Berberine chloride inhibits proliferation and angiogenesis in triple-negative breast cancer by down-regulating HIF-1α/VEGF/Ang pathway
DOI:
https://doi.org/10.3329/bjp.v20i2.80837Keywords:
Ang pathway, Angiogenesis, Berberine chloride, HIF-1α pathway, MTT assay, Triple-negative breast cancer, VEGF pathwayAbstract
In triple-negative breast cancer, intratumoral hypoxia drives tumor progression via HIF-1α-mediated angiogenesis. The study aims to analyze the efficacy of berberine chloride on tumor proliferation and angiogenesis in triple-negative breast cancer mediated by HIF-1α. The triple-negative breast cancer cells were subjected to berberine chloride, and the effects on cell viability, apoptosis, and angiogenic gene expression were assessed. MTT assay determined the IC50 as 9.5 µM. Fluorescent imaging confirmed apoptosis through membrane disintegration, fragmented DNA, and the presence of apoptotic bodies. Real-time PCR analysis showed significant down-regulation of HIF-1α (p<0.01), VEGF (p<0.05), Ang1 (p<0.05), and Ang2 (p<0.01) after berberine chloride treatment. These findings indicate the efficacy of berberine chloride in inhibiting triple-negative breast cancer cell proliferation and angiogenesis, highlighting its potential as a therapeutic candidate.
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Afsar T, Trembley JH, Salomon CE, Razak S, Khan MR, Ahmed K. Growth inhibition and apoptosis in cancer cells induced by polyphenolic compounds of Acacia hydaspica: Involvement of multiple signal transduction pathways. Sci Rep. 2016; 6: 23077.
Asahara T, Chen D, Takahashi T, Fujikawa K, Kearney M, Magner M, Yancopoulos GD, Isner JM. Tie2 receptor ligands, angiopoietin-1 and angiopoietin-2, modulate VEGF-induced postnatal neovascularization. Circ Res. 1998; 83: 233-40.
Bailey CM, Liu Y, Peng G, Zhang H, He M, Sun D, Zheng P, Liu Y, Wang Y. Liposomal formulation of HIF-1alpha inhibitor echinomycin eliminates established metastases of triple-negative breast cancer. Nanomedicine 2020; 29: 102278-78.
Baskic D, Popovic S, Ristic P, Arsenijevic N. Analysis of cycloheximide-induced apoptosis in human leukocytes: Fluorescence microscopy using annexin V/propidium iodide versus acridine orange/ethidium bromide. Cell Biol Int. 2006; 30: 924-32.
Bianchini G, Balko JM, Mayer IA, Sanders ME, Gianni L. Triple-negative breast cancer: Challenges and opportunities of a heterogeneous disease. Nat Rev Clin Oncol. 2016; 13: 674-90.
Briggs KJ, Koivunen P, Cao S, Backus KM, Olenchock BA, Patel H, Zhang Q, Signoretti S, Gerfen GJ, Richardson AL, Witkiewicz AK. Paracrine induction of HIF by glutamate in breast cancer: EglN1 senses cysteine. Cell. 2016; 166: 126-39.
Cui HJ, Yang AL, Zhou HJ, Wang C, Luo JK, Lin Y, Zong YX, Tang T. Buyang Huanwu decoction promotes angiogenesis via vascular endothelial growth factor receptor-2 activation through the PI3K/Akt pathway in a mouse model of intracerebral hemorrhage. BMC Complement Altern Med. 2015; 15: 91-97.
Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA, Lickley LA, Rawlinson E, Sun P, Narod SA. Triple-negative breast cancer: Clinical features and patterns of recurrence. Clin Cancer Res. 2007; 13: 4429-34.
El Khalki L, Maire V, Dubois T, Zyad A. Berberine impairs the survival of triple-negative breast cancer cells: Cellular and molecular analyses. Molecules 2020; 25: 506-06.
Elisa P, Elisa D, Fiorenza O, Guendalina L, Beatrice B, Paolo L, Carmela S, Cristina G, Abele D, Mauro P. Antiangiogenic and antitumor activities of berberine derivative NAX014 compound in a transgenic murine model of HER2/neu-positive mammary carcinoma. Carcinogenesis 2015; 36: 1169-79.
Fazeela MBSM, Sankarram M. Phytochemical characterization by GC-MS and in vitro evaluation of antiproliferative and antimigratory studies of Leucas aspera leaf extracts on MDA-MB-231 cell line. Bio Technologia (Pozn). 2024; 105: 55-68.
Filli M, Ibrahim A, Kesse S, Aquib M, Boakye-Yiadom K, Farooq M. Synthetic berberine derivatives as potential new drugs. Braz J Pharm Sci. 2020; 58: 1-19.
Hacker G. The morphology of apoptosis. Cell Tissue Res. 2000; 301: 5-17.
Hamsa TP, Kuttan G. Antiangiogenic activity of berberine is mediated through the downregulation of hypoxia-inducible factor-1, VEGF, and proinflammatory mediators. Drug Chem Toxicol. 2011; 35: 57–70.
Hoff PM, Machado K. Role of angiogenesis in the pathogenesis of cancer. Cancer Treat Rev. 2012; 38: 825-33.
Jin J, Qiu S, Wang P, Liang X, Huang F, Wu H, Zhang B, Zhang W, Tian X, Xu R, Shi H, Wu X. Cardamonin inhibits breast cancer growth by repressing HIF-1alpha-dependent metabolic reprogramming. J Exp Clin Cancer Res. 2019; 38: 377.
Khosravi SZ, Ramshe SM, Farsani MA, Solali S, Moonesi M, Hagh MF. Investigating the expression pattern of the angiopoietin-Tie system in ALL and its correlation with baseline characteristics. Blood Res. 2021; 56: 79-85.
Letasiova S, Jantova S, Miko M, Ovadekova R, Horvathova M. Effect of berberine on proliferation, biosynthesis of macromolecules, cell cycle, and induction of intercalation with DNA, dsDNA damage, and apoptosis in Ehrlich ascites carcinoma cells. J Pharm Pharmacol. 2006; 58: 263-70.
Li Q, Zhao H, Chen W, Huang P. Berberine induces apoptosis and arrests the cell cycle in multiple cancer cell lines. AMS. 2023; 19: 1530-37.
Liu ZJ, Semenza GL, Zhang HF. Hypoxia-inducible factor 1 and breast cancer metastasis. J Zhejiang Univ Sci B. 2015; 16: 32-43.
Magar AG, Morya VK, Kwak MK, Oh JU, Noh KC. A molecular perspective on HIF-1α and angiogenic stimulator networks and their role in solid tumors: An update. Int J Mol Sci. 2024; 25: 3313.
Mazzieri R, Pucci F, Moi D. Targeting the ANG2/TIE2 axis inhibits tumor growth and metastasis by impairing angiogenesis and disabling rebounds of proangiogenic myeloid cells. Cancer Cell. 2011; 19: 512-26.
Mir Hassani Z, Nabiuni M, Parivar K, Abdirad S, Karimzadeh L. Melittin inhibits the expression of key genes involved in tumor microenvironment formation by suppressing HIF-1alpha signaling in breast cancer cells. Med Oncol. 2021; 38: 77.
Rajoriya M, Kataria N, Kumar M, Saini A. Berberine chloride inhibits TNBC cell metastasis by downregulating expression of matrix metalloproteinases. Ann Oncol. 2021; 32: S1363-64.
Saharinen P, Eklund L, Pulkki K, Bono P, Alitalo K. VEGF and angiopoietin signaling in tumor angiogenesis and metastasis. Trends Mol Med. 2011; 17: 347-62.
Salek A, Selmi M, Barboura M, Martinez MC, Chekir-Ghedira L, Andriantsitohaina R. Enhancement of the in vitro antitumor effects of berberine chloride when encapsulated within small extracellular vesicles. Pharmaceutics 2022; 9: 1913.
Slemc L, Kunej T. Transcription factor HIF1A: downstream targets, associated pathways, polymorphic hypoxia response element (HRE) sites, and initiative for standardization of reporting in scientific literature. Tumour Biol. 2016; 37: 14851-61.
Su Q, Wang J, Wu Q, Ullah A, Ghauri MA, Sarwar A, Chen L, Liu F, Zhang Y. Sanguinarine combats hypoxia-induced activation of EphB4 and HIF-1alpha pathways in breast cancer. Phytomedicine 2021; 84: 153503-03.
Wang K, Feng X, Chai L, Cao S, Qiu F. The metabolism of berberine and its contribution to the pharmacological effects. Drug Metab Rev. 2017; 49: 139-57.
Yadav L, Puri N, Rastogi V, Satpute P, Sharma V. Tumour angiogenesis and angiogenic inhibitors: A review. J Clin Diagn Res. 2015; 9: XE01-05.
Yam C, Mani SA, Moulder SL. Targeting the molecular subtypes of triple-negative breast cancer: understanding the diversity to progress the field. Oncologist 2017; 22: 1086-93.
Yamakawa M, Liu LX, Date T, Belanger AJ, Vincent KA, Akita GY, Kuriyama T, Cheng SH, Gregory RJ, Jiang C. Hypoxia-inducible factor-1 mediates activation of cultured vascular endothelial cells by inducing multiple angiogenic factors. Circ Res. 2003; 93: 664-73.
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Copyright (c) 2025 Nishmaa Sulthan Mohideen, Venkatalakshmi Ranganathan, Fazeela Mahaboob Begum S. Mohamed Nainar
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