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Wikstromol from Wikstroemia indica induces apoptosis and suppresses migration of MDA-MB-231 cells via inhibiting PI3K/Akt pathway

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Abstract

Triple negative breast cancer (TNBC) is the most severe type of breast cancer due to the lack of specific targets and rapid metastasis, which result in the poor prognosis. Recently, phosphatidylinositol 3-kinase (PI3K)/Akt pathway has emerged as a potential target for the treatment of TNBC. In our research interest to discover phytochemicals targeting TNBC, we have investigated wikstromol from Wikstroemia indica using the human TNBC MDA-MB-231 cells. The results showed wikstromol at 10 μM inhibited cell growth of MDA-MB-231 cells which was confirmed by MTT assay. Further DAPI staining has revealed wikstromol at 10 μM induced apoptosis of cancer cells, which was associated with the activation of caspase-3 following down-regulation of Bcl-2 as well as up-regulation of Bax, cleaved PARP and phosphorylated p53. Meanwhile, it was observed at 0.1 μM wikstromol suppressed the migration of the cancer cells via decreasing transcription of NF-κB and reducing activity and secretion of downstream MMP-9. In addition, p-PI3K and p-Akt were down-regulated in MDA-MB-231 cells in the presence of wikstromol at 0.1 μM, which indicated inactivation of PI3K/Akt pathway was involved in these inhibitory effects.

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References

  1. Harbeck N, Gnant M (2017) Breast cancer. Lancet 389:1134–1150

    Article  Google Scholar 

  2. Garrido-Castro AC, Winer EP (2018) Predicting breast cancer therapeutic response. Nat Med 24:535–537

    Article  CAS  Google Scholar 

  3. Denkert C, Liedtke C, Tutt A, von Minckwitz G (2018) Molecular alterations in triple-negative breast cancer-the road to new treatment strategies. Lancet 389:2430–2442

    Article  Google Scholar 

  4. Pareja F, Reis-Filho JS (2018) Triple-negative breast cancers-a panoply of cancer types. Nat Rev Clin Oncol 15:347–348

    Article  CAS  Google Scholar 

  5. Bianchini G, Balko JM, Mayer IA, Sanders ME, Gianni L (2016) Triple-negative breast cancer: challenges and opportunities of a heterogeneous disease. Nat Rev Clin Oncol 13:674–690

    Article  CAS  Google Scholar 

  6. Delaloge S, DeForceville L (2017) Targeting PI3K/AKT pathway in triple-negative breast cancer. Lancet Oncol 18:1293–1294

    Article  CAS  Google Scholar 

  7. Goncalves MD, Hopkins BD, Cantley LC (2018) Phosphatidylinositol 3-kinase, growth disorders, and cancer. N Engl J Med 379:2052–2062

    Article  CAS  Google Scholar 

  8. Engelman JA (2009) Targeting PI3K signalling in cancer: opportunities, challenges and limitations. Nat Rev Cancer 9:550–562

    Article  CAS  Google Scholar 

  9. Vivanco I, Sawyers CL (2002) The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat Rev Cancer 2:489–501

    Article  CAS  Google Scholar 

  10. Khan MA, Jain VK, Rizwanullah M, Ahmad J, Jain K (2019) PI3K/AKT/mTOR pathway inhibitors in triple-negative breast cancer: a review on drug discovery and future challenges. Drug Discov Today 24:2181–2191

    Article  CAS  Google Scholar 

  11. Hong OY, Noh EM, Jang HY, Lee YR, Lee BK, Jung SH, Kim JS, Youn HJ (2017) Epigallocatechin gallate inhibits the growth of MDA-MB-231 breast cancer cells via inactivation of the β-catenin signaling. Oncol Lett 14:441–446

    Article  CAS  Google Scholar 

  12. Wang HC, Hu HH, Chang FR, Tsai JY, Kuo CY, Wu YC, Wu CC (2019) Different effects of 4-hydroxywithanolide E and withaferin A, two withanolides from Solanaceae plants, on the Akt signaling pathway in human breast cancer cells. Phytomedicine 53:213–222

    Article  CAS  Google Scholar 

  13. Kato A, Hashimoto Y, Kidokoro M (1979) (+)-Nortrachelogenin, a new pharmacologically active lignan from Wikstroemia indica. J Nat Prod 42:159–162

    Article  CAS  Google Scholar 

  14. Torrance SJ, Hoffmann JJ, Cole JR (1979) Wikstromol, antitumor lignan from Wikstroemia foetida var. oahuensis Gray and Wikstroemia uva-ursi Gray (Thymelaeaceae). J Pharm Sci 68:664–665

    Article  CAS  Google Scholar 

  15. Laavola M, Leppänen T, Eräsalo H, Hämäläinen M, Nieminen R, Moilanen E (2017) Anti-inflammatory effects of nortrachelogenin in murine J774 macrophages and in sarrageenan-induced paw edema model in the mouse. Planta Med 83:519–526

    CAS  PubMed  Google Scholar 

  16. Lee H, Ji YR, Ryoo ZY, Choi MS, Woo ER, Lee DG (2016) Antibacterial mechanism of (-)-nortrachelogenin in Escherichia coli O157. Curr Microbiol 72:48–54

    Article  CAS  Google Scholar 

  17. Peuhu E, Paul P, Remes M, Holmbom T, Eklund P, Sjöholm R, Eriksson JE (2013) The antitumor lignan nortrachelogenin sensitizes prostate cancer cells to TRAIL-induced cell death by inhibition of the Akt pathway and growth factor signaling. Biochem Pharmacol 86:571–583

    Article  CAS  Google Scholar 

  18. Yodkeeree S, Ampasavate C, Sung B, Aggarwal BB, Limtrakul P (2010) Demethoxycurcumin suppresses migration and invasion of MDA-MB-231 human breast cancer cell line. Eur J Pharmacol 627:8–15

    Article  CAS  Google Scholar 

  19. Julien O, Wells JA (2017) Caspases and their substrates. Cell Death Differ 24:1380–1389

    Article  CAS  Google Scholar 

  20. Budihardjo I, Oliver H, Lutter M, Luo X, Wang X (1999) Biochemical pathways of caspase activation during apoptosis. Annu Rev Cell Dev Biol 15:269–290

    Article  CAS  Google Scholar 

  21. Riedl SJ, Shi Y (2004) Molecular mechanisms of caspase regulation during apoptosis. Nat Rev Mol Cell Biol 5:897–907

    Article  CAS  Google Scholar 

  22. Duriez PJ, Shah GM (1997) Cleavage of poly(ADP-ribose) polymerase: a sensitive parameter to study cell death. Biochem Cell Biol 75:337–349

    Article  CAS  Google Scholar 

  23. Ola MS, Nawaz M, Ahsan H (2011) Role of Bcl-2 family proteins and caspases in the regulation of apoptosis. Mol Cell Biochem 351:41–58

    Article  CAS  Google Scholar 

  24. Youle RJ, Strasser A (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9:47–59

    Article  CAS  Google Scholar 

  25. Siddiqui WA, Ahad A, Ahsan H (2015) The mystery of BCL2 family: Bcl-2 proteins and apoptosis: an update. Arch Toxicol 89:289–317

    Article  CAS  Google Scholar 

  26. Choi YH, Yoo YH (2012) Taxol-induced growth arrest and apoptosis is associated with the upregulation of the Cdk inhibitor, p21WAF1/CIP1, in human breast cancer cells. Oncol Rep 28:2163–2169

    Article  CAS  Google Scholar 

  27. Rashmi KC, Raj MH, Paul M, Girish KS, Salimath BP, Aparna HS (2019) A new pyrrole based small molecule from Tinospora cordifolia induces apoptosis in MDA-MB-231 breast cancer cells via ROS mediated mitochondrial damage and restoration of p53 activity. Chem Biol Interact 299:120–130

    Article  CAS  Google Scholar 

  28. Guan X (2015) Cancer metastases: challenges and opportunities. Acta Pharm Sin B 5:402–418

    Article  Google Scholar 

  29. Dong H, Diao H, Zhao Y, Xu H, Pei S, Gao J, Wang J, Hussain T, Zhao D, Zhou X, Lin D (2019) Overexpression of matrix metalloproteinase-9 in breast cancer cell lines remarkably increases the cell malignancy largely via activation of transforming growth factor beta/SMAD signaling. Cell Prolif 52:e12633

    PubMed  PubMed Central  Google Scholar 

  30. Westermarck J, Kahari VM (1999) Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J 13:781–792

    Article  CAS  Google Scholar 

  31. Sliva D (2004) Signaling pathways responsible for cancer cell invasion as targets for cancer therapy. Curr Cancer Drug Targets 4:327–336

    Article  CAS  Google Scholar 

  32. Liu P, Cheng H, Roberts TM, Zhao JJ (2009) Targeting the phosphoinositide3-kinase pathway in cancer. Nat Rev Drug Discov 8:627–644

    Article  CAS  Google Scholar 

  33. Chen ZJ, Wei W, Jiang GM, Liu H, Wei WD, Yang X, Wu YM, Liu H, Wong CK, Du J, Wang HS (2016) Activation of GPER suppresses epithelial mesenchymal transition of triple negative breast cancer cells via NF-κB signals. Mol Oncol 10:775–788

    Article  CAS  Google Scholar 

  34. Tungsukruthai S, Petpiroon N, Chanvorachote P (2018) Molecular mechanisms of breast cancer metastasis and potential anti-metastatic compounds. Anticancer Res 38:2607–2618

    CAS  PubMed  Google Scholar 

  35. Abraham AG, O’Neill E (2014) PI3K/Akt-mediated regulation of p53 in cancer. Biochem Soc Trans 42:798–803

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of Pharmacy, Xuzhou Medical University, No. 209 Tongshan Road, Xuzhou, 221004, Jiangsu, China

    Huankai Yao, Nan Zhang, Yan Li & Qunli Wei

  2. Shanxian Central Hospital, Heze, 274300, Shandong, China

    Xiuli Zhang

  3. Department of Pharmacy, The Hospital Affiliated to Nanjing University of Traditional Chinese Medicine (Taizhou People’s Hospital), Taizhou, 225300, Jiangsu, China

    Jindong Li

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  1. Huankai Yao
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  2. Xiuli Zhang
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  5. Yan Li
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  6. Qunli Wei
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Correspondence to Yan Li.

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Yao, H., Zhang, X., Zhang, N. et al. Wikstromol from Wikstroemia indica induces apoptosis and suppresses migration of MDA-MB-231 cells via inhibiting PI3K/Akt pathway. J Nat Med 75, 178–185 (2021). https://doi.org/10.1007/s11418-020-01447-0

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  • DOI: https://doi.org/10.1007/s11418-020-01447-0

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