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BMC Cancer
Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

Tanshinone IIA combined with adriamycin inhibited malignant biological behaviors of NSCLC A549 cell line in a synergistic way

Authors: Jun Xie, Jia-Hui Liu, Heng Liu, Xiao-Zhong Liao, Yuling Chen, Mei-Gui Lin, Yue-Yu Gu, Tao-Li Liu, Dong-Mei Wang, Hui Ge, Sui-Lin Mo

Published in: BMC Cancer | Issue 1/2016

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Abstract

Background

The study was designed to develop a platform to verify whether the extract of herbs combined with chemotherapy drugs play a synergistic role in anti-tumor effects, and to provide experimental evidence and theoretical reference for finding new effective sensitizers.

Methods

Inhibition of tanshinone IIA and adriamycin on the proliferation of A549, PC9 and HLF cells were assessed by CCK8 assays. The combination index (CI) was calculated with the Chou-Talalay method, based on the median-effect principle. Migration and invasion ability of A549 cells were determined by wound healing assay and transwell assay. Flow cytometry was used to detect the cell apoptosis and the distribution of cell cycles. TUNEL staining was used to detect the apoptotic cells. Immunofluorescence staining was used to detect the expression of Cleaved Caspase-3. Western blotting was used to detect the proteins expression of relative apoptotic signal pathways. CDOCKER module in DS 2.5 was used to detect the binding modes of the drugs and the proteins.

Results

Both tanshinone IIA and adriamycin could inhibit the growth of A549, PC9, and HLF cells in a dose- and time-dependent manner, while the proliferative inhibition effect of tanshinone IIA on cells was much weaker than that of adriamycin. Different from the cancer cells, HLF cells displayed a stronger sensitivity to adriamycin, and a weaker sensitivity to tanshinone IIA. When tanshinone IIA combined with adriamycin at a ratio of 20:1, they exhibited a synergistic anti-proliferation effect on A549 and PC9 cells, but not in HLF cells. Tanshinone IIA combined with adriamycin could synergistically inhibit migration, induce apoptosis and arrest cell cycle at the S and G2 phases in A549 cells. Both groups of the single drug treatment and the drug combination up-regulated the expressions of Cleaved Caspase-3 and Bax, but down-regulated the expressions of VEGF, VEGFR2, p-PI3K, p-Akt, Bcl-2, and Caspase-3 protein. Compared with the single drug treatment groups, the drug combination groups were more statistically significant. The molecular docking algorithms indicated that tanshinone IIA could be docked into the active sites of all the tested proteins with H-bond and aromatic interactions, compared with that of adriamycin.

Conclusions

Tanshinone IIA can be developed as a novel agent in the postoperative adjuvant therapy combined with other anti-tumor agents, and improve the sensibility of chemotherapeutics for non-small cell lung cancer with fewer side effects. In addition, this experiment can not only provide a reference for the development of more effective anti-tumor medicine ingredients, but also build a platform for evaluating the anti-tumor effects of Chinese herbal medicines in combination with chemotherapy drugs.
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Literature
1.
Nagel R, Stigter-van Walsum M, Buijze M, van den Berg J, van der Meulen IH, Hodzic J, Piersma SR, Pham TV, Jimenez CR, van Beusechem VW, et al. Genome-wide siRNA Screen Identifies the Radiosensitizing Effect of Downregulation of MASTL and FOXM1 in NSCLC. Mol Cancer Ther. 2015;14(6):1434–44.CrossRefPubMed
2.
Ling CQ, Yue XQ, Ling C. Three advantages of using traditional Chinese medicine to prevent and treat tumor. J Integr Med. 2014;12(4):331–5.CrossRefPubMed
3.
Campelo RG, Massuti B, Mosquera J, Rosell R. 10(th) Congress on Lung Cancer-updates on clinical trials: goal. Transl Lung Cancer Res. 2014;3(2):66–9.PubMedPubMedCentral
4.
Bunn Jr PA, Thatcher N. Systemic treatment for advanced (stage IIIb/IV) non-small cell lung cancer: more treatment options; more things to consider. Conclusion. Oncologist. 2008;37 Suppl 1:46.
5.
Thorn CF, Oshiro C, Marsh S, Hernandez-Boussard T, McLeod H, Klein TE, Altman RB. Doxorubicin pathways: pharmacodynamics and adverse effects. Pharmacogenet Genomics. 2011;21(7):440–6.CrossRefPubMedPubMedCentral
6.
Hanusova V, Bousova I, Skalova L. Possibilities to increase the effectiveness of doxorubicin in cancer cells killing. Drug Metab Rev. 2011;43(4):540–57.CrossRefPubMed
7.
Xu S, Liu P. Tanshinone II-A: new perspectives for old remedies. Expert Opin Ther Pat. 2013;23(2):149–53.CrossRefPubMed
8.
Liu F, Yu G, Wang G, Liu H, Wu X, Wang Q, Liu M, Liao K, Wu M, Cheng X, et al. An NQO1-initiated and p53-independent apoptotic pathway determines the anti-tumor effect of tanshinone IIA against non-small cell lung cancer. PloS One. 2012;7(7):e42138.CrossRefPubMedPubMedCentral
9.
Kan S, Cheung WM, Zhou Y, Ho WS. Enhancement of doxorubicin cytotoxicity by tanshinone IIA in HepG2 human hepatoma cells. Planta Med. 2014;80(1):70–6.CrossRefPubMed
10.
Su CC. Tanshinone IIA inhibits human gastric carcinoma AGS cell growth by decreasing BiP, TCTP, Mcl1 and BclxL and increasing Bax and CHOP protein expression. Int J Mol Med. 2014;34(6):1661–8.PubMed
11.
Huang CY, Chiu TL, Kuo SJ, Chien SY, Chen DR, Su CC. Tanshinone IIA inhibits the growth of pancreatic cancer BxPC3 cells by decreasing protein expression of TCTP, MCL1 and BclxL. Mol Med Rep. 2013;7(3):1045–9.PubMed
12.
Xie J, Liu J, Liu H, Liang S, Lin M, Gu Y, Liu T, Wang D, Ge H, Mo SL. The antitumor effect of tanshinone IIA on anti-proliferation and decreasing VEGF/VEGFR2 expression on the human non-small cell lung cancer A549 cell line. Acta Pharm Sin B. 2015;5(6):554–63.CrossRefPubMedPubMedCentral
13.
Hong HJ, Liu JC, Chen PY, Chen JJ, Chan P, Cheng TH. Tanshinone IIA prevents doxorubicin-induced cardiomyocyte apoptosis through Akt-dependent pathway. Int J Cardiol. 2012;157(2):174–9.CrossRefPubMed
14.
Chou TC. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev. 2006;58(3):621–81.CrossRefPubMed
15.
Chou TC, Talalay P. Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors. Adv Enzym Regul. 1984;22:27–55.CrossRef
16.
Damaraju VL, Bouffard DY, Wong CK, Clarke ML, Mackey JR, Leblond L, Cass CE, Grey M, Gourdeau H. Synergistic activity of troxacitabine (Troxatyl (TM)) and gemcitabine in pancreatic cancer. BMC Cancer. 2007;7:121.
17.
Tung YT, Chen HL, Lee CY, Chou YC, Lee PY, Tsai HC, Lin YL, Chen CM. Active Component of Danshen (Salvia miltiorrhiza Bunge), Tanshinone I, Attenuates Lung Tumorigenesis via Inhibitions of VEGF, Cyclin A, and Cyclin B Expressions. Evid Based Complement Alternat Med : eCAM. 2013;2013:319247.PubMedPubMedCentral
18.
Wei X, Zhou L, Hu L, Huang Y. Tanshinone IIA arrests cell cycle and induces apoptosis in 786-O human renal cell carcinoma cells. Oncol Lett. 2012;3(5):1144–8.PubMedPubMedCentral
19.
Wang J, Xu X, Zhou R, Guo K. Effects of itraconazole plus doxorubicin on proliferation and apoptosis in acute myeloid leukemia cells. Zhonghua Yi Xue Za Zhi. 2015;95(4):299–305.PubMed
20.
Ma ZL, Zhang BJ, Wang DT, Li X, Wei JL, Zhao BT, Jin Y, Li YL, Jin YX. Tanshinones suppress AURKA through up-regulation of miR-32 expression in non-small cell lung cancer. Oncotarget. 2015;6(24):20111–20.CrossRefPubMedPubMedCentral
21.
Kim KJ, Li B, Winer J, Armanini M, Gillett N, Phillips HS, Ferrara N. Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumour growth in vivo. Nature. 1993;362(6423):841–4.CrossRefPubMed
22.
Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L. VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol. 2006;7(5):359–71.CrossRefPubMed
23.
Karpanen T, Bry M, Ollila HM, Seppanen-Laakso T, Liimatta E, Leskinen H, Kivela R, Helkamaa T, Merentie M, Jeltsch M, et al. Overexpression of vascular endothelial growth factor-B in mouse heart alters cardiac lipid metabolism and induces myocardial hypertrophy. Circ Res. 2008;103(9):1018–26.CrossRefPubMedPubMedCentral
24.
Wang P, Luo Y, Duan H, Xing S, Zhang J, Lu D, Feng J, Yang D, Song L, Yan X. MicroRNA 329 suppresses angiogenesis by targeting CD146. Mol Cell Biol. 2013;33(18):3689–99.CrossRefPubMedPubMedCentral
25.
Jiang TX, Zhuang J, Duan HX, Luo YT, Zeng QQ, Fan KL, Yan HW, Lu D, Ye Z, Hao JF, et al. CD146 is a coreceptor for VEGFR-2 in tumor angiogenesis. Blood. 2012;120(11):2330–9.CrossRefPubMed
26.
Roskoski Jr R. VEGF receptor protein-tyrosine kinases: structure and regulation. Biochem Biophys Res Commun. 2008;375(3):287–91.CrossRefPubMed
27.
Choi HS, Lee K, Kim MK, Lee KM, Shin YC, Cho SG, Ko SG. DSGOST inhibits tumor growth by blocking VEGF/VEGFR2-activated angiogenesis. Oncotarget. 2016;7(16):21775–85.PubMedPubMedCentral
28.
Kim BR, Seo SH, Park MS, Lee SH, Kwon Y, Rho SB. sMEK1 inhibits endothelial cell proliferation by attenuating VEGFR-2-dependent-Akt/eNOS/HIF-1alpha signaling pathways. Oncotarget. 2015;6(31):31830–43.PubMedPubMedCentral
29.
Breier G. Endothelial receptor tyrosine kinases involved in blood vessel development and tumor angiogenesis. Adv Exp Med Biol. 2000;476:57–66.CrossRefPubMed
30.
Ferrara N. Role of vascular endothelial growth factor in regulation of physiological angiogenesis. Am J Physiol Cell Physiol. 2001;280(6):C1358–66.PubMed
31.
Meyer RD, Rahimi N. Comparative structure-function analysis of VEGFR-1 and VEGFR-2: What have we learned from chimeric systems? Ann N Y Acad Sci. 2003;995:200–7.CrossRefPubMed
32.
Zhang H, He S, Spee C, Ishikawa K, Hinton DR. SIRT1 mediated inhibition of VEGF/VEGFR2 signaling by Resveratrol and its relevance to choroidal neovascularization. Cytokine. 2015;76(2):549–52.CrossRefPubMedPubMedCentral
33.
Won SH, Lee HJ, Jeong SJ, Lee HJ, Lee EO, Jung DB, Shin JM, Kwon TR, Yun SM, Lee MH, et al. Tanshinone IIA induces mitochondria dependent apoptosis in prostate cancer cells in association with an inhibition of phosphoinositide 3-kinase/AKT pathway. Biol Pharm Bull. 2010;33(11):1828–34.CrossRefPubMed
34.
35.
Raynaud FI, Eccles S, Clarke PA, Hayes A, Nutley B, Alix S, Henley A, Di-Stefano F, Ahmad Z, Guillard S, et al. Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Res. 2007;67(12):5840–50.CrossRefPubMed
36.
Willems L, Tamburini J, Chapuis N, Lacombe C, Mayeux P, Bouscary D. PI3K and mTOR signaling pathways in cancer: new data on targeted therapies. Curr Oncol Rep. 2012;14(2):129–38.CrossRefPubMed
37.
Guo S, Lopez-Marquez H, Fan KC, Choy E, Cote G, Harmon D, Nielsen GP, Yang C, Zhang C, Mankin H, et al. Synergistic effects of targeted PI3K signaling inhibition and chemotherapy in liposarcoma. PloS One. 2014;9(4):e93996.CrossRefPubMedPubMedCentral
38.
Hernando E, Charytonowicz E, Dudas ME, Menendez S, Matushansky I, Mills J, Socci ND, Behrendt N, Ma L, Maki RG, et al. The AKT-mTOR pathway plays a critical role in the development of leiomyosarcomas. Nat Med. 2007;13(6):748–53.CrossRefPubMed
39.
Zhang J, Yu XH, Yan YG, Wang C, Wang WJ. PI3K/Akt signaling in osteosarcoma. Clin Chim Acta. 2015;444:182–92.CrossRefPubMed
40.
Su CC. Tanshinone IIA potentiates the efficacy of 5-FU in Colo205 colon cancer cells in vivo through downregulation of P-gp and LC3-II. Exp Ther Med. 2012;3(3):555–9.PubMed
41.
Su CC, Lin YH. Tanshinone IIA down-regulates the protein expression of ErbB-2 and up-regulates TNF-alpha in colon cancer cells in vitro and in vivo. Int J Mol Med. 2008;22(6):847–51.PubMed
42.
Rini BI, Small EJ. Biology and clinical development of vascular endothelial growth factor-targeted therapy in renal cell carcinoma. J Clin Oncol. 2005;23(5):1028–43.CrossRefPubMed
43.
Hong TM, Chen YL, Wu YY, Yuan A, Chao YC, Chun YC, Wu MH, Yan SC, Pan SH, Shih JY, et al. Targeting neuropilin 1 as an antitumor strategy in lung cancer. Clin Cancer Res. 2007;13(16):4759–68.CrossRefPubMed
44.
Los M, Voest EE, Rinkes IHMB. VEGF as a target of therapy in gastrointestinal oncology. Digest Surg. 2005;22(4):282–93.CrossRef
45.
Huang Y, Hua K, Zhou X, Jin H, Chen X, Lu X, Yu Y, Zha X, Feng Y. Activation of the PI3K/AKT pathway mediates FSH-stimulated VEGF expression in ovarian serous cystadenocarcinoma. Cell Res. 2008;18(7):780–91.CrossRefPubMed
46.
Wu J, Wu X, Zhong D, Zhai W, Ding Z, Zhou Y. Short Hairpin RNA (shRNA) Ether a go-go 1 (Eag1) inhibition of human osteosarcoma angiogenesis via VEGF/PI3K/AKT signaling. Int J Mol Sci. 2012;13(10):12573–83.CrossRefPubMedPubMedCentral
47.
Wang N, Han Y, Tao J, Huang M, You Y, Zhang H, Liu S, Zhang X, Yan C. Overexpression of CREG attenuates atherosclerotic endothelium apoptosis via VEGF/PI3K/AKT pathway. Atherosclerosis. 2011;218(2):543–51.CrossRefPubMed
48.
49.
Rosse T, Olivier R, Monney L, Rager M, Conus S, Fellay I, Jansen B, Borner C. Bcl-2 prolongs cell survival after Bax-induced release of cytochrome c. Nature. 1998;391(6666):496–9.CrossRefPubMed
50.
Yang J, Liu X, Bhalla K, Kim CN, Ibrado AM, Cai J, Peng TI, Jones DP, Wang X. Prevention of apoptosis by Bcl-2: release of cytochrome c from mitochondria blocked. Science. 1997;275(5303):1129–32.CrossRefPubMed
51.
Tian HL, Yu T, Xu NN, Feng C, Zhou LY, Luo HW, Chang DC, Le XF, Luo KQ. A novel compound modified from tanshinone inhibits tumor growth in vivo via activation of the intrinsic apoptotic pathway. Cancer Lett. 2010;297(1):18–30.CrossRefPubMed
52.
Liu JJ, Lin DJ, Liu PQ, Huang M, Li XD, 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. 2006;13(6):813–23.CrossRefPubMed
53.
Li G, Shan C, Liu L, Zhou T, Zhou J, Hu X, Chen Y, Cui H, Gao N. Tanshinone IIA inhibits HIF-1alpha and VEGF expression in breast cancer cells via mTOR/p70S6K/RPS6/4E-BP1 signaling pathway. PloS One. 2015;10(2):e0117440.CrossRefPubMedPubMedCentral
54.
Xing Y, Tu J, Zheng L, Guo L, Xi T. Anti-angiogenic effect of tanshinone IIA involves inhibition of the VEGF/VEGFR2 pathway in vascular endothelial cells. Oncology reports. 2015;33(1):163–70.PubMed
55.
Chiu TL, 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. 2010;25(2):231–6.PubMed
56.
Zhang J, Wang J, Jiang JY, Liu SD, Fu K, Liu HY. Tanshinone IIA induces cytochrome c-mediated caspase cascade apoptosis in A549 human lung cancer cells via the JNK pathway. Int J Oncol. 2014;45(2):683–90.PubMed
57.
Xu W, Yang J, Wu LM. Cardioprotective effects of tanshinone IIA on myocardial ischemia injury in rats. Pharmazie. 2009;64(5):332–6.PubMed
58.
Xu ZH, Wu LJ, Sun YW, Guo YD, Qin GP, Mu SZ, Fan RH, Wang BF, Gao WJ, Zhang ZX. Tanshinone IIA pretreatment protects free flaps against hypoxic injury by upregulating stem cell-related biomarkers in epithelial skin cells. BMC Complem Altern M. 2014;14:331.CrossRef
59.
Li S, Lou S, Lei BU, Chan TF, Kwan YW, Chan SW, Leung GP, Tsui SK, Lee SM. Transcriptional profiling of angiogenesis activities of calycosin in zebrafish. Mol BioSyst. 2011;7(11):3112–21.CrossRefPubMed
60.
Katoh Y, Katoh M. Comparative integromics on VEGF family members. Int J Oncol. 2006;28(6):1585–9.PubMed
61.
Zhang Y, Furumura M, Morita E. Distinct signaling pathways confer different vascular responses to VEGF 121 and VEGF 165. Growth Factors. 2008;26(3):125–31.CrossRefPubMed
62.
Kilarski WW, Jura N, Gerwins P. Inactivation of Src family kinases inhibits angiogenesis in vivo: implications for a mechanism involving organization of the actin cytoskeleton. Exp Cell Res. 2003;291(1):70–82.CrossRefPubMed
63.
Zhang ZR, Li JH, Li S, Liu AL, Hoi PM, Tian HY, Ye WC, Lee SMY, Jiang RW. In vivo Angiogenesis Screening and Mechanism of Action of Novel Tanshinone Derivatives Produced by One-Pot Combinatorial Modification of Natural Tanshinone Mixture from Salvia Miltiorrhiza. PloS One. 2014;9(7):e100416.CrossRefPubMedPubMedCentral
64.
Murga M, Fernandez-Capetillo O, Tosato G. Neuropilin-1 regulates attachment in human endothelial cells independently of vascular endothelial growth factor receptor-2. Blood. 2005;105(5):1992–9.CrossRefPubMed
Metadata
Title
Tanshinone IIA combined with adriamycin inhibited malignant biological behaviors of NSCLC A549 cell line in a synergistic way
Authors
Jun Xie
Jia-Hui Liu
Heng Liu
Xiao-Zhong Liao
Yuling Chen
Mei-Gui Lin
Yue-Yu Gu
Tao-Li Liu
Dong-Mei Wang
Hui Ge
Sui-Lin Mo
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2921-x

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