Baicalin inhibits growth and induces apoptosis of human osteosarcoma cells by suppressing the AKT pathway

Liu,Yu; Hong,Zhenqiang; Chen,Peng; Wang,Jinzhao; Zhou,Yimin; Huang,Jianyun

doi:10.3892/ol.2019.10617

Baicalin inhibits growth and induces apoptosis of human osteosarcoma cells by suppressing the AKT pathway

Authors:
- Yu Liu
- Zhenqiang Hong
- Peng Chen
- Jinzhao Wang
- Yimin Zhou
- Jianyun Huang
View Affiliations

Affiliations: Fujian University of Traditional Chinese Medicine, Key Laboratory of Orthopedics and Traumatology of Traditional Chinese Medicine and Rehabilitation, Ministry of Education, Fuzhou, Fujian 350122, P.R. China, Department of Orthopedics, Third Affiliated Hospital of Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, P.R. China
Published online on: July 15, 2019 https://doi.org/10.3892/ol.2019.10617
Pages: 3188-3194
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Osteosarcoma (OS) is one of the most prevalent types of bone malignancies with poor overall prognosis, and is reported mainly in children and adolescents. Therefore, the investigation of novel and efficient treatment strategies for patients with OS is required. Baicalin exhibits potential anticancer effects, including in OS. However, its therapeutic effect against OS and the underlying mechanisms have not been fully evaluated. In the present study, the effect of baicalin on the proliferation and apoptosis of OS cells and its underlying mechanism of AKT pathway activation was explored. Cell confluence and cell number counts revealed suppressed the growth of OS cells that were treated with baicalin. Analysis of cell viability, cell survival and cell cycle, as well as cell apoptosis revealed decreased cell viability and survival, induced cell cycle arrest and apoptosis of treated cells. Western blot analysis demonstrated significantly decreased ratios of phosphorylated‑AKT/AKT and Bcl‑2/Bax, and decreased protein levels of cyclin D1 and CDK4 in cells treated with baicalin. Thus, the findings from the present study suggest that the suppression of the AKT pathway may be the underlying mechanism of the antitumor effect of baicalin in OS cells.

View Figures

View References

1	Mirabello L, Troisi RJ and Savage SA: Osteosarcoma incidence and survival rates from 1973 to 2004: Data from the surveillance, epidemiology, and end results program. Cancer. 115:1531–1543. 2009. View Article : Google Scholar : PubMed/NCBI
2	Dong F, Liu T, Jin H and Wang W: Chimaphilin inhibits human osteosarcoma cell invasion and metastasis through suppressing the TGF-β1-induced epithelial-to-mesenchymal transition markers via PI-3K/Akt, ERK1/2, and Smad signaling pathways. Can J Physiol Pharmacol. 96:1–7. 2018. View Article : Google Scholar : PubMed/NCBI
3	Wang Y, Li L, Shao N, Hu Z, Chen H, Xu L, Wang C, Cheng Y and Xiao J: Triazine-modified dendrimer for efficient TRAIL gene therapy in osteosarcoma. Acta Biomater. 17:115–124. 2015. View Article : Google Scholar : PubMed/NCBI
4	Bienemann K, Staege MS, Howe SJ, Sena-Esteves M, Hanenberg H and Kramm CM: Targeted expression of human folylpolyglutamate synthase for selective enhancement of methotrexate chemotherapy in osteosarcoma cells. Cancer Gene Ther. 20:514–520. 2013. View Article : Google Scholar : PubMed/NCBI
5	Wu G, Liang Q and Liu Y: Primary osteosarcoma of frontal bone: A case report and review of literature. Medicine (Baltimore). 96:e93922017. View Article : Google Scholar : PubMed/NCBI
6	Liu J, Zhang L, Ren Y, Gao Y, Kang L and Qiao Q: Anticancer and immunoregulatory activity of Gynostemma pentaphyllum polysaccharides in H22 tumor-bearing mice. Int J Biol Macromol. 69:1–4. 2014. View Article : Google Scholar : PubMed/NCBI
7	Li B, Wan L, Li Y, Yu Q, Chen P, Gan R, Yang Q, Han Y and Guo C: Baicalin, a component of Scutellaria baicalensis, alleviates anorexia and inhibits skeletal muscle atrophy in experimental cancer cachexia. Tumour Biol. 35:12415–12425. 2014. View Article : Google Scholar : PubMed/NCBI
8	Gao Z, Huang K and Xu H: Protective effects of flavonoids in the roots of Scutellaria baicalensis Georgi against hydrogen peroxide-induced oxidative stress in HS-SY5Y cells. Pharmacol Res. 43:173–178. 2001. View Article : Google Scholar : PubMed/NCBI
9	Ikezoe T, ChenS S, Heber D, Taguchi H and Koeffler HP: Baicalin is a major component of PC-SPES which inhibits the proliferation of human cancer cells via apoptosis and cell cycle arrest. Prostate. 49:285–292. 2001. View Article : Google Scholar : PubMed/NCBI
10	Shen YC, Chiou WF, Chou YC and Chen CF: Mechanisms in mediating the anti-inflammatory effects of baicalin and baicalein in human leukocytes. Eur J Pharmacol. 465:171–181. 2003. View Article : Google Scholar : PubMed/NCBI
11	Dong LH, Wen JK, Miao SB, Jia Z, Hu HJ, Sun RH, Wu Y and Han M: Baicalin inhibits PDGF-BB-stimulated vascular smooth muscle cell proliferation through suppressing PDGFRβ-ERK signaling and increase in p27 accumulation and prevents injury-induced neointimal hyperplasia. Cell Res. 20:1252–1262. 2010. View Article : Google Scholar : PubMed/NCBI
12	Chen WC, Kuo TH, Tzeng YS and Tsai YC: Baicalin induces apoptosis in SW620 human colorectal carcinoma cells in vitro and suppresses tumor growth in vivo. Molecules. 17:3844–3857. 2012. View Article : Google Scholar : PubMed/NCBI
13	Yu Y, Pei M and Li L: Baicalin induces apoptosis in hepatic cancer cells in vitro and suppresses tumor growth in vivo. Int J Clin Exp Med. 8:8958–8967. 2015.PubMed/NCBI
14	Wang H, Li H, Chen F, Luo J, Gu J, Wang H, Wu H and Xu Y: Baicalin extracted from Huangqin (Radix Scutellariae Baicalensis) induces apoptosis in gastric cancer cells by regulating B cell lymphoma (Bcl-2)/Bcl-2-associated X protein and activating caspase-3 and caspase-9. J Tradit Chin Med. 37:229–235. 2017. View Article : Google Scholar : PubMed/NCBI
15	Dou J, Wang Z, Ma L, Peng B, Mao K, Li C, Su M, Zhou C and Peng G: Baicalein and baicalin inhibit colon cancer using two distinct fashions of apoptosis and senescence. Oncotarget. 9:20089–20102. 2018. View Article : Google Scholar : PubMed/NCBI
16	Zhou T, Zhang A, Kuang G, Gong X, Jiang R, Lin D, Li J and Li H, Zhang X, Wan J and Li H: Baicalin inhibits the metastasis of highly aggressive breast cancer cells by reversing epithelial-to-mesenchymal transition by targeting β-catenin signaling. Oncol Rep. 38:3599–3607. 2017.PubMed/NCBI
17	Wang XF, Zhou QM, Du J, Zhang H, Lu YY and Su SB: Baicalin suppresses migration, invasion and metastasis of breast cancer via p38MAPK signaling pathway. Anticancer Agents Med Chem. 13:923–931. 2013. View Article : Google Scholar : PubMed/NCBI
18	Wang Z, Ma L, Su M, Zhou Y, Mao K, Li C, Peng G, Zhou C, Shen B and Dou J: Baicalin induces cellular senescence in human colon cancer cells via upregulation of DEPP and the activation of Ras/Raf/MEK/ERK signaling. Cell Death Dis. 9:2172018. View Article : Google Scholar : PubMed/NCBI
19	Wang Q, Xu H and Zhao X: Baicalin inhibits human cervical cancer cells by suppressing protein kinase C/signal transducer and activator of transcription (PKC/STAT3) signaling pathway. Med Sci Monit. 24:1955–1961. 2018. View Article : Google Scholar : PubMed/NCBI
20	Wan D and Ouyang H: Baicalin induces apoptosis in human osteosarcoma cell through ROS-mediated mitochondrial pathway. Nat Prod Res. 32:1996–2000. 2018. View Article : Google Scholar : PubMed/NCBI
21	Wang Y, Wang H, Zhou R, Zhong W, Lu S, Ma Z and Chai Y: Baicalin inhibits human osteosarcoma cells invasion, metastasis, and anoikis resistance by suppressing the transforming growth factor-β1-induced epithelial-to-mesenchymal transition. Anticancer Drugs. 28:581–587. 2017. View Article : Google Scholar : PubMed/NCBI
22	Abeyrathna P and Su Y: The critical role of Akt in cardiovascular function. Vascul Pharmacol. 74:38–48. 2015. View Article : Google Scholar : PubMed/NCBI
23	Martini M, De Santis MC, Braccini L, Gulluni F and Hirsch E: PI3K/AKT signaling pathway and cancer: An updated review. Ann Med. 46:372–383. 2014. View Article : Google Scholar : PubMed/NCBI
24	Porta C, Paglino C and Mosca A: Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol. 4:642014. View Article : Google Scholar : PubMed/NCBI
25	Zhang J, Yu XH, Yan YG, Wang C and Wang WJ: PI3K/Akt signaling in osteosarcoma. Clin Chim Acta. 444:182–192. 2015. View Article : Google Scholar : PubMed/NCBI
26	Zhou Y, Zhu LB, Peng AF, Wang TF, Long XH, Gao S, Zhou RP and Liu ZL: LY294002 inhibits the malignant phenotype of osteosarcoma cells by modulating the phosphatidylinositol 3-kinase/Akt/fatty acid synthase signaling pathway in vitro. Mol Med Rep. 11:1352–1357. 2015. View Article : Google Scholar : PubMed/NCBI
27	Zhang B, Li YL, Zhao JL, Zhen O, Yu C, Yang BH and Yu XR: Hypoxia-inducible factor-1 promotes cancer progression through activating AKT/Cyclin D1 signaling pathway in osteosarcoma. Biomed Pharmacother. 105:1–9. 2018. View Article : Google Scholar : PubMed/NCBI
28	Ren L, Hong ES, Mendoza A, Issaq S, Tran Hoang C, LeBlanc A and Khanna C: Metabolomics uncovers a link between inositol metabolism and osteosarcoma metastasis. Oncotarget. 8:38541–38553. 2017.PubMed/NCBI
29	Zhang Y, Hu H, Song L, Cai L, Wei R and Jin W: Epirubicin-mediated expression of miR-302b is involved in osteosarcoma apoptosis and cell cycle regulation. Toxicol Lett. 222:1–9. 2013. View Article : Google Scholar : PubMed/NCBI
30	Zhang K, Tian F, Zhang Y, Zhu Q, Xue N, Zhu H, Wang H and Guo X: MACC1 is involved in the regulation of proliferation, colony formation, invasion ability, cell cycle distribution, apoptosis and tumorigenicity by altering Akt signaling pathway in human osteosarcoma. Tumour Biol. 35:2537–2548. 2014. View Article : Google Scholar : PubMed/NCBI
31	Li G, Cai M, Fu D, Chen K, Sun M, Cai Z and Cheng B: Heat shock protein 90B1 plays an oncogenic role and is a target of microRNA-223 in human osteosarcoma. Cell Physiol Biochem. 30:1481–1490. 2012. View Article : Google Scholar : PubMed/NCBI
32	Atif F, Yousuf S and Stein DG: Anti-tumor effects of progesterone in human glioblastoma multiforme: Role of PI3K/Akt/mTOR signaling. J Steroid Biochem Mol Biol. 146:62–73. 2015. View Article : Google Scholar : PubMed/NCBI
33	Zhuo B, Li Y, Li Z, Qin H, Sun Q, Zhang F, Shen Y, Shi Y and Wang R: PI3K/Akt signaling mediated Hexokinase-2 expression inhibits cell apoptosis and promotes tumor growth in pediatric osteosarcoma. Biochem Biophys Res Commun. 464:401–406. 2015. View Article : Google Scholar : PubMed/NCBI
34	Wang Y, Wan D, Zhou R, Zhong W, Lu S and Chai Y: Geraniin inhibits migration and invasion of human osteosarcoma cancer cells through regulation of PI3K/Akt and ERK1/2 signaling pathways. Anticancer Drugs. 28:959–966. 2017. View Article : Google Scholar : PubMed/NCBI
35	Angulo P, Kaushik G, Subramaniam D, Dandawate P, Neville K, Chastain K and Anant S: Natural compounds targeting major cell signaling pathways: A novel paradigm for osteosarcoma therapy. J Hematol Oncol. 10:102017. View Article : Google Scholar : PubMed/NCBI
36	Lee J and Kim JH: Kaempferol inhibits pancreatic cancer cell growth and migration through the blockade of EGFR-related pathway in vitro. PLoS One. 11:e01552642016. View Article : Google Scholar : PubMed/NCBI
37	Li L, Wei L, Shen A, Chu J, Lin J and Peng J: Oleanolic acid modulates multiple intracellular targets to inhibit colorectal cancer growth. Int J Oncol. 47:2247–2254. 2015. View Article : Google Scholar : PubMed/NCBI