.09 µm/min in 20 nM nocodazole, compared to 0.62 ± 0.17 µm/min in controls) (Extended Data Fig. 5c).…”

Section: To Confirm the Effect Of Cenp-e Inhibitors On Cenp-e Localiz...mentioning

confidence: 99%

CENP-E activation by Aurora A and B controls kinetochore fibrous corona disassembly

Eibes

Rajendraprasad

Guasch-Boldu

et al. 2023

Preprint

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Accurate chromosome segregation in mitosis depends on multiprotein structures called kinetochores (KTs) that are built on the centromeric region of sister chromatids and serve to capture mitotic spindle microtubules (MTs). In early mitosis, unattached KTs expand a crescent-shaped structure called fibrous corona whose function is to facilitate initial KT-MT attachments and chromosome transport by MTs. Subsequently, the fibrous corona must be timely disassembled to prevent segregation errors. Although recent studies provided new insights on the molecular content and mechanism of fibrous corona assembly, it remains unknown what triggers the disassembly of the outermost and dynamic layer of the KT. Here, we show that Aurora A and B kinases (AurA and AurB) phosphorylate CENP-E to release it from an autoinhibited state. At KTs, AurB phosphorylates CENP-E to prevent its premature removal together with other corona proteins by dynein. At the spindle poles, AurA phosphorylates CENP-E to promote chromosome congression and prevent accumulation of corona proteins at the centrosomes, allowing for their intracellular redistribution. Thus, the AurA/B-CENP-E axis establishes the long-sought mechanism of fibrous corona disassembly that is essential for accurate chromosome segregation.

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Section: To Confirm the Effect Of Cenp-e Inhibitors On Cenp-e Localiz...mentioning

confidence: 99%

CENP-E activation by Aurora A and B controls kinetochore fibrous corona disassembly

Eibes

Rajendraprasad

Guasch-Boldu

et al. 2023

Preprint

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“…Several derivatives of nocodazole have been developed and studied for their anticancer potential. [72,73]…”

Section: Centauriedinmentioning

confidence: 99%

Natural therapeutics for cancer treatment: success, challenges, and prospect

Dubey,

Rath,

Meher

et al. 2023

J Bio-X Res

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Cancer is a terrifying disease that has become one of the world’s most challenging health concerns, necessitating a proactive approach to its treatment. Nature is a rich source of new chemical entities and a promising avenue for cancer research. Because of their different modes of action on target events in many ways, nature-derived chemicals are considered good possibilities for anticancer drug development. The current review article highlights recent breakthroughs in cancer therapeutics, including natural therapeutic molecules and their mechanisms of action against cancer treatment, as well as their limits, challenges, and prospect. For the review, article data have been collected from previously studied and published research reports, clinical evaluations, case studies, and clinical statistical data generated by scientific research organizations of repute. The chemical structures have been drawn using computational software (chemsketch). The development of promising candidates that can prevent or reduce the proliferation of cancer cells without causing adverse effects from these therapeutics is now underway. Further, nature-derived products are a game-changer because they are simple, safer, environmentally friendly, low-cost, quick, and less toxic than traditional treatment techniques. However, many bioactive chemicals and their analogs have been discovered as possible anticancer treatment options. In the review, the potent therapeutics phytochemicals derived from nature with their tremendous anticancer effects with limitations and prospects have been studied and analyzed based on previously published articles and reports.

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“…This event results in mitotic arrest, leading to cell death, or triggers cell division with uncongressed chromosomes. The failure of kinetochore‐microtubule on the uncongressed chromosomes to reach the cell equator causes a substantial delay in cell division, eventually causing cell death (Rajendraprasad et al, 2021).…”

Section: Commentarymentioning

confidence: 99%

Benzimidazole‐carbamate anthelmintics: Perspective candidates for the anticancer drug development

Prasher

Sharma

2022

Drug Development Research

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Cellular oncogenesis involves a complex interplay between the several synchronized, interdependent pathways that collectively determine the pathogenesis and pathophysiology of cancer. Limited therapeutic success with the existing anticancer drugs drew huge interest in the design and development of new pharmacophores with improved clinical efficacy, however despite huge investments in anticancer RD; the average number of Food and Drug Administration‐approved anticancer drugs declined since the 1990s. The contemporary anticancer medications possess high attrition rates, bear substantial costs, and experience low efficacy owing to the drug resistance expressed by the aggressive tumors. Mainly, the translation of novel candidate anticancer drugs into clinical practice, their commercialization, and transformation from the bench to bedside require a long timeframe of 10–15 years and capital worth millions of dollars. The repurposing strategy substantially accelerated the anticancer drug development regime as the approved drugs with tested safety and efficacy ensure a minimal risk of failure, and nominal R&D expenses as anticipated for the newly identified candidate drugs yet to enter the clinical trials. In addition, the repurposed drugs ensure a rapid clinical translation due to a validated clinical profile and their ability to target the identified hallmarks and hitherto unknown vulnerabilities of cancer. The flagship project “Repurposing Drugs in Oncology” (ReDO) identified 268 “hard repurposing” noncancer medications as candidate drugs with a promising anticancer profile (https://www.anticancerfund.org/en/redo-db). However, the generic profile of 84% of repurposed drugs in ReDO data set discourages the commercial sponsors from funding the repurposing trials, especially the Phase III efficacy trials that require significant capital.

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TH588 and Low-Dose Nocodazole Impair Chromosome Congression by Suppressing Microtubule Turnover within the Mitotic Spindle

Cited by 11 publications

References 61 publications

CENP-E activation by Aurora A and B controls kinetochore fibrous corona disassembly

CENP-E activation by Aurora A and B controls kinetochore fibrous corona disassembly

Natural therapeutics for cancer treatment: success, challenges, and prospect

Benzimidazole‐carbamate anthelmintics: Perspective candidates for the anticancer drug development

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