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Triple negative breast cancer, Tabebuia avellanedae, Cell cycle, RB signaling, Cellular apoptosis, Caspase 3/7 activity
Background: Tabebuia avellanedae (TA) is a tree that is indigenous to the Amazon rainforest. The experiments in the present study were designed to examine the inhibitory effects of TA, and to identify mechanistic targets for its efficacy in the estrogen-α receptor (ER-α), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER-2) negative MDA-MB-231 model for triple negative breast cancer (TNBC).
Methods: Non-fractionated aqueous extract from the inner bark of TA was used in the experiments. Anchorage dependent growth, anchorage independent (AI) colony formation, cell cycle progression, and expressions of relevant regulatory proteins represented quantitative end points.
Results: Long-term treatment for 21 days with the maximum cytostatic concentration of 2.5% TA resulted in a 90% inhibition (P=0.014) in AI colony number. Short-term treatment for 2 days with 1.0% TA (IC50) resulted in about a 1.3 fold increase (P=0.014) in G1: S+G2/M ratio, about a 1.48 fold increase (P=0.010) in the sub G0 (apoptotic) cells and about a 3.2 fold increase (P=0.014) in the pro-apoptotic caspase 3/7 activity. Mechanistically, the short-term treatment with 2.5% TA decreased Cyclin D1 expression by about 83.3%, and pRB expression by about 73.3%.
Conclusion: TNBC represents an aggressive cancer notable for its resistance to conventional and targeted therapy. Non-toxic natural substances may represent testable alternatives. This study identifies potential mechanistic leads for TA as a novel naturally occurring testable alternative for secondary prevention/therapy of TNBC, and validates a novel mechanistic approach to evaluate efficacious non-toxic phytochemicals and herbs as testable alternatives against therapy resistant breast cancer.
2. Baselga J, Swain SM. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer. 2009;9(7):463-75.
3. Dinh P, Sotiriou C, Piccart MJ. The evolution of treatment strategies: aiming at the target. The Breast. 2007;16:10-6.
4. Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proceedings of the National Academy of Sciences. 2001;98(19): 10869-74.
5. Anders CK, Winer EP, Ford JM, Dent R, Silver DP, Sledge GW, et al. Poly (ADP-Ribose) polymerase inhibition:“targeted” therapy for triple-negative breast cancer. Clinical Cancer Research. 2010;16(19):4702-10.
6. Dean M, Fojo T, Bates S. Tumour stem cells and drug resistance. Nature Reviews Cancer. 2005; 5(4):275-84.
7. Ye L, Jia Y, Ji K, Sanders AJ, Xue K, Ji J, et al. Traditional Chinese medicine in the prevention and treatment of cancer and cancer metastasis. Oncology letters. 2015;10(3):1240-50.
8. Helyer LK, Chin S, Chui BK, Fitzgerald B, Verma S, Rakovitch E, et al. The use of complementary and alternative medicines among patients with locally advanced breast cancer–a descriptive study. BMC cancer. 2006;6(1):1-8.
9. Mukherjee B, Telang N, Wong G. Growth inhibition of estrogen receptor positive human breast cancer cells by Taheebo from the inner bark of Tabebuia avellandae tree. International journal of molecular medicine. 2009;24(2):253-60.
10. Telang N, Li G, Sepkovic D, Bradlow HL, Wong GY. Comparative efficacy of extracts from Lycium barbarum bark and fruit on estrogen receptor positive human mammary carcinoma MCF-7 cells. Nutrition and cancer. 2014;66(2):278-84.
11. Telang N, Nair HB, Wong GY. Growth inhibitory efficacy and anti‑aromatase activity of Tabebuia avellanedae in a model for post‑menopausal Luminal A breast cancer. Biomedical reports. 2019;11(5):222-9.
12. Telang N, Nair HB, Wong G. Efficacy of Dipsacus asperoides (DA) in a model for triple negative breast cancer. Cancer Res. 2017;77(4 Suppl):4-13.
13. Telang NT, Nair HB, Wong GY. Growth inhibitory efficacy of Cornus officinalis in a cell culture model for triple‑negative breast cancer. Oncology letters. 2019;17(6):5261-6.
14. Ueda S, Tokuda H, Hirai K, Kanazawa K, Hatanaka H, Nishino M, inventorsA novel anti-tumor compound 2-(1-hydrymethyl)-5-hydroxynaptho [2, 3-b] furan-4, 9-dione and anti-tumor agents comprising this compound. United States of America 1997.
15. Ebina T. Antitumor Effect of Hot-Water Extract of TAHEEBO Tea-Comparison with Other Biological Preparations. Biotheraphy-Tokyo. 2002;16(4):321-8.
16. Queiroz ML, Valadares MC, Torello CO, Ramos AL, Oliveira AB, Rocha FD, et al. Comparative studies of the effects of Tabebuia avellanedae bark extract and β-lapachone on the hematopoietic response of tumour-bearing mice. Journal of ethnopharmacology. 2008;117(2): 228-35.
17. Neve RM, Chin K, Fridlyand J, Yeh J, Baehner FL, Fevr T, et al. A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell. 2006;10(6):515-27.
18. Subik K, Lee JF, Baxter L, Strzepek T, Costello D, Crowley P, et al. The Expression Patterns of ER, PR, HER2, CK5/6, EGFR, Ki-67 and AR by Immunohistochemical Analysis in Breast Cancer Cell Lines. Breast Cancer (Auckl). 2010;4:35-41.
19. Telang NT, Li G, Sepkovic DW, Bradlow HL, Wong GY. Anti-proliferative effects of Chinese herb Cornus officinalis in a cell culture model for estrogen receptor-positive clinical breast cancer. Mol Med Rep. 2012;5(1):22-8.
20. 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. 2006;55:48-55.
21. 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. 2010;2:140-4.
22. Brisson M, Nguyen T, Vogt A, Yalowich J, Giorgianni A, Tobi D, et al. Discovery and characterization of novel small molecule inhibitors of human Cdc25B dual specificity phosphatase. Molecular pharmacology. 2004;66(4):824-33.
23. Bey EA, Bentle MS, Reinicke KE, Dong Y, Yang CR, Girard L, et al. An NQO1- and PARP-1-mediated cell death pathway induced in non-small-cell lung cancer cells by beta-lapachone. Proc Natl Acad Sci U S A. 2007;104(28):11832-7.
24. Huang X, Motea EA, Moore ZR, Yao J, Dong Y, Chakrabarti G, et al. Leveraging an NQO1 bioactivatable drug for tumor-selective use of poly (ADP-ribose) polymerase inhibitors. Cancer cell. 2016;30(6):940-52.
25. Lee J, Choi D, Chung H, Seo H, Woo H, Choi B, et al. β-lapachone induces growth inhibition and apoptosis in bladder cancer cells by modulation of Bcl-2 family and activation of caspases. Experimental oncology. 2006:28:30-35.
26. Cox LA, Chen G, Eva Y-HL. Tumor suppressor genes and their roles in breast cancer. Breast cancer research and treatment. 1994;32(1):19-38.
27. Burkhart DL, Sage J. Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nature Reviews Cancer. 2008;8(9):671-82.
28. Bosco EE, Knudsen ES. RB in breast cancer: the crossroads of tumorigenesis and treatment. Cell cycle. 2007;6(6):667-71.
29. Hudis CA, Gianni L. Triple-negative breast cancer: an unmet medical need. Oncologist. 2011;16 Suppl 1:1-11.
30. VanArsdale T, Boshoff C, Arndt KT, Abraham RT. Molecular pathways: targeting the cyclin D–CDK4/6 axis for cancer treatment. Clinical cancer research. 2015;21(13):2905-10.
31. Ichim G, Tait SW. A fate worse than death: apoptosis as an oncogenic process. Nature Reviews Cancer. 2016;16(8):539.
32. Tait SW, Green DR. Mitochondria and cell death: outer membrane permeabilization and beyond. Nature reviews Molecular cell biology. 2010;11(9):621-32.
33. Telang N, Li G, Katdare M, Sepkovic D, Bradlow L, Wong G. Inhibitory effects of Chinese nutritional herbs in isogenic breast carcinoma cells with modulated estrogen receptor function. Oncol Lett. 2016;12(5):3949-57.
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