Growth inhibitory efficacy and anti‑aromatase activity of Tabebuia avellanedae in a model for post‑menopausal Luminal A breast cancer

Telang,Nitin; Nair,Hareesh  B.; Wong,George  Y.C.

doi:10.3892/br.2019.1244

Growth inhibitory efficacy and anti‑aromatase activity of Tabebuia avellanedae in a model for post‑menopausal Luminal A breast cancer

Authors:
- Nitin Telang
- Hareesh B. Nair
- George Y.C. Wong
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Affiliations: Cancer Prevention Research Program, Palindrome Liaisons Consultants, Montvale, NJ 07645‑1559, USA, Department of Obstetrics and Gynecology, University of Texas Health Sciences Center, San Antonio, TX 78229, USA, American Foundation for Chinese Medicine, New York, NY 11103, USA
Published online on: October 3, 2019 https://doi.org/10.3892/br.2019.1244
Pages: 222-229

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Abstract

Aromatase inhibitors (AIs) represent a treatment option for post‑menopausal estrogen receptor‑positive (ER+) breast cancer as monotherapy, or in combination with cyclin‑dependent kinase 4/6 or mTOR inhibitors. Long‑term treatment with these agents leads to dose‑limiting toxicity and drug resistance. Natural substances provide testable alternatives to current therapy. Tabebuia avellanedae (TA) tree is indigenous to the Amazon rainforest. The inner bark of TA represents a medicinal dietary supplement known as Taheebo. Non‑fractionated aqueous extract from TA is an effective growth inhibitor in the Luminal A and triple negative breast cancer models. The quinone derivative naphthofurandione (NFD) is a major bioactive agent in TA. The present study examined the efficacy of finely ground powder from the inner bark of TA, available under the name of Taheebo‑NFD‑Marugoto (TNM). The ER+ MCF‑7 cells stably transfected with the aromatase gene MCF‑7AROM represented a model for aromatase‑expressing post‑menopausal breast cancer. Anchorage‑independent colony formation, cell cycle progression, pro‑apoptotic caspase 3/7 activity, apoptosis‑specific gene expression, aromatase activity and select estradiol (E2) target gene expression represented the mechanistic end points. Treatment of MCF‑7AROM cells with TNM induced a dose‑dependent reduction in E2‑promoted anchorage‑independent colony number. Mechanistic assays on TNM‑treated MCF‑7AROM cells demonstrated that TNM at a concentration of 10 µg (NFD content: 2 ng), induced S‑phase arrest, increased pro‑apoptotic caspase 3/7 activity, increased pro‑apoptotic BAX and decreased anti‑apoptotic BCL‑2 gene expression, and inhibited aromatase activity. Additionally, TNM treatment downregulated ESR‑1 (gene for ER‑α), aromatase and progesterone gene expression and reduced mRNA levels of E2 target genes pS2, GRB2 and cyclin D1. Inhibition of aromatase activity, based on the NFD content of TNM was superior to the clinical AIs Letrozole and Exemestane. These data demonstrated the potential efficacy of TNM as a nutritional alternative for current therapy of aromatase positive, post‑menopausal breast cancer.

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1	Johnston SRD and Dowsett M: Aromatase inhibitors for breast cancer: Lessons from the laboratory. Nat Rev Cancer. 3:821–831. 2003.PubMed/NCBI View Article : Google Scholar
2	Ali S and Coombes RC: Endocrine-responsive breast cancer and strategies for combating resistance. Nat Rev Cancer. 2:101–112. 2002.PubMed/NCBI View Article : Google Scholar
3	Ma CX, Reinert T, Chmielewska I and Ellis MJ: Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer. 15:261–275. 2015.PubMed/NCBI View Article : Google Scholar
4	Ma CK, Gao F, Luo J, Northfeld DW, Goetz M, Forero A, Hoog J, Naughton M, Ademuyiwa F, Suresh R, et al: NeoPalAna: Neoadjuvant Palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and Anastrozole for clinical stage 2 or 3 estrogen receptor- positive breast cancer. Clin Cancer Res. 23:4055–4065. 2017.PubMed/NCBI View Article : Google Scholar
5	Taglieri L, De Iuliis F, Giuffrida A, Giantulli S, Silvestri I and Scarpa S: Resistance to the mTOR inhibitor everolimus is reversed by the downregulation of survivin in breast cancer cells. Oncol Lett. 14:3832–3838. 2017.PubMed/NCBI View Article : Google Scholar
6	Brodie A, Jelovac D and Long BJ: Predictions from a preclinical model: Studies of aromatase inhibitors and antiestrogens. Clin Cancer Res. 9:455S–459S. 2003.PubMed/NCBI
7	Boér K: Impact of palbociclib combinations on treatment of advanced estrogen receptor-positive/human epidermal growth factor 2-negative breast cancer. OncoTargets Ther. 9:6119–6125. 2016.PubMed/NCBI View Article : Google Scholar
8	Alves CL, Elias D, Lyng M, Bak M, Kirkegaard T, Lykkesfeldt AE and Ditzel HJ: High CDK6 protects cells from Fulvestrant-mediated apoptosis and is predictor of resistance to Fulvestrant in estrogen receptor-positive metastatic breast cancer. Clin Cancer Res. 22:5514–5526. 2016.PubMed/NCBI View Article : Google Scholar
9	Hole S, Pedersen AM, Hansen SK, Lundqvist J, Yde CW and Lykkesfeldt AE: New cell culture model for aromatase inhibitor-resistant breast cancer shows sensitivity to fulvestrant treatment and cross-resistance between letrozole and exemestane. Int J Oncol. 46:1481–1490. 2015.PubMed/NCBI View Article : Google Scholar
10	Sabnis G and Brodie A: Understanding resistance to endocrine agents: Molecular mechanisms and potential for intervention. Clin Breast Cancer. 10:E6–E15. 2010.PubMed/NCBI View Article : Google Scholar
11	Moy B and Goss PE: Estrogen receptor pathway: Resistance to endocrine therapy and new therapeutic approaches. Clin Cancer Res. 12:4790–4793. 2006.PubMed/NCBI View Article : Google Scholar
12	O'Hara J, Vareslija D, McBryan J, Bane F, Tibbitts P, Byrne C, Conroy RM, Hao Y, Gaora PO, Hill ADK, et al: AIB1:ERα transcriptional activity is selectively enhanced in aromatase inhibitor-resistant breast cancer cells. Clin Cancer Res. 18:3305–3315. 2012.PubMed/NCBI View Article : Google Scholar
13	Ebina T: Anti-tumor effect of hot water extract of Taheebo tea: Comparison with other biological preparations. Biotherapy. 16:321–327. 2002.
14	Brisson M, Nguyen T, Vogt A, Yalowich J, Giorgianni A, Tobi D, Bahar I, Stephenson CR, Wipf P and Lazo JS: Discovery and characterization of novel small molecule inhibitors of human Cdc25B dual specificity phosphatase. Mol Pharmacol. 66:824–833. 2004.PubMed/NCBI View Article : Google Scholar
15	Choi YH, Kang HS and Yoo MA: Suppression of human prostate cancer cell growth by β-lapachone via down-regulation of pRB phosphorylation and induction of Cdk inhibitor p21 (WAF1/CIP1). J Biochem Mol Biol. 36:223–229. 2003.PubMed/NCBI
16	Lee JH, Cheong J, Park YM and Choi YH: Down-regulation of cyclooxygenase-2 and telomerase activity by β-lapachone in human prostate carcinoma cells. Pharmacol Res. 51:553–560. 2005.PubMed/NCBI View Article : Google Scholar
17	Mukherjee B, Telang N and Wong GYC: Growth inhibition of estrogen receptor positive human breast cancer cells by Taheebo from the inner bark of Tabebuia avellanedae tree. Int J Mol Med. 24:253–260. 2009.PubMed/NCBI View Article : Google Scholar
18	Telang NT, Nair HB and Wong GYC: Efficacy of Tabebuia avellanedae extract on a cell culture model for triple negative breast cancer. Cancer Res. 74 (Suppl):SABCS, P5-14-02. 2014.
19	Liu YG, Tekmal RR, Binkley PA, Nair HB, Schenken RS and Kirma NB: Induction of endometrial epithelial cell invasion and c-fms expression by transforming growth factor β. Mol Hum Reprod. 15:665–673. 2009.PubMed/NCBI View Article : Google Scholar
20	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
21	Nair HB, Luthra R, Kirma N, Liu YG, Flowers L, Evans D and Tekmal RR: Induction of aromatase expression in cervical carcinomas: Effects of endogenous estrogen on cervical cancer cell proliferation. Cancer Res. 65:11164–11173. 2005.PubMed/NCBI View Article : Google Scholar
22	American Cancer Society: Cancer facts and figures. American Cancer Society, Atlanta, GA, 2018.
23	Gupta A, Mehta R, Alimirah F, Peng X, Murillo G, Wiehle R and Mehta RG: Efficacy and mechanism of action of Proellex, an antiprogestin in aromatase overexpressing and Letrozole resistant T47D breast cancer cells. J Steroid Biochem Mol Biol. 133:30–42. 2013.PubMed/NCBI View Article : Google Scholar
24	Panda SP, Panigrahy UP, Panda S and Jena BR: Stem extract of Tabebuia chrysantha induces apoptosis by targeting sEGFR in Ehrlich Ascites Carcinoma. J Ethnopharmacol. 235:219–226. 2019.PubMed/NCBI View Article : Google Scholar
25	Bacowsky H: Investigations on effects of Taheebo extract on various blood parameters and quality of life in 12 patients suffering from different form of cancer in different stages. J New Rem Clin. 55:48–55. 2006.
26	Hirata S: An examination of supplement dose dependence and safety in integrative medicine for cancer: Based on the experience of Tabebuia avellanedae, a South American medicinal plant commonly known as Taheebo. Int J Integr Med. 2:140–144. 2010.
27	Lippman ME, Osborne CK, Knazek R and Young N: In vitro model systems for the study of hormone-dependent human breast cancer. N Engl J Med. 296:154–159. 1977.PubMed/NCBI View Article : Google Scholar
28	Telang NT, Li G, Sepkovic DW, Bradlow HL and Wong GYC: Anti-proliferative effects of Chinese herb Cornus officinalis in a cell culture model for estrogen receptor-positive clinical breast cancer. Mol Med Rep. 5:22–28. 2012.PubMed/NCBI View Article : Google Scholar
29	Telang N, Li G, Sepkovic D, Bradlow HL and Wong GYC: Comparative efficacy of extracts from Lycium barbarum bark and fruit on estrogen receptor positive human mammary carcinoma MCF-7 cells. Nutr Cancer. 66:278–284. 2014.PubMed/NCBI View Article : Google Scholar
30	Telang N, Li G, Katdare M, Sepkovic D, Bradlow L and Wong G: Inhibitory effects of Chinese nutritional herbs in isogenic breast carcinoma cells with modulated estrogen receptor function. Oncol Lett. 12:3949–3957. 2016.PubMed/NCBI View Article : Google Scholar
31	Telang NT, Li G, Katdare M, Sepkovic DW, Bradlow HL and Wong GYC: The nutritional herb Epimedium grandiflorum inhibits the growth in a model for the Luminal A molecular subtype of breast cancer. Oncol Lett. 13:2477–2482. 2017.PubMed/NCBI View Article : Google Scholar
32	Tait SW and Green DR: Mitochondria and cell death: Outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol. 11:621–632. 2010.PubMed/NCBI View Article : Google Scholar
33	Chottanapund S, Van Duursen MB, Navasumrit P, Hunsonti P, Timtavorn S, Ruchirawat M and Van den Berg M: Anti-aromatase effect of resveratrol and melatonin on hormonal positive breast cancer cells co-cultured with breast adipose fibroblasts. Toxicol In Vitro. 28:1215–1221. 2014.PubMed/NCBI View Article : Google Scholar
34	Adams LS, Zhang Y, Seeram NP, Heber D and Chen S: Pomegranate ellagitannin-derived compounds exhibit antiproliferative and antiaromatase activity in breast cancer cells in vitro. Cancer Prev Res (Phila). 3:108–113. 2010.PubMed/NCBI View Article : Google Scholar
35	Castro NP, Rangel MC, Merchant AS, MacKinnon G, Cuttitta F, Salomon DS and Kim YS: Sulforphane suppresses the growth of triple negative breast cancer stem-like cells in vitro and in vivo. Cancer Prev Res (Phila). 12:147–158. 2019.PubMed/NCBI View Article : Google Scholar
36	Kim SH and Singh SV: Role of Krüppel-like factor4-p21^CIP1 axis in breast cancer stem-like cell inhibition by benzyl isothiocyanate. Cancer Prev Res (Phila). 12:125–134. 2019.PubMed/NCBI View Article : Google Scholar
37	Telang N: Targeting drug resistant stem cells in a human epidermal growth factor receptor-2-enriched breast cancer model. World Acad. Sci. J. 1:86–91. 2019. View Article : Google Scholar
38	Kinoshita Y and Chen S: Induction of aromatase (CYP19) expression in breast cancer cells through a nongenomic action of estrogen receptor α. Cancer Res. 63:3546–3555. 2003.PubMed/NCBI
39	Woo HJ and Choi YH: Growth inhibition of A549 human lung carcinoma cells by β-lapachone through induction of apoptosis and inhibition of telomerase activity. Int J Oncol. 26:1017–1023. 2005.PubMed/NCBI View Article : Google Scholar
40	Jeon YJ, Bang W, Shin JC, Park SM, Cho JJ, Choi YH, Seo KS, Choi NJ, Shim JH and Chae JI: Downregulation of Sp1 is involved in β-lapachone-induced cell cycle arrest and apoptosis in oral squamous cell carcinoma. Int J Oncol. 46:2606–2612. 2015.PubMed/NCBI View Article : Google Scholar
41	Bang W, Jeon YJ, Cho JH, Lee RH, Park SM, Shin JC, Choi NJ, Choi YH, Cho JJ, Seo JM, et al: Shim JH ad Chae JI: β-lapachone suppresses the proliferation of human malignant melanoma by targeting specificity protein 1. Oncol Rep. 35:1109–1116. 2016.PubMed/NCBI View Article : Google Scholar
42	Queiroz ML, Valadares MC, Torello CO, Ramos AL, Oliveira AB, Rocha FD, Arruda VA and Accorci WR: Comparative studies of the effects of Tabebuia avellanedae barh extract and β-lapachone on hematopoietic response of tumor bearing mice. J Ethnopharmacol. 117:228–235. 2008.PubMed/NCBI View Article : Google Scholar