Gubenyiliu II Inhibits Breast Tumor Growth and Metastasis Associated with Decreased Heparanase Expression and Phosphorylation of ERK and AKT Pathways

Overview

Journal Molecules

Publisher MDPI

Specialty Biology

Date 2017 May 16

PMID 28505136

Citations 5

Authors

Yi Zhang

Gan-Lin Zhang

Xu Sun

Ke-Xin Cao

Ya-Wen Shang

Mu-Xin Gong

Cong Ma

Nan Nan

Jin-Ping Li

Ming-Wei Yu

Guo-Wang Yang

Xiao-Min Wang

Affiliations

Soon will be listed here.

Abstract

II (GYII), a Traditional Chinese Medicine (TCM) formula used in our hospital, has shown beneficial effects in cancer patients. In this study, we investigated the molecular mechanisms underlying the beneficial effects of GYII on murine breast cancer models. GYII showed significant inhibitory effects on tumor growth and metastasis in the murine breast cancer model. Additionally, GYII suppressed the proliferation of 4T1 and MCF-7 cells in a dose-dependent manner. A better inhibitory effect on 4T1 cell proliferation and migration was found in the decomposed recipes (DR) of GYII. Moreover, heparanase expression and the degree of angiogenesis were reduced in tumor tissues. Western blot analysis showed decreased expression of heparanase and growth factors in the cells treated with GYII and its decomposed recipes (DR2 and DR3), and thereby a reduction in the phosphorylation of extracellular signal-regulated kinase (ERK) and serine-threonine kinase (AKT). These results suggest that GYII exerts anti-tumor growth and anti-metastatic effects in the murine breast cancer model. The anti-tumor activity of GYII and its decomposed recipes is, at least partly, associated with decreased heparanase and growth factor expression, which subsequently suppressed the activation of the ERK and AKT pathways.

Citing Articles

Recent Advances in Anti-Metastatic Approaches of Herbal Medicines in 5 Major Cancers: From Traditional Medicine to Modern Drug Discovery.

Park J, Jeong D, Song M, Kim B Antioxidants (Basel). 2021; 10(4).

PMID: 33801741 PMC: 8065873. DOI: 10.3390/antiox10040527.

CDCA5 promotes the progression of prostate cancer by affecting the ERK signalling pathway.

Ji J, Shen T, Li Y, Liu Y, Shang Z, Niu Y Oncol Rep. 2021; 45(3):921-932.

PMID: 33650660 PMC: 7859918. DOI: 10.3892/or.2021.7920.

Hinokitiol reduces tumor metastasis by inhibiting heparanase via extracellular signal-regulated kinase and protein kinase B pathway.

Wu Y, Hsu W, Wu L, Liou H, Pangilinan C, Tyan Y Int J Med Sci. 2020; 17(3):403-413.

PMID: 32132875 PMC: 7053356. DOI: 10.7150/ijms.41177.

Targeting VEGF/VEGFRs Pathway in the Antiangiogenic Treatment of Human Cancers by Traditional Chinese Medicine.

Zhang C, Wang N, Tan H, Guo W, Li S, Feng Y Integr Cancer Ther. 2018; 17(3):582-601.

PMID: 29807443 PMC: 6142106. DOI: 10.1177/1534735418775828.

Anti‑cancer effects of fisetin on mammary carcinoma cells via regulation of the PI3K/Akt/mTOR pathway: In vitro and in vivo studies.

Sun X, Ma X, Li Q, Yang Y, Xu X, Sun J Int J Mol Med. 2018; 42(2):811-820.

PMID: 29749427 PMC: 6034928. DOI: 10.3892/ijmm.2018.3654.

References

Lou C, Zhu Z, Zhao Y, Zhu R, Zhao H . Arctigenin, a lignan from Arctium lappa L., inhibits metastasis of human breast cancer cells through the downregulation of MMP-2/-9 and heparanase in MDA-MB-231 cells. Oncol Rep. 2016; 37(1):179-184. DOI: 10.3892/or.2016.5269. View

Liang F, Li L, Wang M, Niu X, Zhan J, He X . Molecular network and chemical fragment-based characteristics of medicinal herbs with cold and hot properties from Chinese medicine. J Ethnopharmacol. 2013; 148(3):770-9. DOI: 10.1016/j.jep.2013.04.055. View

Guo Q, Li J, Lin H . Effect and Molecular Mechanisms of Traditional Chinese Medicine on Regulating Tumor Immunosuppressive Microenvironment. Biomed Res Int. 2015; 2015:261620. PMC: 4486742. DOI: 10.1155/2015/261620. View

Li S, Chen H, Ou-Yang C, Wang X, Yang Z, Tong Y . The efficacy of Chinese herbal medicine as an adjunctive therapy for advanced non-small cell lung cancer: a systematic review and meta-analysis. PLoS One. 2013; 8(2):e57604. PMC: 3585199. DOI: 10.1371/journal.pone.0057604. View

Cohen I, Pappo O, Elkin M, San T, Bar-Shavit R, Hazan R . Heparanase promotes growth, angiogenesis and survival of primary breast tumors. Int J Cancer. 2005; 118(7):1609-17. DOI: 10.1002/ijc.21552. View

Ilan N, Elkin M, Vlodavsky I . Regulation, function and clinical significance of heparanase in cancer metastasis and angiogenesis. Int J Biochem Cell Biol. 2006; 38(12):2018-39. DOI: 10.1016/j.biocel.2006.06.004. View

Xiong F, Jiang M, Huang Z, Chen M, Chen K, Zhou J . A novel herbal formula induces cell cycle arrest and apoptosis in association with suppressing the PI3K/AKT pathway in human lung cancer A549 cells. Integr Cancer Ther. 2013; 13(2):152-60. DOI: 10.1177/1534735413503544. View

Deng W, Sui H, Wang Q, He N, Duan C, Han L . A Chinese herbal formula, Yi-Qi-Fu-Sheng, inhibits migration/invasion of colorectal cancer by down-regulating MMP-2/9 via inhibiting the activation of ERK/MAPK signaling pathways. BMC Complement Altern Med. 2013; 13:65. PMC: 3617034. DOI: 10.1186/1472-6882-13-65. View

Doviner V, Maly B, Kaplan V, Gingis-Velitski S, Ilan N, Vlodavsky I . Spatial and temporal heparanase expression in colon mucosa throughout the adenoma-carcinoma sequence. Mod Pathol. 2006; 19(6):878-88. DOI: 10.1038/modpathol.3800603. View

10.

Liu H, Zhang W, Dong S, Song L, Zhao S, Wu C . Protective effects of sea buckthorn polysaccharide extracts against LPS/d-GalN-induced acute liver failure in mice via suppressing TLR4-NF-κB signaling. J Ethnopharmacol. 2015; 176:69-78. DOI: 10.1016/j.jep.2015.10.029. View

11.

Wang N, Feng Y, Cheung F, Wang X, Zhang Z, Feng Y . A Chinese medicine formula Gegen Qinlian decoction suppresses expansion of human renal carcinoma with inhibition of matrix metalloproteinase-2. Integr Cancer Ther. 2014; 14(1):75-85. DOI: 10.1177/1534735414550036. View

12.

Pierpaoli E, Damiani E, Orlando F, Lucarini G, Bartozzi B, Lombardi P . Antiangiogenic and antitumor activities of berberine derivative NAX014 compound in a transgenic murine model of HER2/neu-positive mammary carcinoma. Carcinogenesis. 2015; 36(10):1169-79. DOI: 10.1093/carcin/bgv103. View

13.

Vlodavsky I, Friedmann Y . Molecular properties and involvement of heparanase in cancer metastasis and angiogenesis. J Clin Invest. 2001; 108(3):341-7. PMC: 209369. DOI: 10.1172/JCI13662. View

14.

Yamanoi A, Ono T, Kohno H, Nagasue N . The clinicopathological significance of heparanase and basic fibroblast growth factor expressions in hepatocellular carcinoma. Clin Cancer Res. 2001; 7(5):1299-305. View

15.

Miao H, Elkin M, Aingorn E, Stein C, Vlodavsky I . Inhibition of heparanase activity and tumor metastasis by laminarin sulfate and synthetic phosphorothioate oligodeoxynucleotides. Int J Cancer. 1999; 83(3):424-31. DOI: 10.1002/(sici)1097-0215(19991029)83:3<424::aid-ijc20>3.0.co;2-l. View

16.

Li J . Heparin, heparan sulfate and heparanase in cancer: remedy for metastasis?. Anticancer Agents Med Chem. 2008; 8(1):64-76. DOI: 10.2174/187152008783330824. View

17.

Sun X, Zhang G, Nian J, Yu M, Chen S, Zhang Y . Elevated heparanase expression is associated with poor prognosis in breast cancer: a study based on systematic review and TCGA data. Oncotarget. 2017; 8(26):43521-43535. PMC: 5522166. DOI: 10.18632/oncotarget.16575. View

18.

Chen T, Li D, Fu Y, Hu W . Screening of QHF formula for effective ingredients from Chinese herbs and its anti-hepatic cell cancer effect in combination with chemotherapy. Chin Med J (Engl). 2008; 121(4):363-8. View

19.

Liu X, Fang H, Yang Z, Wang X, Ruan L, Fang D . Matrine inhibits invasiveness and metastasis of human malignant melanoma cell line A375 in vitro. Int J Dermatol. 2008; 47(5):448-56. DOI: 10.1111/j.1365-4632.2008.03627.x. View

20.

Ferro V, Dredge K, Liu L, Hammond E, Bytheway I, Li C . PI-88 and novel heparan sulfate mimetics inhibit angiogenesis. Semin Thromb Hemost. 2007; 33(5):557-68. DOI: 10.1055/s-2007-982088. View