Targeting mitotic pathways for endocrine-related cancer therapeutics

Agarwal, Shivangi; Varma, Dileep

doi:10.1530/erc-17-0080

Cited by 7 publications

(7 citation statements)

References 208 publications

(100 reference statements)

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“…Microtubules, the structural components of the cystoskeleton, are comprised of α ‐ and β ‐tubulins, whose formation is critical for cellular structure and cell division (i.e., mitosis). [ 50 ] Anticancer drugs that target tubulins can work by either preventing tubulin formation or by stabilizing microtubules when they are not required. The tubulin dimer contains 20 cysteine residues of which 12 are in α ‐tubulin and eight are in β ‐tubulin.…”

Section: Covalent Protein Modifications By Natural Products and Theirmentioning

confidence: 99%

Covalent Modification of Proteins by Plant‐Derived Natural Products: Proteomic Approaches and Biological Impacts

et al. 2020

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Plant‐derived natural products (NPs) with electrophilic functional groups engage various subsets of the proteome via covalent modification of nucleophilic cysteine residues. This electrophile‐nucleophile interaction can change protein conformation, alter protein function, and modulate their biological action. The biological significance of these covalent protein modifications in health and disease is increasingly recognized. One way to understand covalent NP‐protein interactions is to utilize traditional proteomics and modern mass spectrometry (MS)‐based proteomic strategies. These strategies have proven effective in uncovering specific NP protein targets and are critical first steps that allow for a much deeper understanding of the ability of NPs to modulate cellular processes. Here, plant‐derived NPs that covalently modify proteins are reviewed, the biological significance of these covalent modifications, and the different proteomic strategies that have been employed to study these NP‐protein interactions.

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Section: Covalent Protein Modifications By Natural Products and Theirmentioning

confidence: 99%

Covalent Modification of Proteins by Plant‐Derived Natural Products: Proteomic Approaches and Biological Impacts

et al. 2020

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“…Blockade of mitotic progression is an effective approach to induce mitotic catastrophe to kill cancer cells [10][11][12] . The inhibition of several steps during mitosis, such as mitotic checkpoint, microtubule polymerization, chromatid segregation, cytokinesis and the exit from mitosis, have been considered to develop anti-mitotic drugs [11] .…”

Section: Implications Of All the Available Evidencementioning

confidence: 99%

“…Blocking mitotic exit has been regarded as a promising strategy to induce tumor cell death [10][11][12] . Owing to the pivotal role of Cdc20 in both mitotic exit and carcinogenesis, the development of small molecule inhibitors targeting Cdc20 to suppress Cdc20-APC/C activity has attracted substantial attention in the field of cancer therapy.…”

Section: Protac a Novel Strategy To Eliminate Oncogenic Proteins Shmentioning

confidence: 99%

A novel strategy to block mitotic progression for targeted therapy

Chi

Zhou

et al. 2019

eBioMedicine

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Background: Blockade of mitotic progression is an ideal approach to induce mitotic catastrophe that suppresses cancer cell expansion. Cdc20 is a critical mitotic factor governing anaphase initiation and the exit from mitosis through recruiting substrates to APC/C for degradation. Results from recent TCGA (The Cancer Genome Atlas) and pathological studies have demonstrated a pivotal oncogenic role for Cdc20-APC/C in tumor progression as well as drug resistance. Thus, deprivation of the mitotic role for Cdc20-APC/C by either inhibition of Cdc20-APC/C activity or elimination of Cdc20 protein via induced protein degradation emerges as an effective therapeutic strategy to control cancer. Methods: We designed a proteolysis targeting chimera, called CP5V, which comprises a Cdc20 ligand and VHL binding moiety bridged by a PEG5 linker that induces Cdc20 degradation. We characterized the effect of CP5V in destroying Cdc20, arresting mitosis, and inhibiting tumor progression by measuring protein degradation, 3D structure dynamics, cell cycle control, tumor cell killing and tumor inhibition using human breast cancer xenograft mouse model. Findings: Results from our study demonstrate that CP5V can specifically degrade Cdc20 by linking Cdc20 to the VHL/VBC complex for ubiquitination followed by proteasomal degradation. Induced degradation of Cdc20 by CP5V leads to significant inhibition of breast cancer cell proliferation and resensitization of Taxol-resistant cell lines. Results based on a human breast cancer xenograft mouse model show a significant role for CP5V in suppressing breast tumor progression. Interpretation: CP5V-mediated degradation of Cdc20 could be an effective therapeutic strategy for antimitotic therapy.

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“…Use of classical microtubule poisons has still been widely and often successfully used to combat a variety of cancers, but their non-selective interference in other crucial physiologic processes necessitate the identification of novel druggable components specific to the cell cycle/division pathway. [3] Counting mitotic figures (MFs) are used in the World Health Organization grading of brain tumors. [4] To study cells proliferation and differentiation are used research of complex combinations of multicomponent schemes.…”

Section: Introductionmentioning

confidence: 99%