Danshensu, a major water‑soluble component of Salvia miltiorrhiza, enhances the radioresponse for Lewis Lung Carcinoma xenografts in mice

Cao,Hong‑Ying; Ding,Rui‑Lin; Li,Meng; Yang,Mao‑Nan; Yang,Ling‑Lin; Wu,Jing‑Bo; Yang,Bo; Wang,Jing; Luo,Cui‑Lian; Wen,Qing‑Lian

doi:10.3892/ol.2016.5508

Danshensu, a major water‑soluble component of Salvia miltiorrhiza, enhances the radioresponse for Lewis Lung Carcinoma xenografts in mice

Authors:
- Hong‑Ying Cao
- Rui‑Lin Ding
- Meng Li
- Mao‑Nan Yang
- Ling‑Lin Yang
- Jing‑Bo Wu
- Bo Yang
- Jing Wang
- Cui‑Lian Luo
- Qing‑Lian Wen
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Affiliations: Department of Emergency, The Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan 646000, P.R. China, Department of Oncology, The Affiliated Hospital of Luzhou Medical College, Luzhou, Sichuan 646000, P.R. China
Published online on: December 16, 2016 https://doi.org/10.3892/ol.2016.5508
Pages: 605-612
Copyright: © Cao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The molecule 3-(3,4-dihydroxyphenyl)-2-hydroxypropanoic acid (danshensu), a herbal preparation used in traditional Chinese medicine, has been found to possess potential antitumor and anti‑angiogenesis effects. The aim of the present study was to investigate the efficacy of the combination of radiation therapy (RT) with danshensu in the treatment of Lewis lung carcinoma (LLC) xenografts, whilst exploring and evaluating the mechanism involved. In total, 8‑week old female C57BL/6J mice were randomly assigned into 3 groups to receive: RT, RT + cisplatin and RT + danshensu, respectively, when LLC reached 100‑150 mm3. Each group was divided into 7 subgroups according to the different irradiation doses that were administered. Tumor growth curves were created and the sensitization enhancement ratios of the drugs were calculated. The experiment was then repeated, and the 4 groups of tumor‑bearing mice were treated with natural saline, danshensu, RT + danshensu and RT, respectively. The mice were sacrificed on day 7, and tumor tissue and blood were collected to determine microvessel density, the expression of proangiogenic factors, and the levels of blood thromboxane B2 and 6‑keto‑prostaglandin‑F1α. Tumor hypoxia was also detected using in vivo fluorescence imaging. With respect to LLC xenografts, treatment with danshensu + RT significantly enhanced the effects of tumor growth inhibition (P<0.05). Furthermore, tumor vasculature was remodeled and microcirculation was improved, which significantly reduced tumor hypoxia (P<0.05). The present study demonstrated that danshensu significantly enhanced the radioresponse of LLC xenografts in mice. The mechanism involved may be associated with the alleviation of tumor cell hypoxia following treatment with danshensu + RT, caused by the improvement of tumor microcirculation and the remodeling of tumor vasculature.

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1	Chen W, Zheng R, Zhang S, Zhao P, Zeng H, Zou X and He J: Annual report on status of cancer in China, 2010. Chin J Cancer Res. 26:48–58. 2014.PubMed/NCBI
2	Tyldesley S, Boyd C, Schulze K, Walker H and Mackillop WJ: Estimating the need for radiotherapy for lung cancer: An evidence-based, epidemiologic approach. Int J Radiat Oncol Biol Phys. 49:973–985. 2001. View Article : Google Scholar : PubMed/NCBI
3	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar : PubMed/NCBI
4	Jain RK: Normalizing tumor microenvironment to treat cancer: Bench to bedside to biomarkers. J Clin Oncol. 31:2205–2218. 2013. View Article : Google Scholar : PubMed/NCBI
5	Vaupel P: Tumor microenvironmental physiology and its implications for radiation oncology. Semin Radiat Oncol. 14:198–206. 2004. View Article : Google Scholar : PubMed/NCBI
6	Winkler F, Kozin SV, Tong RT, Chae SS, Booth MF, Garkavtsev I, Xu L, Hicklin DJ, Fukumura D, di Tomaso E, et al: Kinetics of vascular normalization by VEGFR2 blockade governs brain tumor response to radiation: Role of oxygenation, angiopoietin-1, and matrix metalloproteinases. Cancer Cell. 6:553–563. 2004. View Article : Google Scholar : PubMed/NCBI
7	Meng MB, Jiang XD, Deng L, Na FF, He JZ, Xue JX, Guo WH, Wen QL, Lan J, Mo XM, et al: Enhanced radioresponse with a novel recombinant human endostatin protein via tumor vasculature remodeling: Experimental and clinical evidence. Radiother Oncol. 106:130–137. 2013. View Article : Google Scholar : PubMed/NCBI
8	Dey N, De P and Brian LJ: Evading anti-angiogenic therapy: Resistance to anti-angiogenic therapy in solid tumors. Am J Transl Res. 7:1675–1698. 2015.PubMed/NCBI
9	Chen SJ and Ren JL: Identification of a potential anticancer target of danshensu by inverse docking. Asian Pac J Cancer Prev. 15:111–116. 2014. View Article : Google Scholar : PubMed/NCBI
10	Yang RX, Huang SY, Yan FF, Lu XT, Xing YF, Liu Y, Liu YF and Zhao YX: Danshensu protects vascular endothelia in a rat model of hyperhomocysteinemia. Acta Pharmacol Sin. 31:1395–1400. 2010. View Article : Google Scholar : PubMed/NCBI
11	Zhang N, Zou H, Jin L, Wang J, Zhong MF, Huang P, Gu BQ, Mao SL, Zhang C and Chen H: Biphasic effects of sodium danshensu on vessel function in isolated rat aorta. Acta Pharmacol Sin. 31:421–428. 2010. View Article : Google Scholar : PubMed/NCBI
12	Ding M, Ye TX, Zhao GR, Yuan YJ and Guo ZX: Aqueous extract of Salvia miltiorrhiza attenuates increased endothelial permeability induced by tumor necrosis factor-alpha. Int Immunopharmacol. 5:1641–1651. 2005. View Article : Google Scholar : PubMed/NCBI
13	Zhang LJ, Chen L, Lu Y, Wu JM, Xu B, Sun ZG, Zheng SZ and Wang AY: Danshensu has anti-tumor activity in B16F10 melanoma by inhibiting angiogenesis and tumor cell invasion. Eur J Pharmacol. 643:195–201. 2010. View Article : Google Scholar : PubMed/NCBI
14	Hu T, Wei G, Xi M, Yan J, Wu X, Wang Y, Zhu Y, Wang C and Wen A: Synergistic cardioprotective effects of Danshensu and hydroxysafflor yellow A against myocardial ischemia-reperfusion injury are mediated through the Akt/Nrf2/HO-1 pathway. Int J Mol Med. 38:83–94. 2016.PubMed/NCBI
15	Chen YC, Cao WW, Cao Y, Zhang L, Chang BB, Yang WL and Liu XQ: Using neural networks to determine the contribution of danshensu to its multiple cardiovascular activities in acute myocardial infarction rats. J Ethnopharmacol. 138:126–134. 2011. View Article : Google Scholar : PubMed/NCBI
16	Gu MJ and Kwon KW: Carbonic anhydrase IX expression is associated with favorable prognostic factors in small intestinal carcinoma. J Histochem Cytochem. 62:205–210. 2014. View Article : Google Scholar : PubMed/NCBI
17	Akudugu JM and Slabbert JP: Modulation of radiosensitivity in Chinese hamster lung fibroblasts by cisplatin. Can J Physiol Pharmacol. 86:257–263. 2008. View Article : Google Scholar : PubMed/NCBI
18	Zhang X, Yang H, Gu K, Chen J, Rui M and Jiang GL: In vitro and in vivo study of a nanoliposomal cisplatin as a radiosensitizer. Int J Nanomedicine. 6:437–444. 2011. View Article : Google Scholar : PubMed/NCBI
19	Yoshimura M, Itasaka S, Harada H and Hiraoka M: Microenvironment and radiation therapy. Biomed Res Int. 2013:6853082013. View Article : Google Scholar : PubMed/NCBI
20	Kizaka-Kondoh S, Tanaka S, Harada H and Hiraoka M: The HIF-1-active microenvironment: An environmental target for cancer therapy. Adv Drug Deliv Rev. 61:623–632. 2009. View Article : Google Scholar : PubMed/NCBI
21	Peng F, Xu Z, Wang J, Chen Y, Li Q, Zuo Y, Chen J, Hu X, Zhou Q, Wang Y, et al: Recombinant human endostatin normalizes tumor vasculature and enhances radiation response in xenografted human nasopharyngeal carcinoma models. PLoS One. 7:e346462012. View Article : Google Scholar : PubMed/NCBI
22	Fukumura D and Jain RK: Tumor microvasculature and microenvironment: Targets for anti-angiogenesis and normalization. Microvasc Res. 74:72–84. 2007. View Article : Google Scholar : PubMed/NCBI
23	Kobayashi H and Lin PC: Antiangiogenic and radiotherapy for cancer treatment. Histol Histopathol. 21:1125–1134. 2006.PubMed/NCBI
24	Han JY, Fan JY, Horie Y, Miura S, Cui DH, Ishii H, Hibi T, Tsuneki H and Kimura I: Ameliorating effects of compounds derived from Salvia miltiorrhiza root extract on microcirculatory disturbance and target organ injury by ischemia and reperfusion. Pharmacol Ther. 117:280–295. 2008. View Article : Google Scholar : PubMed/NCBI
25	Lei XL and Chiou GC: Cardiovascular pharmacology of Panax notoginseng (Burk) F.H. Chen and Salvia miltiorrhiza. Am J Chin Med. 14:145–152. 1986. View Article : Google Scholar : PubMed/NCBI
26	Wu L, Qiao H, Li Y and Li L: Protective roles of puerarin and Danshensu on acute ischemic myocardial injury in rats. Phytomedicine. 14:652–658. 2007. View Article : Google Scholar : PubMed/NCBI
27	Sugiyama A, Zhu BM, Takahara A, Satoh Y and Hashimoto K: Cardiac effects of salvia miltiorrhiza/dalbergia odorifera mixture, an intravenously applicable Chinese medicine widely used for patients with ischemic heart disease in China. Circ J. 66:182–184. 2002. View Article : Google Scholar : PubMed/NCBI
28	Jin UH, Kang SK, Suh SJ, Hong SY, Park SD, Kim DW, Chang HW, Son JK, Lee SH, Son KH and Kim CH: Inhibitory effect of Salvia miltiorrhia BGE on matrix metalloproteinase-9 activity and migration of TNF-alpha-induced human aortic smooth muscle cells. Vascul Pharmacol. 44:345–353. 2006. View Article : Google Scholar : PubMed/NCBI
29	Tian XM, Wang R, Zhang BK, Wang CL, Guo H and Zhang SJ: Impact of Lycium Barbarum Polysaccharide and Danshensu on vascular endothelial growth factor in the process of retinal neovascularization of rabbit. Int J Ophthalmol. 6:59–61. 2013.PubMed/NCBI
30	Cheng F, Wang X, Zhong D, Sun L, Wang Q and Liu C: Significance of detection of serum carbonic anhydrase IX in the diagnosis of lung cancer. Zhongguo Fei Ai Za Zhi. 18:29–33. 2015.(In Chinese). PubMed/NCBI
31	Chen FH, Chiang CS, Wang CC, Tsai CS, Jung SM, Lee CC, McBride WH and Hong JH: Radiotherapy decreases vascular density and causes hypoxia with macrophage aggregation in TRAMP-C1 prostate tumors. Clin Cancer Res. 15:1721–1729. 2009. View Article : Google Scholar : PubMed/NCBI
32	Sundov Z, Tomic S, Alfirevic S, Sundov A, Capkun V, Nincevic Z, Nincevic J, Kunac N, Kontic M, Poljak N and Druzijanic N: Prognostic value of MVD, LVD and vascular invasion in lymph node-negative colon cancer. Hepatogastroenterology. 60:432–438. 2013.PubMed/NCBI
33	Li J, Wang S, Yang X, Pang G, Zheng H, Shen B, Li G, Shi D, Wang J, Feng L, et al: Effect of sulfated polysaccharides from Laminaria japonica on vascular endothelial cells in psychological stress rats. J Ethnopharmacol. 151:601–608. 2014. View Article : Google Scholar : PubMed/NCBI
34	Wang ZJ, Yu YH, Chen J and Zhao YT: Correlation between oligohydramnios and abnormal expressions of TXA2, PGI2 and TXA2R in the umbilical arterial blood and placenta. Nan Fang Yi Ke Da Xue Xue Bao. 29:1917–1918. 2009.(In Chinese). PubMed/NCBI
35	Zhang FH: Effects of acupuncture at 7-9 am and 3-5 pm on plasma thromboxane and prostaglandin in patients with ischemic cerebrovascular disease. J Tradit Chin Med. 30:9–12. 2010. View Article : Google Scholar : PubMed/NCBI
36	Liu HJ, Ma JW, Qiao ZY and Xu B: Study of molecular mechanism of Prostaglandin E1 in inhibiting coronary heart disease. Mol Biol Rep. 40:6701–6708. 2013. View Article : Google Scholar : PubMed/NCBI