Pulchelloid A, a sesquiterpene lactone from the Canadian prairie plant Gaillardia aristata inhibits mitosis in human cells

Bosco, Alessandra; Molina, Layla; Hatzopoulos, Georgios N.; Favez, Tatiana; Gönczy, Pierre; Tantapakul, Cholpisut; Maneerat, Wisanu; Yeremy, Benjamin; Williams, David E.; Andersen, Raymond J.; Golsteyn, Roy M.

doi:10.1007/s11033-021-06554-z

Cited by 6 publications

(3 citation statements)

References 28 publications

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“…Costunolide, a eudesmanolide skeleton, induced mitotic arrest, but not progression to the G2 phase, by upregulating the expression of p-Cdk1 (Tyr 15) and cyclin B1 in HA22T/VGH hepatoma cells [69]. Furthermore, pseudoguaianolide (a 5/7 bicyclic compound) SLs of 6-O-angeloylplenolin, coronopilin, pulchelloid A and hymenoratin caused G2/M-phase arrest by activating cyclin B1-Cdk1/p-Cdk1 in multiple myeloma, leukemia and colon cancer cells, respectively [69][70][71][72][73].…”

Section: Discussionmentioning

confidence: 99%

Anticancer Effects and Molecular Action of 7-α-Hydroxyfrullanolide in G2/M-Phase Arrest and Apoptosis in Triple Negative Breast Cancer Cells

et al. 2022

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Triple negative breast cancer (TNBC) is a breast cancer subtype characterized by the absence of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 expression. TNBC cells respond poorly to targeted chemotherapies currently in use and the mortality rate of TNBC remains high. Therefore, it is necessary to identify new chemotherapeutic agents for TNBC. In this study, the anti-cancer effects of 7-α-hydroxyfrullanolide (7HF), derived from Grangea maderaspatana, on MCF-7, MDA-MB-231 and MDA-MB-468 breast cancer cells were assessed using MTT assay. The mode of action of 7HF in TNBC cells treated with 6, 12 and 24 µM of 7HF was determined by flow cytometry and propidium iodide (PI) staining for cell cycle analysis and annexin V/fluorescein isothiocyanate + PI staining for detecting apoptosis. The molecular mechanism of action of 7HF in TNBC cells was investigated by evaluating protein expression using proteomic techniques and western blotting. Subsequently, 7HF exhibited the strongest anti-TNBC activity toward MDA-MB-468 cells and a concomitantly weak toxicity toward normal breast cells. The molecular mechanism of action of low-dose 7HF in TNBC cells primarily involved G2/M-phase arrest through upregulation of the expression of Bub3, cyclin B1, phosphorylated Cdk1 (Tyr 15) and p53-independent p21. Contrastingly, the upregulation of PP2A-A subunit expression may have modulated the suppression of various cell survival proteins such as p-Akt (Ser 473), FoxO3a and β-catenin. The concurrent apoptotic effect of 7HF on the treated cells was mediated via both intrinsic and extrinsic modes through the upregulation of Bax and active cleaved caspase-7–9 expression and downregulation of Bcl-2 and full-length caspase-7–9 expression. Notably, the proteomic approach revealed the upregulation of the expression of pivotal protein clusters associated with G1/S-phase arrest, G2/M-phase transition and apoptosis. Thus, 7HF exhibits promising anti-TNBC activity and at a low dose, it modulates signal transduction associated with G2/M-phase arrest and apoptosis.

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Section: Discussionmentioning

confidence: 99%

Anticancer Effects and Molecular Action of 7-α-Hydroxyfrullanolide in G2/M-Phase Arrest and Apoptosis in Triple Negative Breast Cancer Cells

et al. 2022

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“…6-O-angeloylplenolin, coronopilin, pulchelloid A, and hymenoratin, 5/7-bicyclic pseudoguaianolide SLs also induce high p-Cdk1 and/or Cdk1 and cyclin B1 expression in certain cancer cell types. ( Bosco et al, 2021 ; Cotugno et al, 2012 ; Liu et al, 2011b ; Molina et al, 2021 ). However, the role of Bub3 and its partners in the modulation of MCC after SL treatment is not clear ( Steinbruck, Pereira & Efferth, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, sesquiterpene lactones (SLs) exhibit anti-MT activity by regulating MT dynamics, and the proposed mechanism of action involves a target protein associated with an arresting of G2/M or M-phases in many cancer cells ( Bosco & Golsteyn, 2017 ). SLs, including parthenolide, costunolide, artesunate, santamarine, calein C, 6-O-angeloylplenolin, coronopilin, pulchelloid A, and hymenoratin, have shown promising anti-MT activity by inducing G2/M or M phase arrest in tested cancer cell lines ( Bosco & Golsteyn, 2017 ; Bosco et al, 2021 ; Caldas et al, 2018 ; Cotugno et al, 2012 ; Dumontet & Jordan, 2010 ; Liu et al, 2011a ; Liu et al, 2011b ; Manchado, Guillamot & Malumbres, 2012 ; Molina et al, 2021 ; Steinbruck, Pereira & Efferth, 2010 ; Whipple et al, 2013 ). The anti-MT activity of SLs has been studied extensively and their mechanism of action has been reported; however, the specific overcome to target MT-binding is not sufficient ( Bosco & Golsteyn, 2017 ; Gallagher & Brian, 2007 ).Therefore, studies for the development of new MT-binding agents that can be used for the development of TNBC-targeted drugs are in progress.…”

Section: Introductionmentioning

confidence: 99%

Anticancer mechanism of 7-α-hydroxyfrullanolide on microtubules and computational prediction of its target binding in triple-negative breast cancer cells

Chimplee

Smythe

Tipmanee

et al. 2022

PeerJ

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Background Triple-negative breast cancer (TNBC) responds poorly to the available drugs; thus, the mortality rate associated with TNBC remains high. 7-α-Hydroxyfrullanolide (7HF) possesses anticancer properties and arrests cells in the G2/M-phase via modulation of several proteins involved in the G2/M-phase transition, as well as the mitotic checkpoint in MDA-MB-468 (TNBC) cells. Microtubules (MTs) dynamically regulate cell division in the G2/M phase and are related to cancer cell stress response. However, antimitotic drug cytotoxicity to multiple cancer resistance developed in response to drugs are obstacles faced to date. Here, the activity and mechanism via which 7HF controls MTs dynamics was investigated in MDA-MB-468 cells. Methods 7HF uptake by MDA-MB-468 cells was assessed using spectrophotometry. The drug-like properties of 7HF were predicted using the Swiss-absorption, distribution, metabolism, and excretion (ADME) webtool. Then, the effect of 7HF treatment (6, 12, and 24 µM) on the dynamic arrangement of MTs was assessed for 1, 12, and 24 h using indirect immunofluorescence. Polymerization of α- and β-tubulin was assessed using different 7HF concentrations in a cell-free system for 1 h. Cell proliferation assay with bromodeoxyuridine plus propidium iodide staining and flow cytometry was performed at different 7HF concentrations and time points. The mechanism of action was assessed by detecting the expression of proteins, including Bub3, cyclin B1, p-Cdk1 (Tyr15), Rb, p-Rb (Ser780), Chk1, p-Chk1 (Ser345), Chk2, p-Chk2 (Ser516), and p-H2AX (Ser139), using western blotting. Molecular docking was used to predict the molecular interactions between 7HF and tubulins in MTs. Results We observed that 7HF was able to enter the MDA-MB-468 cells. The ADME webtool analysis predicted that it possesses the high passive permeation and gastrointestinal absorption properties of drugs. Various concentrations of 7HF disrupted the dynamic arrangement of spindle MTs by causing radial spindle array shrinkage and expansion of fibrous spindle density and radial array lengths in a time-dependent manner. 7HF reduced polymerization of α-, β-tubulin in dose-dependent manner. 7HF also triggered DNA damage response by inducing G2/M and G1 phase arrests in a concentration and time-dependent manner, which occurred due to the upregulation of Bub3, Chk1, p-Chk1 (Ser345), p-Cdk1 (Tyr15), and cyclin B1. According to molecular docking analysis, 7HF preferred to bind to β-tubulin over α-tubulin. The lactone, ketone, and hydroxyl groups of 7HF supported the 7HF-tubulin interactions. Hydrogen bonding with a hydrocarbon ring and salt bridge attractive forces were responsible for the binding versatility of 7HF. Conclusions This is the first study to investigate the molecular mechanism, MTs interacting sites, and the internalization and drug-like properties of 7HF in TNBC cells. The findings will be useful for developing 7HF-based treatment for patients with TNBC.

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An anti-mitotic compound, (+)-6-tuliposide A, isolated from the Canadian glacier lily, Erythronium grandiflorum

Healy Knibb,

Yeremy,

Williams

et al. 2024

Fitoterapia

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Pulchelloid A, a sesquiterpene lactone from the Canadian prairie plant Gaillardia aristata inhibits mitosis in human cells

Cited by 6 publications

References 28 publications

Anticancer Effects and Molecular Action of 7-α-Hydroxyfrullanolide in G2/M-Phase Arrest and Apoptosis in Triple Negative Breast Cancer Cells

Anticancer Effects and Molecular Action of 7-α-Hydroxyfrullanolide in G2/M-Phase Arrest and Apoptosis in Triple Negative Breast Cancer Cells

Anticancer mechanism of 7-α-hydroxyfrullanolide on microtubules and computational prediction of its target binding in triple-negative breast cancer cells

An anti-mitotic compound, (+)-6-tuliposide A, isolated from the Canadian glacier lily, Erythronium grandiflorum

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