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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
› Further Information
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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.

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  • References

  • 1 Osborne CK. Tamoxifen in the treatment of breast cancer. N Engl J Med 1998; 339: 1609-1618
    CrossrefPubMedGoogle Scholar
  • 2 García-Becerra R, Santos N, Díaz L, Camacho J. Mechanisms of resistance to endocrine therapy in breast cancer: focus on signaling pathways, miRNAs and genetically based resistance. Int J Mol Sci 2013; 14: 108-145
    CrossrefPubMedGoogle Scholar
  • 3 Musgrove EA, Sutherland RL. Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer 2009; 9: 631
    CrossrefPubMedGoogle Scholar
  • 4 Faridi J, Wang L, Endemann G, Roth RA. Expression of constitutively active Akt-3 in MCF-7 breast cancer cells reverses the estrogen and tamoxifen responsivity of these cells in vivo. Clin Cancer Res 2003; 9: 2933-2939
    PubMedGoogle Scholar
  • 5 DeGraffenried LA, Friedrichs WE, Fulcher L, Fernandes G, Silva JM, Peralba JM, Hilalgo M. Eicosapentaenoic acid restores tamoxifen sensitivity in breast cancer cells with high Akt activity. Ann Oncol 2003; 14: 1051-1056
    CrossrefPubMedGoogle Scholar
  • 6 Miller TW, Balko JM, Arteaga CL. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol 2011; 29: 445-446
    CrossrefPubMedGoogle Scholar
  • 7 Amin A, Gali-Muhtasib H, Ocker M, Schneider-Stock R. Overview of major classes of plant-derived anticancer drugs. Int J Biomed Sci 2009; 5: 1-11
    CrossrefPubMedGoogle Scholar
  • 8 Itokawa H, Morita H, Sumitomo T, Totsuka N, Takeya K. Antitumour principles from Alpinia galanga. Planta Med 1987; 53: 32-33
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Kobayashi Y, Nakae D, Akai H, Kishida H, Okajima E, Kitayama W, Denda A, Tsujiuchi T, Murakami A, Koshimizu K, Ohigashi H, Konishi Y. Prevention by 1′-acetoxychavicol acetate of the induction but not growth of putative preneoplastic, glutathione S-transferase placental form-positive, focal lesions in the livers of rats fed a choline-deficient, L-amino acid-defined diet. Carcinogenesis 1998; 19: 1809-1814
    CrossrefPubMedGoogle Scholar
  • 10 Kawabata K, Tanaka T, Yamamoto T, Ushida J, Hara A, Murakami A, Koshimizu K, Ohigashi H, Stoner GD, Mori H. Suppression of N-Nitrosomethylbenzylamine-induced rat esophageal tumorigenesis by dietary feeding of 1′-acetoxychavicol acetate. Jpn J Cancer Res 2000; 91: 148-155
    CrossrefPubMedGoogle Scholar
  • 11 Campbell CT, Prince M, Landry GM, Kha V, Kleiner HE. Pro-apoptotic effects of 1′-acetoxychavicol acetate in human breast carcinoma cells. Toxicol Lett 2007; 173: 151-160
    CrossrefPubMedGoogle Scholar
  • 12 Sagawa M, Tabayashi T, Kimura Y, Tomikawa T, Nemoto-Anan T, Watanabe R, Tokuhira M, Ri M, Hashimoto Y, Iida S, Kizaki M. TM-233, a novel analog of 1′-acetoxychavicol acetate, induces cell death in myeloma cells by inhibiting both JAK/STAT and proteasome activities. Cancer Sci 2015; 106: 438-446
    CrossrefPubMedGoogle Scholar
  • 13 Guttridge DC, Albanese C, Reuther JY, Pestell RG, Baldwin AS. NF-κB controls cell growth and differentiation through transcriptional regulation of cyclin D1. Mol Cell Biol 1999; 19: 5785-5799
    CrossrefPubMedGoogle Scholar
  • 14 Hinz M, Krappmann D, Eichten A, Heder A, Scheidereit C, Strauss M. NF-κB function in growth control: regulation of cyclin D1 expression and G0/G1-to-S-phase transition. Mol Cell Biol 1999; 19: 2690-2698
    CrossrefPubMedGoogle Scholar
  • 15 Duyao MP, Buckler AJ, Sonenshein GE. Interaction of an NF-kappa B-like factor with a site upstream of the c-myc promoter. Proc Natl Acad Sci U S A 1990; 87: 4727-4731
    CrossrefPubMedGoogle Scholar
  • 16 Helbig G, Christopherson KW, Bhat-Nakshatri P, Kumar S, Kishimoto H, Miller KD, Broxmeyer HE, Nakshatri H. NF-kappaB promotes breast cancer cell migration and metastasis by inducing the expression of the chemokine receptor CXCR4. J Biol Chem 2003; 278: 21631-21638
    CrossrefPubMedGoogle Scholar
  • 17 Moreau M, Mourah S, Dosquet C. β-Catenin and NF-κB cooperate to regulate the uPA/uPAR system in cancer cells. Int J Cancer 2011; 128: 1280-1292
    CrossrefPubMedGoogle Scholar
  • 18 Xing RH, Rabbani SA. Transcriptional regulation of urokinase (uPA) gene expression in breast cancer cells: role of DNA methylation. Int J Cancer 1999; 81: 443-450
    CrossrefPubMedGoogle Scholar
  • 19 Chilov D, Kukk E, Taira S, Jeltsch M, Kaukonen J, Palotie A, Joukov V, Alitalo K. Genomic organization of human and mouse genes for vascular endothelial growth factor C. J Biol Chem 1997; 272: 25176-25183
    CrossrefPubMedGoogle Scholar
  • 20 Kim HR, Heo YM, Jeong KI, Kim YM, Jang HL, Lee KY, Yeo CY, Kim SH, Lee HK, Kim SR. FGF-2 inhibits TNF-α mediated apoptosis through up-regulation of Bcl2-A1 and Bcl-xL in ATDC5 cells. BMB Rep 2012; 45: 287-292
    CrossrefPubMedGoogle Scholar
  • 21 Aukes K, Forsman C, Brady NJ, Astleford K, Blixt N, Sachdev D, Jensen ED, Mansky KC, Schwertfeger KL. Breast cancer cell-derived fibroblast growth factors enhance osteoclast activity and contribute to the formation of metastatic lesions. PLoS One 2017; 12: e0185736
    CrossrefPubMedGoogle Scholar
  • 22 Lei H, Deng CX. Fibroblast growth factor receptor 2 signaling in breast cancer. Int J Biol Sci 2017; 13: 1163
    CrossrefPubMedGoogle Scholar
  • 23 Pang X, Zhang L, Lai L, Chen J, Wu Y, Yi Z, Zhang J, Qu W, Aggarwal BB, Liu M. 1′-acetoxychavicol acetate suppresses angiogenesis-mediated human prostate tumor growth by targeting VEGF-mediated Src-FAK-Rho GTPase-signaling pathway. Carcinogenesis 2011; 32: 904-912
    CrossrefPubMedGoogle Scholar
  • 24 Wang J, Zhang L, Chen G, Zhang J, Li Z, Lu W, Liu M, Pang X. Small molecule 1′-acetoxychavicol acetate suppresses breast tumor metastasis by regulating the SHP-1/STAT3/MMPs signaling pathway. Breast Cancer Res Treat 2014; 148: 279-289
    CrossrefPubMedGoogle Scholar
  • 25 Azuma H, Aizawa Y, Higashitani N, Tsumori T, Kojima-Yuasa A, Matsui-Yuasa I, Nagasaki T. Biological activity of water-soluble inclusion complexes of 1′-acetoxychavicol acetate with cyclodextrins. Bioorg Med Chem 2011; 19: 3855-3863
    CrossrefPubMedGoogle Scholar
  • 26 Murakami A, Toyota K, Ohura S, Koshimizu K, Ohigashi H. Structure-activity relationships of (1′ S)-1′-acetoxychavicol acetate, a major constituent of a Southeast Asian condiment plant Languas galanga, on the inhibition of tumor-promoter-induced Epstein-Barr virus activation. J Agric Food Chem 2000; 48: 1518-1523
    CrossrefPubMedGoogle Scholar
  • 27 Lin LY, Shen KH, Yeh XY, Huang BY, Wang HE, Chen KC, Peng RY. Integrated process for production of galangal acetate, the “wasabi-like” spicy compound, and analysis of essential oils of Rhizoma Alpinia officinarum (Hance) Farw. J Food Sci 2016; 81: H1565-H1575
    CrossrefPubMedGoogle Scholar
  • 28 Kern FG, McLeskey SW, Zhang L, Kurebayashi J, Liu Y, Ding IYF, Kharbanda S, Chen D, Miller D, Cullen K. Transfected MCF-7 cells as a model for breast cancer progression. Breast Canc Res Treat 1994; 31: 153-165
    CrossrefPubMedGoogle Scholar
  • 29 De Laurentiis M, Arpino G, Massarelli E, Ruggiero A, Carlomagno C, Ciardiello F, Tortora G, DʼAgostino D, Caputo F, Cancello G. A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer. Clin Cancer Res 2005; 11: 4741-4748
    CrossrefPubMedGoogle Scholar
  • 30 Viedma-Rodríguez R, Baiza-Gutman L, Salamanca-Gómez F, Diaz-Zaragoza M, Martínez-Hernández G, Esparza-Garrido RR, Velázquez-Flores MA, Arenas-Aranda D. Mechanisms associated with resistance to tamoxifen in estrogen receptor-positive breast cancer (review). Oncol Rep 2014; 32: 3-15
    CrossrefPubMedGoogle Scholar
  • 31 Chen B, Liu J, Ho TT, Ding X, Mo YY. ERK-mediated NF-κB activation through ASIC1 in response to acidosis. Oncogenesis 2016; 5: e279
    CrossrefPubMedGoogle Scholar
  • 32 Bai D, Ueno L, Vogt PK. Akt-mediated regulation of NFκB and the essentialness of NFκB for the oncogenicity of PI3K and Akt. Int J Cancer 2009; 125: 2863-2870
    CrossrefPubMedGoogle Scholar
  • 33 Jiang J, Sarwar N, Peston D, Kulinskaya E, Shousha S, Coombes RC, Ali S. Phosphorylation of estrogen receptor-α at Ser167 is indicative of longer disease-free and overall survival in breast cancer patients. Clin Cancer Res 2007; 13: 5769-5776
    CrossrefPubMedGoogle Scholar
  • 34 Burandt E, Jens G, Holst F, Jänicke F, Müller V, Quaas A, Choschzick M, Wilczak W, Terracciano L, Simon R, Sauter G, Lebeau A. Prognostic relevance of AIB1 (NCoA3) amplification and overexpression in breast cancer. Breast Cancer Res Treat 2013; 137: 745-753
    CrossrefPubMedGoogle Scholar
  • 35 Giavazzi R, Sennino B, Coltrini D, Garofalo A, Dossi R, Ronca R, Tosatti MPA, Presta M. Distinct role of fibroblast growth factor-2 and vascular endothelial growth factor on tumor growth and angiogenesis. Am J Pathol 2003; 162: 1913-1926
    CrossrefPubMedGoogle Scholar
  • 36 Sasich LD, Sukkari SR. The US FDAs withdrawal of the breast cancer indication for Avastin (bevacizumab). Saudi Pharm J 2012; 20: 381-385
    CrossrefPubMedGoogle Scholar
  • 37 Zhao M, Yu Z, Li Z, Tang J, Lai X, Liu L. Expression of angiogenic growth factors VEGF, bFGF and ANG1 in colon cancer after bevacizumab treatment in vitro: a potential self-regulating mechanism. Oncol Rep 2017; 37: 601-607
    CrossrefPubMedGoogle Scholar
  • 38 Liew SK, Azmi MN, In LLA, Awang K, Nagoor NH. Anti-proliferative, apoptotic induction, and anti-migration effects of hemi-synthetic 1′S-1′-acetoxychavicol acetate analogs on MDA-MB-231 breast cancer cells. Drug Des Devel Ther 2017; 11: 2763
    CrossrefPubMedGoogle Scholar
  • 39 Ishikawa T, Seto M, Banno H, Kawakita Y, Oorui M, Taniguchi T, Ohta Y, Tamura T, Nakayama A, Miki H. Design and synthesis of novel human epidermal growth factor receptor 2 (HER2)/epidermal growth factor receptor (EGFR) dual inhibitors bearing a pyrrolo [3,2-d] pyrimidine scaffold. J Med Chem 2011; 54: 8030-8050
    CrossrefPubMedGoogle Scholar
  • 40 Addie M, Ballard P, Buttar D, Crafter C, Currie G, Davies BR, Debreczeni J, Dry H, Dudley P, Greenwood R. Discovery of 4-Amino-N-[(1S)-1-(4-chlorophenyl)-3-hydroxypropyl]-1-(7H-pyrrolo [2,3-d] pyrimidin-4-yl) piperidine-4-carboxamide (AZD5363), an orally bioavailable, potent inhibitor of Akt kinases. J Med Chem 2013; 56: 2059-2073
    CrossrefPubMedGoogle Scholar
  • 41 Ward RA, Bethel P, Cook C, Davies E, Debreczeni JE, Fairley G, Feron L, Flemington V, Graham MA, Greenwood R, Griffin N, Hanson L, Hopcroft P, Howard TD, Hudson J, James M, Jones CD, Jones CR, Lamont S, Lewis R, Lindsay N, Roberts K, Simpson I, St-Gallay S, Swallow S, Tang J, Tonge M, Wang Z, Zhai B. Structure-guided discovery of potent and selective inhibitors of ERK1/2 from a modestly active and promiscuous chemical start point. J Med Chem 2017; 60: 3438-3450
    CrossrefPubMedGoogle Scholar
  • 42 Shiau AK, Barstad D, Loria PM, Cheng L, Kushner PJ, Agard DA, Greene GL. The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen. Cell 1998; 95: 927-937
    CrossrefPubMedGoogle Scholar
  • 43 Jiang L, Zhang X, Zhou Y, Chen Y, Luo Z, Li J, Yuan C, Huang M. Halogen bonding for the design of inhibitors by targeting the S1 pocket of serine proteases. RSC Adv 2018; 8: 28189-28197
    CrossrefPubMedGoogle Scholar
  • 44 Lu H, Chang DJ, Baratte B, Meijer L, Schulze-Gahmen U. Crystal structure of a human cyclin-dependent kinase 6 complex with a flavonol inhibitor, fisetin. J Med Chem 2005; 48: 737-743
    CrossrefPubMedGoogle Scholar
  • 45 Schlessinger J, Plotnikov AN, Ibrahimi OA, Eliseenkova AV, Yeh BK, Yayon A, Linhardt RJ, Mohammadi M. Crystal structure of a ternary FGF-FGFR-heparin complex reveals a dual role for heparin in FGFR binding and dimerization. Mol Cell 2000; 6: 743-750
    CrossrefPubMedGoogle Scholar
  • 46 Frisch MJ, Trucks GW, Schlegel HB, Scuseria GE, Robb MA, Cheeseman JR, Scalmani G, Barone V, Mennucci B, Petersson GA, Nakatsuji H, Caricato M, Li X, Hratchian HP, Izmaylov AF, Bloino J, Zheng G, Sonnenberg JL, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Vreven T, Montgomery JA, Peralta JE, Ogliaro F, Bearpark MJ, Heyd J, Brothers EN, Kudin KN, Staroverov VN, Kobayashi R, Normand J, Raghavachari K, Rendell AP, Burant JC, Iyengar SS, Tomasi J, Cossi M, Rega N, Millam NJ, Klene M, Knox JE, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Martin RL, Morokuma K, Zakrzewski VG, Voth GA, Salvador P, Dannenberg JJ, Dapprich S, Daniels AD, Farkas Ö, Foresman JB, Ortiz JV, Cioslowski J, Fox DJ. Gaussian 09. Wallingford, CT, USA: Gaussian, Inc.; 2009
    Google Scholar
  • 47 Wu G, Robertson DH, Brooks CL, Vieth M. Detailed analysis of grid-based molecular docking: a case study of CDOCKER-A CHARMm-based MD docking algorithm. J Comput Chem 2003; 24: 1549-1562
    CrossrefPubMedGoogle Scholar
  • 48 Pradubyat N, Sakunrangsit N, Mutirangura A, Ketchart W. NADPH: Quinone oxidoreductase 1 (NQO1) mediated anti-cancer effects of plumbagin in endocrine resistant MCF7 breast cancer cells. Phytomedicine 2020; 66: 153133
    CrossrefPubMedGoogle Scholar
  • 49 Sobanska M, Scholz S, Nyman AM, Cesnaitis R, Alonso SG, Klüver N, Kühne R, Tyle H, de Knecht J, Dang Z, Lundbergh I, Carlon C, De Coen W. Applicability of the fish embryo acute toxicity (FET) test (OECD 236) in the regulatory context of Registration, Evaluation, Authorisation, and Restriction of Chemicals (REACH). Environ Toxicol Chem 2018; 37: 657-670
    CrossrefPubMedGoogle Scholar