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Planta Med 2022; 88(02): 163-178
DOI: 10.1055/a-1307-3997
Biological and Pharmacological Activity
Original Papers

1′-Acetoxychavicol Acetate from Alpinia galanga Represses Proliferation and Invasion, and Induces Apoptosis via HER2-signaling in Endocrine-Resistant Breast Cancer Cells

Nalinee Pradubyat
1   Institute of Translational Medicine, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom of Great Britain
2   Overcoming cancer drug resistance research unit, Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
3   Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
,
Athina Giannoudis
1   Institute of Translational Medicine, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom of Great Britain
,
Taha Elmetwali
1   Institute of Translational Medicine, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom of Great Britain
,
Panupong Mahalapbutr
4   Department of Biochemistry, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
,
Carlo Palmieri
1   Institute of Translational Medicine, Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom of Great Britain
5   Clatterbridge Cancer Centre, NHS Foundation Trust, Liverpool, United Kingdom of Great Britain
,
Chalermchai Mitrpant
3   Department of Biochemistry, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
6   Perron Institute for Neurological and Translational Science, Perth, Nedlands, Perth, Western Australia, Australia
,
Wannarasmi Ketchart 
2   Overcoming cancer drug resistance research unit, Department of Pharmacology, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
› Author AffiliationsSupported by: Capacity Building Program for New Researcher 2018 from National Research Council of Thailand (NRCT)
Supported by: Ratchadaphiseksomphot fund RA 61/093
Supported by: National Research council Thailand (Thailand Grand Challenge: Precision Medicine)
Supported by: 90th Anniversary of Chulalongkorn University Fund (Ratchadaphiseksomphot Endowment Fund) GCUGR1125611027D
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Abstract

Estrogen receptor-positive breast cancer patients have a good prognosis, but 30% of these patients will experience recurrence due to the development of resistance through various signaling pathways. This study aimed to evaluate the mode of anticancer effects of 1′-acetoxychavicol acetate, which is isolated from the rhizomes of Alpinia galanga in estrogen receptor positive (MCF7) human epidermal growth factor receptor 2-overexpressed (MCF7/HER2), and endocrine-resistant breast cancer cells (MCF7/LCC2 and MCF7/LCC9). 1′-Acetoxychavicol acetate showed antiproliferation in a concentration- and time-dependent fashion and had higher potency in human epidermal growth factor receptor 2-overexpressed cell lines. This was associated with down-regulation of human epidermal growth factor receptor 2, pERK1/2, pAKT, estrogen receptor coactivator, cyclin D1, and MYC proto-oncogene while in vivo and significant reduction in the tumor mass of 1′-acetoxychavicol acetate-treated zebrafish-engrafted breast cancer groups. The anti-invasive effects of 1′-acetoxychavicol acetate were confirmed in vitro by the matrigel invasion assay and with down-regulation of C – X-C chemokine receptor type 4, urokinase plasminogen activator, vascular endothelial growth factor, and basic fibroblast growth factor 2 genes. The down-regulation of urokinase plasminogen activator and fibroblast growth factor 2 proteins was also validated by molecular docking analysis. Moreover, 1′-acetoxychavicol acetate-treated cells exhibited lower expression levels of the anti-apoptotic Bcl-2 and Mcl-1 proteins in addition to enhanced stress-activated kinases/c-Jun N-terminal kinase 1/2 and poly-ADP ribose polymerase cleavage, indicating apoptotic cell induction by 1′-acetoxychavicol acetate. Moreover, 1′-acetoxychavicol acetate had higher potency in human epidermal growth factor receptor 2-overexpressed cell lines regarding its inhibition on human epidermal growth factor receptor 2, pAKT, pERK1/2, PSer118, and PSer167-ERα proteins. Our findings suggest 1′-acetoxychavicol acetate mediates its anti-cancer effects via human epidermal growth factor receptor 2 signaling pathway.

Key words

1′-Acetoxychavicol acetate - Alpinia galangal - anticancer - endocrine-resistant breast cancer - invasion - zebrafish - Zingiberaceae

Supporting Information

    The effect of ACA on MTT solution in cell-free system, the effect of ACA on the down-regulation of uPA, FGF2, CCND1, C-myc, CXCR4, FGF2, and NCOA3 genes expressions, real-time qPCR conditions, and primer sets and sequences for studied genes associated with this study are available as Supporting Information.

  • Supporting Information


Publication History

Received: 03 July 2020

Accepted after revision: 10 November 2020

Article published online:
14 January 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
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