Tanshinone IIA exerts antitumor activity against vestibular schwannoma cells by inhibiting the expression of hypoxia-inducible factor-1α

Kim,Ju  Yeon; Song,Jae‑Jun; Kwon,Byoung‑Mog; Lee,Jong   Dae

doi:10.3892/mmr.2015.3932

Tanshinone IIA exerts antitumor activity against vestibular schwannoma cells by inhibiting the expression of hypoxia-inducible factor-1α

Authors:
- Ju Yeon Kim
- Jae‑Jun Song
- Byoung‑Mog Kwon
- Jong Dae Lee
View Affiliations

Affiliations: Department of Otorhinolaryngology ‑ Head and Neck Surgery, Soonchunhyang University College of Medicine, Bucheon‑si, Gyeonggi‑do 420‑767, Republic of Korea, Department of Otorhinolaryngology ‑ Head and Neck Surgery, Korea University College of Medicine, Seoul 158‑867, Republic of Korea, Laboratory of Chemical Biology and Genomics, Korea Research Institute of Bioscience and Biotechnology, University of Science and Technology, Daejeon 300‑718, Republic of Korea
Published online on: June 15, 2015 https://doi.org/10.3892/mmr.2015.3932
Pages: 4604-4609

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

The aim of the present study was to evaluate the effect of the herbal medicine, tanshinone IIA (Tan IIA), on vestibular schwannoma (VS) cells and assess the functional targets of Tan IIA. HEI‑193 cells and Nf2‑/‑mouse Schwann (SC4) cells were used to investigate the inhibitory effects of Tan IIA on VS. Cell viability was measured using an MTT assay and apoptosis was assessed by flow cytometry. Western blot analysis and reverse transcription quantitative polymerase chain reaction (RT‑qPCR) were performed to assess the expression of hypoxia‑inducible factor‑1α (HIF‑1α) and its signaling pathways. In addition, the effect of Tan IIA on HIF‑1α transcription was determined using a luciferase reporter assay. Schwannoma cell proliferation was observed to be inhibited as the Tan IIA concentration increased under normoxic and hypoxic conditions. Furthermore, Tan IIA induced apoptosis in the HEI‑193 cells and inhibited the protein expression of HIF‑1α in the HEI‑193 cells under hypoxia, thus repressing the transcriptional activity of HIF‑1α. The present study demonstrated that HIF‑1α is expressed in hypoxic VS cells and Tan IIA inhibits VS cells by suppressing the activity of HIF‑1α. In conclusion, these results indicate that Tan IIA is a potential chemotherapeutic agent for the treatment of VS.

View Figures

View References

1	Theodosopoulos PV and Pensak ML: Contemporary management of acoustic neuromas. Laryngoscope. 121:1133–1137. 2011. View Article : Google Scholar : PubMed/NCBI
2	Zhou L, Zuo Z and Chow MS: Danshen: An overview of its chemistry, pharmacology, pharmacokinetics, and clinical use. J Clin Pharmacol. 45:1345–1359. 2005. View Article : Google Scholar : PubMed/NCBI
3	Fan GW, Gao XM, Wang H, Zhu Y, Zhang J, Hu LM, Su YF, Kang LY and Zhang BL: The anti-inflammatory activities of Tanshinone IIA, an active component of TCM, are mediated by estrogen receptor activation and inhibition of iNOS. J Steroid Biochem Mol Biol. 113:275–280. 2009. View Article : Google Scholar : PubMed/NCBI
4	Wang AM, Sha SH, Lesniak W and Schacht J: Tanshinone (Salviae miltiorrhizae extract) preparations attenuate aminogly-coside-induced free radical formation in vitro and ototoxicity in vivo. Antimicrob Agents Chemother. 47:1836–1841. 2003. View Article : Google Scholar : PubMed/NCBI
5	Dong Y, Morris-Natschke SL and Lee KH: Biosynthesis, total syntheses, and antitumor activity of tanshinones and their analogs as potential therapeutic agents. Nat Prod Rep. 28:529–542. 2011. View Article : Google Scholar : PubMed/NCBI
6	Wang GL, Jiang BH, Rue EA and Semenza GL: Hypoxia-inducible factor 1 is a basic helix-loop-helix-PAS heterodimer regulated by cellular O₂ tension. Proc Natl Acad Sci USA. 92:5510–5514. 1995. View Article : Google Scholar
7	Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL and Simons JW: Overexpression of hypoxia-inducible factor 1alpha in common human cancers and their metastases. Cancer Res. 59:5830–5835. 1999.PubMed/NCBI
8	Maxwell PH, Dachs GU, Gleadle JM, Nicholls LG, Harris AL, Stratford IJ, Hankinson O, Pugh CW and Ratcliffe PJ: Hypoxia-inducible factor-1 modulates gene expression in solid tumors and influences both angiogenesis and tumor growth. Proc Natl Acad Sci USA. 94:8104–8109. 1997. View Article : Google Scholar : PubMed/NCBI
9	Poon E, Harris AL and Ashcroft M: Targeting the hypoxia-inducible factor (HIF) pathway in cancer. Expert Rev Mol Med. 11:e262009. View Article : Google Scholar : PubMed/NCBI
10	Sughrue ME, Yeung AH, Rutkowski MJ, Cheung SW and Parsa AT: Molecular biology of familial and sporadic vestibular schwannomas: Implications for novel therapeutics. J Neurosurg. 114:359–366. 2011. View Article : Google Scholar
11	Aggarwal BB and Shishodia S: Molecular targets of dietary agents for prevention and therapy of cancer. Biochem Pharmacol. 71:1397–1421. 2006. View Article : Google Scholar : PubMed/NCBI
12	Wang X, Wei Y, Yuan S, Liu G, Lu Y, Zhang J and Wang W: Potential anticancer activity of tanshinone IIA against human breast cancer. Int J Cancer. 116:799–807. 2005. View Article : Google Scholar : PubMed/NCBI
13	Liu JJ, Lin DJ, Liu PQ, Huang M, Li XD and Huang RW: Induction of apoptosis and inhibition of cell adhesive and invasive effects by tanshinone IIA in acute promyelocytic leukemia cells in vitro. J Biomed Sci. 13:813–823. 2006. View Article : Google Scholar : PubMed/NCBI
14	Chiu TL and Su CC: Tanshinone IIA induces apoptosis in human lung cancer A549 cells through the induction of reactive oxygen species and decreasing the mitochondrial membrane potential. Int J Mol Med. 25:231–236. 2010.PubMed/NCBI
15	Su CC, Chen GW and Lin JG: Growth inhibition and apoptosis induction by tanshinone I in human colon cancer Colo 205 cells. Int J Mol Med. 22:613–618. 2008.PubMed/NCBI
16	Yuan SL, Wei YQ, Wang XJ, Xiao F, Li SF and Zhang J: Growth inhibition and apoptosis induction of tanshinone II-A on human hepatocellular carcinoma cells. World J Gastroenterol. 10:2024–2028. 2004.PubMed/NCBI
17	Semenza GL: HIF-1 and tumor progression: Pathophysiology and therapeutics. Trends Mol Med. 8(4 Suppl): S62–S67. 2002. View Article : Google Scholar : PubMed/NCBI
18	Semenza GL: Targeting HIF-1 for cancer therapy. Nat Rev Cancer. 3:721–732. 2003. View Article : Google Scholar : PubMed/NCBI
19	Nagle DG and Zhou YD: Natural product-based inhibitors of hypoxia-inducible factor 1 (HIF-1). Curr Drug Targets. 7:355–369. 2006. View Article : Google Scholar : PubMed/NCBI
20	Xu M, Cao F, Liu L, Zhang B, Wang Y, Dong H, Cui Y, Dong M, Xu D, Liu Y, et al: Tanshinone IIA-induced attenuation of lung injury in endotoxemic mice is associated with reduction of hypoxia-inducible factor 1vα expression. Am J Respir Cell Mol Biol. 45:1028–1035. 2011. View Article : Google Scholar : PubMed/NCBI
21	Minet E, Michel G, Mottet D, Raes M and Michiels C: Transduction pathways involved in Hypoxia-Inducible Factor-1 phosphorylation and activation. Free Radic Biol Med. 31:847–855. 2001. View Article : Google Scholar : PubMed/NCBI
22	Xia Y, Choi HK and Lee K: Recent advances in hypoxia-inducible factor (HIF)-1 inhibitors. Eur J Med Chem. 49:24–40. 2012. View Article : Google Scholar : PubMed/NCBI
23	Melillo G: Targeting hypoxia cell signaling for cancer therapy. Cancer metastasis Rev. 26:341–352. 2007. View Article : Google Scholar : PubMed/NCBI