Microtubule destabilising agents: far more than just antimitotic anticancer drugs

Bates, Darcy; Eastman, Alan

doi:10.1111/bcp.13126

Cited by 250 publications

(226 citation statements)

References 96 publications

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“…Other researchers are designing cathepsin D (CDSD) inhibitors for the treatment of breast cancer . Also, there are successful anticancer drugs designed whose mechanism is explained by their ability to disrupt microtubules and so halt cell cycle and induce apoptosis . Thus, detected protein changes in AML patients’ blasts are advantageous for cancer treatment.…”

Section: Discussionmentioning

confidence: 99%

Oxidative phosphorylation inhibition induces anticancerous changes in therapy‐resistant–acute myeloid leukemia patient cells

Vitkevičienė

Janulis

Žučenka

et al. 2019

Molecular Carcinogenesis

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Treatment of acute myeloid leukemia (AML) is still a challenge because of common relapses or resistance to treatment. Therefore, the development of new therapeutic approaches is necessary. Various studies have shown that certain cancers, including some chemoresistant AML subsets, have upregulated oxidative phosphorylation. In this study, we aimed to assess treatment‐resistant AML patients’ cell modulation using oxidative phosphorylation inhibitors metformin and atovaquone alone and in various combinations with cytosine analog cytarabine and apoptosis inducer venetoclax. Metabolic activity analysis using Agilent Seahorse XF Extracellular Flux Analyzer revealed that peripheral blood mononuclear cells’ metabolic state was different among treatment‐resistant AML patients. We demonstrated that metformin decreased therapy‐resistant–AML cell oxidative phosphorylation ex vivo, cotreatment with cytarabine and venetoclax slightly increased the effect. However, treatment with atovaquone did not have a marked effect in our experiment. Cell treatment had a slight effect on cell proliferation inhibition; combination of metformin, cytarabine, and venetoclax had the strongest effect. Moreover, a slightly higher effect on cell proliferation and cell cycle regulation was demonstrated in the cells with higher initial oxidative phosphorylation rate as demonstrated by gene expression analysis using reverse transcription quantitative polymerase chain reaction (RT‐qPCR). Proteomic analysis by liquid chromatography–mass spectrometry demonstrated that chemoresistant AML cell treatment with metformin modulated metabolic pathways, while metformin combination with cytarabine and venetoclax boosted the effect. We suggest that oxidative phosphorylation inhibition is effective but not sufficient for chemoresistant AML treatment. Indeed, it causes anticancerous changes that might have an important additive role in combinatory treatment.

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Section: Discussionmentioning

confidence: 99%

Oxidative phosphorylation inhibition induces anticancerous changes in therapy‐resistant–acute myeloid leukemia patient cells

Vitkevičienė

Janulis

Žučenka

et al. 2019

Molecular Carcinogenesis

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“…Particular MTAs cause cell cycle arrest during G2/M phase, activating the apoptotic signalling pathway in tumour cells [2.3]. Additionally, MTAs have been shown to affect cells in interphase (G1) . Thus, the suppression of microtubule dynamics without the accumulation of mitotic cells also induces apoptosis of cancer cells .…”

Section: Introductionmentioning

confidence: 99%

“…Additionally, MTAs have been shown to affect cells in interphase (G1) . Thus, the suppression of microtubule dynamics without the accumulation of mitotic cells also induces apoptosis of cancer cells . Previous studies have suggested that MTAs exert their cytotoxic effects by altering mitochondrial function and cellular signalling, which is independent of the cell cycle .…”

Section: Introductionmentioning

confidence: 99%

“…Vincristine (VCR) is a vinca alkaloid from the plant Catharanthus roseus , which disrupts microtubule polymerization and induces G2/M cell cycle arrest . VCR has been used as a chemotherapeutic agent in the treatment of acute lymphoblastic leukaemia (ALL) and certain lymphomas . The combination of VCR with other chemotherapeutic agents has also been reported to improve the treatment of colorectal cancer, lung cancer and breast cancer .…”

Section: Introductionmentioning

confidence: 99%

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SIRT3, PP2A and TTP protein stability in the presence of TNF‐α on vincristine‐induced apoptosis of leukaemia cells

Wang

Chiou

Lee

et al. 2020

J Cellular Molecular Medi

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The contribution of vincristine (VCR)‐induced microtubule destabilization to evoke apoptosis in cancer cells remains to be resolved. Thus, we investigated the cytotoxic mechanism of VCR on U937 and HL‐60 human leukaemia cell lines. We discovered that VCR treatment resulted in the up‐regulation of TNF‐α expression and activation of the death receptor pathway, which evoked apoptosis of U937 cells. Moreover, VCR induced microtubule destabilization and mitotic arrest. VCR treatment down‐regulated SIRT3, and such down‐regulation caused mitochondrial ROS to initiate phosphorylation of p38 MAPK. p38 MAPK suppressed MID1‐modulated degradation of the protein phosphatase 2A (PP2A) catalytic subunit. The SIRT3‐ROS‐p38 MAPK‐PP2A axis inhibited tristetraprolin (TTP)‐controlled TNF‐α mRNA degradation, consequently, up‐regulating TNF‐α expression. Restoration of SIRT3 and TTP expression, or inhibition of the ROS‐p38 MAPK axis increased the survival of VCR‐treated cells and repressed TNF‐α up‐regulation. In contrast to suppression of the ROS‐p38 MAPK axis, overexpression of SIRT3 modestly inhibited the effect of VCR on microtubule destabilization and mitotic arrest in U937 cells. Apoptosis of HL‐60 cells, similarly, went through the same pathway. Collectively, our data indicate that the SIRT3‐ROS‐p38 MAPK‐PP2A‐TTP axis modulates TNF‐α expression, which triggers apoptosis of VCR‐treated U937 and HL‐60 cells. We also demonstrate that the apoptotic signalling is not affected by VCR‐elicited microtubule destabilization.

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“…[2] Microtubules (MTs), key protein filaments of the cytoskeleton, are constructed by the regular arrangement of globular a/b-tubulin heterodimers in ah ighly dynamic manner. [5] Further to some known naturalproduct MT stabilizing/destabilizing agents (for example, paclitaxel and vinca alkaloids), [6] tubulin-targeted antimitotic peptides have become alternative or even prime candidates for innovative drug discovery and development, mainly due to their immense advantages in avoiding the general cytotoxicity and multidrug resistance of conventional chemotherapeutic compounds. [5] Further to some known naturalproduct MT stabilizing/destabilizing agents (for example, paclitaxel and vinca alkaloids), [6] tubulin-targeted antimitotic peptides have become alternative or even prime candidates for innovative drug discovery and development, mainly due to their immense advantages in avoiding the general cytotoxicity and multidrug resistance of conventional chemotherapeutic compounds.…”

mentioning

confidence: 99%

Targeted Polypeptide–Microtubule Aggregation with Cucurbit[8]uril for Enhanced Cell Apoptosis

Zhang

Wen

et al. 2019

Angewandte Chemie

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Tunable protein assemblies not only hold adominant position in vital biological events but are also as ignificant theme in supramolecular chemistry.H erein, we demonstrated that the intertubular aggregation of microtubules (MTs) could be efficiently regulated by as ynergistic polypeptide-tubulin interaction and host-guest complexation. The benzylimidazolium-modified antimitotic peptide (BP) could recognizet he MTs and concurrently form stable inclusion complexes with avirulent cucurbit[7]uril (CB[7]) and cucurbit[8]uril (CB[8]) in different binding stoichiometries.T he self-assembling morphology of MTs was converted from fibrous to nanoparticulate aggregates via extensive BP&CB[8] cross-linkage,l eading to significant cell apoptosis and tumor ablation in vivo.T he targeted (BP&CB[8])@MT ternary assembly provides afacile supramolecular method to enhance the protein-protein interactions,which may be developed as atherapyfor degenerative diseases,such as cancer.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.

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Microtubule destabilising agents: far more than just antimitotic anticancer drugs

Cited by 250 publications

References 96 publications

Oxidative phosphorylation inhibition induces anticancerous changes in therapy‐resistant–acute myeloid leukemia patient cells

Oxidative phosphorylation inhibition induces anticancerous changes in therapy‐resistant–acute myeloid leukemia patient cells

SIRT3, PP2A and TTP protein stability in the presence of TNF‐α on vincristine‐induced apoptosis of leukaemia cells

Targeted Polypeptide–Microtubule Aggregation with Cucurbit[8]uril for Enhanced Cell Apoptosis

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