Pradubyat, Nalinee
(2020)
The effect of 1’ acetoxychavicol acetate on cell proliferation, metastasis, and angiogenesis in human endocrine-resistant breast cancer cells.
PhD thesis, University of Liverpool.
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Abstract
Background: Oestrogen receptor (ER)-positive breast cancer patients have a good prognosis, but 30% of these developed resistance through hyperactivation of PI3K/AKT, ERK1/2, and NFκB, which interconnected with ER signalling. In this study, the effects of 1’ acetoxychavicol acetate (ACA), a plant-metabolite acetate ester compound with an NF-kB inhibitory activity, were investigated in a panel of endocrine-resistant breast cancer cells. Methods: Plant material was purified by chromatographic methods and followed by structural identification using nuclear magnetic resonance and mass spectroscopy. In vitro and in vivo antiproliferative effects of ACA were studied in MCF7/LCC2 and MCF7/LCC9 endocrine-resistant cells using the MTT assay and the zebrafish xenograft model respectively. Anti-invasion of ACA was performed by the matrigel invasion assay, while its mechanism of action was elucidated through molecular docking simulation, real-time PCR, and western blotting. Western blot analysis was also used to investigate its effect on apoptosis. Results: ACA inhibited the proliferation of MCF7, MCF7/LCC2, and MCF7/LCC9 cells at a concentration- and time-dependent fashion. This was associated with down-regulation of HER2 receptor, estrogen receptor coactivator (NCOA3), pERK1/2, pAKT, and proliferative markers (CCND1, C-myc). While in vivo, significant reduction in the tumour mass of ACA-treated zebrafish engrafted MCF7/LCC9 groups was observed compared to the control treatment. Furthermore, the anti-invasive effects of ACA were confirmed in vitro by the matrigel invasion assay and with reduction in the expression levels of CXCR4, uPA and proangiogenic factors, VEGF and FGF2 in ACA-treated cells compared to untreated control. The repressed expression of uPA and FGF2 was also validated by molecular docking analysis. Moreover, ACA-treated cells exhibited lower expression levels of the anti-apoptotic BCL2 and MCL1 proteins in addition to increase JNK/SAPK expression and enhance PARP cleavage, indicating apoptotic cell induction by ACA. Conclusion: This research suggested that the ACA inhibited cell proliferation and induce apoptosis in breast cancer cells through HER2/MAPK/ERK1/2 and PI3K/AKT pathways. In addition, the anti-angiogenic and anti-invasive activity of ACA was through the downregulation of VEGF, FGF2, uPA, and CXCR4.
| Item Type: | Thesis (PhD) |
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| Uncontrolled Keywords: | 1’ Acetoxychavicol acetate; endocrine-resistant breast cancer; proliferation, invasion, apoptosis, zebrafish |
| Divisions: | Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences > School of Medicine |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 07 Dec 2020 16:11 |
| Last Modified: | 18 Jan 2023 23:30 |
| DOI: | 10.17638/03103352 |
| Supervisors: |
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| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3103352 |
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