Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
BMC Complementary Medicine and Therapies
Published in: BMC Complementary Medicine and Therapies 1/2018

Open Access 01-12-2018 | Research article

Antrodia cinnamomea extract inhibits the proliferation of tamoxifen-resistant breast cancer cells through apoptosis and skp2/microRNAs pathway

Authors: Yu-Shih Lin, Yin-Yin Lin, Yao-Hsu Yang, Chun-Liang Lin, Feng-Che Kuan, Cheng-Nan Lu, Geng-He Chang, Ming-Shao Tsai, Cheng-Ming Hsu, Reming-Albert Yeh, Pei-Rung Yang, I-Yun Lee, Li-Hsin Shu, Yu-Ching Cheng, Hung-Te Liu, Kuan-Der Lee, De-Ching Chang, Ching-Yuan Wu

Published in: BMC Complementary Medicine and Therapies | Issue 1/2018

Login to get access

Abstract

Background

Breast cancer is the most common cancer in women and affects 1.38 million women worldwide per year. Antiestrogens such as tamoxifen, a selective estrogen receptor (ER) modulator, are widely used in clinics to treat ER-positive breast tumors. However, remissions of breast cancer are often followed by resistance to tamoxifen and disease relapse. Despite the increasing understanding of the resistance mechanisms, effective regimens for treating tamoxifen-resistant breast cancer are limited. Antrodia cinnamomea is a traditional medicinal mushroom native only to Taiwan. In this study, we aimed to examine in vitro effect of antrodia cinnamomea in the tamoxifen-resistant cancer.

Methods

Antrodia cinnamomea was studied for its biological activity against proliferation of tamoxifen-resistant breast cancer by XTT assay. Next, the underlying mechanism was studied by flow cytometry, qPCR and Western’s blotting assay.

Results

Our results revealed that the ethanol extract of antrodia cinnamomea (AC) can inhibit the growth of breast cancer cells, including MCF-7 cell and tamoxifen-resistant MCF-7 cell lines. Combination treatment with AC and 10− 6 M tamoxifen have the better inhibitory effect on the proliferation of tamoxifen-resistant MCF-7 cells than only AC did. AC can induce apoptosis in these breast cancer cells. Moreover, it can suppress the mRNA expression of skp2 (S-phase kinase-associated protein 2) by increasing the expressions of miR-21-5p, miR-26-5p, and miR-30-5p in MCF-7 and tamoxifen-resistant MCF-7 cells.

Conclusions

These results suggest that the ethanol extract of antrodia cinnamomea could be a novel anticancer agent in the armamentarium of tamoxifen-resistant breast cancer management. Moreover, we hope to identify additional pure compounds that could serve as promising anti-breast cancer candidates for further clinical trials.
Literature
1.
Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127(12):2893–917.CrossRefPubMed
2.
Gutierrez MC, Detre S, Johnston S, Mohsin SK, Shou J, Allred DC, Schiff R, Osborne CK, Dowsett M. Molecular changes in tamoxifen-resistant breast cancer: relationship between estrogen receptor, HER-2, and p38 mitogen-activated protein kinase. J Clin Oncol. 2005;23(11):2469–76.CrossRefPubMed
3.
Viedma-Rodriguez R, Baiza-Gutman L, Salamanca-Gomez F, Diaz-Zaragoza M, Martinez-Hernandez G, Ruiz Esparza-Garrido R, Velazquez-Flores MA, Arenas-Aranda D. Mechanisms associated with resistance to tamoxifen in estrogen receptor-positive breast cancer (review). Oncol Rep. 2014;32(1):3–15.CrossRefPubMed
4.
Martin HL, Smith L, Tomlinson DC. Multidrug-resistant breast cancer: current perspectives. Breast Cancer. 2014;6:1–13.PubMedPubMedCentral
5.
Chen JJ, Lin WJ, Liao CH, Shieh PC. Anti-inflammatory benzenoids from Antrodia camphorata. J Nat Prod. 2007;70(6):989–92.CrossRefPubMed
6.
Huang CC, Hsu MC, Huang WC, Yang HR, Hou CC. Triterpenoid-rich extract from Antrodia camphorata improves physical fatigue and exercise performance in mice. Evid Based Complement Alternat Med. 2012;2012:364741.PubMedPubMedCentral
7.
Hsu YL, Kuo PL, Cho CY, Ni WC, Tzeng TF, Ng LT, Kuo YH, Lin CC. Antrodia cinnamomea fruiting bodies extract suppresses the invasive potential of human liver cancer cell line PLC/PRF/5 through inhibition of nuclear factor kappaB pathway. Food Chem Toxicol. 2007;45(7):1249–57.CrossRefPubMed
8.
Ker YB, Peng CC, Chang WL, Chyau CC, Peng RY. Hepatoprotective bioactivity of the glycoprotein, antrodan, isolated from Antrodia cinnamomea mycelia. PLoS One. 2014;9(4):e93191.CrossRefPubMedPubMedCentral
9.
Wu MD, Cheng MJ, Wang WY, Huang HC, Yuan GF, Chen JJ, Chen IS, Wang BC. Antioxidant activities of extracts and metabolites isolated from the fungus Antrodia cinnamomea. Nat Prod Res. 2011;25(16):1488–96.CrossRefPubMed
10.
Liu JJ, Huang TS, Hsu ML, Chen CC, Lin WS, Lu FJ, Chang WH. Antitumor effects of the partially purified polysaccharides from Antrodia camphorata and the mechanism of its action. Toxicol Appl Pharmacol. 2004;201(2):186–93.CrossRefPubMed
11.
Tsai MY, Hung YC, Chen YH, Chen YH, Huang YC, Kao CW, Su YL, Chiu HH, Rau KM. A preliminary randomised controlled study of short-term Antrodia cinnamomea treatment combined with chemotherapy for patients with advanced cancer. BMC Complement Altern Med. 2016;16(1):322.CrossRefPubMedPubMedCentral
12.
Du YC, Wu TY, Chang FR, Lin WY, Hsu YM, Cheng FT, Lu CY, Yen MH, Tsui YT, Chen HL, et al. Chemical profiling of the cytotoxic triterpenoid-concentrating fraction and characterization of ergostane stereo-isomer ingredients from Antrodia camphorata. J Pharm Biomed Anal. 2012;58:182–92.CrossRefPubMed
13.
Yeh CT, Rao YK, Yao CJ, Yeh CF, Li CH, Chuang SE, Luong JH, Lai GM, Tzeng YM. Cytotoxic triterpenes from Antrodia camphorata and their mode of action in HT-29 human colon cancer cells. Cancer Lett. 2009;285(1):73–9.CrossRefPubMed
14.
Cheng JJ, Yang CJ, Cheng CH, Wang YT, Huang NK, Lu MK. Characterization and functional study of Antrodia camphorata lipopolysaccharide. J Agric Food Chem. 2005;53(2):469–74.CrossRefPubMed
15.
Lee IH, Huang RL, Chen CT, Chen HC, Hsu WC, Lu MK. Antrodia camphorata polysaccharides exhibit anti-hepatitis B virus effects. FEMS Microbiol Lett. 2002;209(1):63–7.CrossRefPubMed
16.
Peng CC, Chen KC, Peng RY, Chyau CC, Su CH, Hsieh-Li HM. Antrodia camphorata extract induces replicative senescence in superficial TCC, and inhibits the absolute migration capability in invasive bladder carcinoma cells. J Ethnopharmacol. 2007;109(1):93–103.CrossRefPubMed
17.
Shen YC, Wang YH, Chou YC, Chen CF, Lin LC, Chang TT, Tien JH, Chou CJ. Evaluation of the anti-inflammatory activity of zhankuic acids isolated from the fruiting bodies of Antrodia camphorata. Planta Med. 2004;70(4):310–4.CrossRefPubMed
18.
Huang HC, Liaw CC, Yang HL, Hseu YC, Kuo HT, Tsai YC, Chien SC, Amagaya S, Chen YC, Kuo YH. Lanostane triterpenoids and sterols from Antrodia camphorata. Phytochemistry. 2012;84:177–83.CrossRefPubMed
19.
Su YK, Shih PH, Lee WH, Bamodu OA, Wu ATH, Huang CC, Tzeng YM, Hsiao M, Yeh CT, Lin CM. Antrodia cinnamomea sensitizes radio−/chemo-therapy of cancer stem-like cells by modulating microRNA expression. J Ethnopharmacol. 2017;207:47–56.CrossRefPubMed
20.
Shang KM, Su TH, Lee WL, Hsiao WW, Chiou CY, Ho BY, Wang SY, Shyur LF. Novel effect and the mechanistic insights of fruiting body extract of medicinal fungus Antrodia cinnamomea against T47D breast cancer. Phytomedicine. 2017;24:39–48.CrossRefPubMed
21.
Kumar KJ, Vani MG, Chueh PJ, Mau JL, Wang SY. Antrodin C inhibits epithelial-to-mesenchymal transition and metastasis of breast cancer cells via suppression of Smad2/3 and beta-catenin signaling pathways. PLoS One. 2015;10(2):e0117111.CrossRefPubMedPubMedCentral
22.
Wu CY, Hsieh CY, Huang KE, Chang C, Kang HY. Cryptotanshinone down-regulates androgen receptor signaling by modulating lysine-specific demethylase 1 function. Int J Cancer. 2012;131(6):1423–34.CrossRefPubMed
23.
Lin YY, Lee IY, Huang WS, Lin YS, Kuan FC, Shu LH, Cheng YC, Yang YH, Wu CY. Danshen improves survival of patients with colon cancer and dihydroisotanshinone I inhibit the proliferation of colon cancer cells via apoptosis and skp2 signaling pathway. J Ethnopharmacol. 2017;209:305–16.CrossRefPubMed
24.
Lee IY, Lin YY, Yang YH, Lin YS, Lin CL, Lin WY, Cheng YC, Shu LH, Wu CY. Dihydroisotanshinone I combined with radiation inhibits the migration ability of prostate cancer cells through DNA damage and CCL2 pathway. BMC Pharmacol Toxicol. 2018;19(1):5.CrossRefPubMedPubMedCentral
25.
Chen C, Ridzon DA, Broomer AJ, Zhou Z, Lee DH, Nguyen JT, Barbisin M, Xu NL, Mahuvakar VR, Andersen MR, et al. Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res. 2005;33(20):e179.CrossRefPubMedPubMedCentral
26.
Wu CY, Cherng JY, Yang YH, Lin CL, Kuan FC, Lin YY, Lin YS, Shu LH, Cheng YC, Liu HT, et al. Danshen improves survival of patients with advanced lung cancer and targeting the relationship between macrophages and lung cancer cells. Oncotarget. 2017;8(53):90925–47.PubMedPubMedCentral
27.
Wu CY, Yang YH, Lin YY, Kuan FC, Lin YS, Lin WY, Tsai MY, Yang JJ, Cheng YC, Shu LH, et al. Anti-cancer effect of danshen and dihydroisotanshinone I on prostate cancer: targeting the crosstalk between macrophages and cancer cells via inhibition of the STAT3/CCL2 signaling pathway. Oncotarget. 2017;8(25):40246–63.PubMedPubMedCentral
28.
Agarwal V, Bell GW, Nam JW, Bartel DP. Predicting effective microRNA target sites in mammalian mRNAs. elife. 2015;4
29.
Huang YL, Chu YL, Ho CT, Chung JG, Lai CI, Su YC, Kuo YH, Sheen LY. Antcin K, an active triterpenoid from the fruiting bodies of basswood-cultivated Antrodia cinnamomea, inhibits metastasis via suppression of integrin-mediated adhesion, migration, and invasion in human hepatoma cells. J Agric Food Chem. 2015;63(18):4561–9.CrossRefPubMed
30.
Du YC, Chang FR, Wu TY, Hsu YM, El-Shazly M, Chen CF, Sung PJ, Lin YY, Lin YH, Wu YC, et al. Antileukemia component, dehydroeburicoic acid from Antrodia camphorata induces DNA damage and apoptosis in vitro and in vivo models. Phytomedicine. 2012;19(8–9):788–96.CrossRefPubMed
31.
Hsieh YC, Rao YK, Whang-Peng J, Huang CY, Shyue SK, Hsu SL, Tzeng YM. Antcin B and its ester derivative from Antrodia camphorata induce apoptosis in hepatocellular carcinoma cells involves enhancing oxidative stress coincident with activation of intrinsic and extrinsic apoptotic pathway. J Agric Food Chem. 2011;59(20):10943–54.CrossRefPubMed
32.
Lee CI, Wu CC, Hsieh SL, Lee CL, Chang YP, Chang CC, Wang YZ, Wang JJ. Anticancer effects on human pancreatic cancer cells of triterpenoids, polysaccharides and 1,3-beta-d-glucan derived from the fruiting body of Antrodia camphorata. Food Funct. 2014;5(12):3224–32.CrossRefPubMed
33.
Lee YP, Tsai WC, Ko CJ, Rao YK, Yang CR, Chen DR, Yang MH, Yang CC, Tzeng YM. Anticancer effects of eleven triterpenoids derived from Antrodia camphorata. Anticancer Res. 2012;32(7):2727–34.PubMed
34.
Liu FS, Yang PY, Hu DN, Huang YW, Chen MJ. Antrodia camphorata induces apoptosis and enhances the cytotoxic effect of paclitaxel in human ovarian cancer cells. Int J Gynecol Cancer. 2011;21(7):1172–9.PubMed
35.
Zhang W, Cao L, Sun Z, Xu J, Tang L, Chen W, Luo J, Yang F, Wang Y, Guan X. Skp2 is over-expressed in breast cancer and promotes breast cancer cell proliferation. Cell Cycle. 2016;15(10):1344–51.CrossRefPubMedPubMedCentral
36.
Chan CH, Lee SW, Li CF, Wang J, Yang WL, Wu CY, Wu J, Nakayama KI, Kang HY, Huang HY, et al. Deciphering the transcriptional complex critical for RhoA gene expression and cancer metastasis. Nat Cell Biol. 2010;12(5):457–67.CrossRefPubMed
37.
He W, Feng J, Zhang Y, Wang Y, Zang W, Zhao G. microRNA-186 inhibits cell proliferation and induces apoptosis in human esophageal squamous cell carcinoma by targeting SKP2. Lab Investig. 2016;96(3):317–24.CrossRefPubMed
38.
Fernandez S, Risolino M, Mandia N, Talotta F, Soini Y, Incoronato M, Condorelli G, Banfi S, Verde P. miR-340 inhibits tumor cell proliferation and induces apoptosis by targeting multiple negative regulators of p27 in non-small cell lung cancer. Oncogene. 2015;34(25):3240–50.CrossRefPubMed
39.
Zhou C, Zhong Q, Rhodes LV, Townley I, Bratton MR, Zhang Q, Martin EC, Elliott S, Collins-Burow BM, Burow ME, et al. Proteomic analysis of acquired tamoxifen resistance in MCF-7 cells reveals expression signatures associated with enhanced migration. Breast Cancer Res. 2012;14(2):R45.CrossRefPubMedPubMedCentral
40.
Fan P, Yue W, Wang JP, Aiyar S, Li Y, Kim TH, Santen RJ. Mechanisms of resistance to structurally diverse antiestrogens differ under premenopausal and postmenopausal conditions: evidence from in vitro breast cancer cell models. Endocrinology. 2009;150(5):2036–45.CrossRefPubMedPubMedCentral
41.
Knowlden JM, Hutcheson IR, Jones HE, Madden T, Gee JM, Harper ME, Barrow D, Wakeling AE, Nicholson RI. Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells. Endocrinology. 2003;144(3):1032–44.CrossRefPubMed
42.
Leung EY, Kim JE, Askarian-Amiri M, Joseph WR, McKeage MJ, Baguley BC. Hormone resistance in two MCF-7 breast Cancer cell lines is associated with reduced mTOR signaling, decreased glycolysis, and increased sensitivity to cytotoxic drugs. Front Oncol. 2014;4:221.PubMedPubMedCentral
43.
Nawata H, Bronzert D, Lippman ME. Isolation and characterization of a tamoxifen-resistant cell line derived from MCF-7 human breast cancer cells. J Biol Chem. 1981;256(10):5016–21.PubMed
44.
Lai CI, Chu YL, Ho CT, Su YC, Kuo YH, Sheen LY. Antcin K, an active triterpenoid from the fruiting bodies of basswood cultivated Antrodia cinnamomea, induces mitochondria and endoplasmic reticulum stress-mediated apoptosis in human hepatoma cells. J Tradit Complement Med. 2016;6(1):48–56.CrossRefPubMed
45.
Gokila Vani M, Kumar KJ, Liao JW, Chien SC, Mau JL, Chiang SS, Lin CC, Kuo YH, Wang SY. Antcin C from Antrodia cinnamomea protects liver cells against free radical-induced oxidative stress and apoptosis in vitro and in vivo through Nrf2-dependent mechanism. Evid Based Complement Alternat Med. 2013;2013:296082.CrossRefPubMedPubMedCentral
46.
Su YC, Liu CT, Chu YL, Raghu R, Kuo YH, Sheen LY. Eburicoic acid, an active triterpenoid from the fruiting bodies of basswood cultivated Antrodia cinnamomea, induces ER stress-mediated autophagy in human hepatoma cells. J Tradit Complement Med. 2012;2(4):312–22.CrossRefPubMedPubMedCentral
47.
Bhatt S, Stender JD, Joshi S, Wu G, Katzenellenbogen BS. OCT-4: a novel estrogen receptor-alpha collaborator that promotes tamoxifen resistance in breast cancer cells. Oncogene. 2016;35(44):5722–34.CrossRefPubMed
48.
Jansen MP, Reijm EA, Sieuwerts AM, Ruigrok-Ritstier K, Look MP, Rodriguez-Gonzalez FG, Heine AA, Martens JW, Sleijfer S, Foekens JA, et al. High miR-26a and low CDC2 levels associate with decreased EZH2 expression and with favorable outcome on tamoxifen in metastatic breast cancer. Breast Cancer Res Treat. 2012;133(3):937–47.
49.
Rodriguez-Gonzalez FG, Sieuwerts AM, Smid M, Look MP, Meijer-van Gelder ME, de Weerd V, Sleijfer S, Martens JW, Foekens JA. MicroRNA-30c expression level is an independent predictor of clinical benefit of endocrine therapy in advanced estrogen receptor positive breast cancer. Breast Cancer Res Treat. 2011;127(1):43–51.CrossRefPubMed
Metadata
Title
Antrodia cinnamomea extract inhibits the proliferation of tamoxifen-resistant breast cancer cells through apoptosis and skp2/microRNAs pathway
Authors
Yu-Shih Lin
Yin-Yin Lin
Yao-Hsu Yang
Chun-Liang Lin
Feng-Che Kuan
Cheng-Nan Lu
Geng-He Chang
Ming-Shao Tsai
Cheng-Ming Hsu
Reming-Albert Yeh
Pei-Rung Yang
I-Yun Lee
Li-Hsin Shu
Yu-Ching Cheng
Hung-Te Liu
Kuan-Der Lee
De-Ching Chang
Ching-Yuan Wu
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Complementary Medicine and Therapies / Issue 1/2018
Electronic ISSN: 2662-7671
DOI
https://doi.org/10.1186/s12906-018-2204-y

Other articles of this Issue 1/2018

BMC Complementary Medicine and Therapies 1/2018 Go to the issue

Research article

Feifukang ameliorates pulmonary fibrosis by inhibiting JAK-STAT signaling pathway

Research article

Oleanolic acid attenuates TGF-β1-induced epithelial-mesenchymal transition in NRK-52E cells

Research article

Assessment of acute, 14-day, and 13-week repeated oral dose toxicity of Tiglium seed extract in rats

Research article

Therapeutic benefits of Indole-3-Carbinol in adjuvant-induced arthritis and its protective effect against methotrexate induced-hepatic toxicity

Research article

Steroidal alkaloids and conessine from the medicinal plant Holarrhena antidysenterica restore antibiotic efficacy in a Galleria mellonella model of multidrug-resistant Pseudomonas aeruginosa infection

Research article

Effect of Moringa oleifera consumption on diabetic rats