Effects of WD‑3 on tumor growth and the expression of integrin αvβ3 and ERK1/2 in mice bearing human gastric cancer using the 18F‑RGD PET/CT imaging system

Jin,Chunhui; Zhang,Bao‑Nan; Wei,Zhipeng; Ma,Bo; Pan,Qi; Hu,Pingping

doi:10.3892/mmr.2017.7827

Effects of WD‑3 on tumor growth and the expression of integrin αvβ3 and ERK1/2 in mice bearing human gastric cancer using the 18F‑RGD PET/CT imaging system

Authors:
- Chunhui Jin
- Bao‑Nan Zhang
- Zhipeng Wei
- Bo Ma
- Qi Pan
- Pingping Hu
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Affiliations: Department of Oncology, Wuxi Hospital of Traditional Chinese Medicine, Wuxi, Jiangsu 214000, P.R. China, Department of Surgery, Affiliated Central Hospital of Huzhou Teachers College, Huzhou, Zhejiang 313000, P.R. China, Department of Oncology, The Second Wuxi Hospital of Traditional Chinese Medicine, Wuxi, Jiangsu 214000, P.R. China
Published online on: October 19, 2017 https://doi.org/10.3892/mmr.2017.7827
Pages: 9295-9300
Copyright: © Jin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Activation of the vitronectin receptor αvβ3 and the phosphorylation of extracellular signal‑regulated kinase (ERK)1/2 are critical events during tumor development and progression. The aim of the present study was to investigate the effects of WD‑3, a formula used in traditional Chinese medicine, on integrin αvβ3 and ERK1/2 expression in vivo using a nude mouse‑human gastric cancer xenograft model combined with non‑invasive, real‑time 18F‑Arg‑Gly‑Asp (RGD) positron emission tomography (PET)/computerized tomography (CT) imaging methods. SGC‑7901 human gastric cancer cells were subcutaneously injected into BALB/c nude mice. Following tumor development, animals were randomly assigned into the following 4 groups (n=6 mice/group): Control group (CG), Chinese medicine group (CMG), Western medicine group (WMG) and Chinese and Western medicine combination group (CMG + WMG). Mice in the CG and CMG received daily intragastric injections of 0.5 ml saline and 0.5 ml WD‑3, respectively. Mice in the WMG received an intravenous injection of albumin‑bound paclitaxel (25 mg/kg) on days 0, 2 and 4 Mice in the CMG + WMG received combination therapy of WD‑3 and albumin‑bound paclitaxel. Tumor growth was monitored using standard caliper technique and via PET imaging. 18F‑RGD PET/CT analysis was performed on days 3, 7, 18 and 24 following drug administration. Radioactivity uptake was measured and expressed as the percentage of injected dose (ID) per tissue weight (%ID/g) and the standardized uptake value (SUV). Animals were sacrificed at 30 days following treatment and tumor weight was measured. Immunohistochemistry was used to detect the expression of phosphorylated (p)‑ERK1/2 protein in tumor tissue samples. No statistically significant differences were observed in %ID/g and SUV among the various groups prior to treatment. At the end of treatment, mice in the CMG, WMG and CMG + WMG exhibited significantly reduced tumor mass when compared with mice in the CG. In addition, mice in the CMG and CMG + WMG demonstrated reduced %ID/g and SUV when compared with mice in the CG. Conversely, mice in the WMG exhibited no significant difference in %ID/g and SUV compared with the CG. Furthermore, p‑ERK1/2 expression was significantly reduced in mice from all treatment groups when compared with those in the CG. The results of the present study suggest that the traditional Chinese formula WD‑3 may inhibit gastric tumor growth, potentially via the downregulation of integrin αvβ3 and the inhibition of ERK1/2 phosphorylation in vivo.

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1	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI
2	Jemal A, Siegel R, Ward E, Murray T, Xu J and Thun MJ: Cancer statistics, 2007. CA Cancer J Clin. 57:43–66. 2007. View Article : Google Scholar : PubMed/NCBI
3	Guan JL: Integrin signaling through FAK in the regulation of mammary stem cells and breast cancer. IUBMB Life. 62:268–276. 2010.PubMed/NCBI
4	Yun SP, Ryu JM and Han HJ: Involvement of β1-integrin via PIP complex and FAK/paxillin in dexamethasone-induced human mesenchymal stem cells migration. J Cell Physiol. 226:683–692. 2011. View Article : Google Scholar : PubMed/NCBI
5	Li D, Ding J, Wang X, Wang C and Wu T: Fibronectin promotes tyrosine phosphorylation of paxillin and cell invasiveness in the gastric cancer cell line AGS. Tumori. 95:769–779. 2009.PubMed/NCBI
6	Missan DS, Mitchell K, Subbaram S and DiPersio CM: Integrin α3β1 signaling through MEK/ERK determines alternative polyadenylation of the MMP-9 mRNA transcript in immortalized mouse keratinocytes. PLoS One. 10:e01195392015. View Article : Google Scholar : PubMed/NCBI
7	Pickarski M, Gleason A, Bednar B and Duong LT: Orally active αvβ3 integrin inhibitor MK-0429 reduces melanoma metastasis. Oncol Rep. 33:2737–2745. 2015. View Article : Google Scholar : PubMed/NCBI
8	Osório-Costa F, Rocha GZ, Dias MM and Carvalheira JB: Epidemiological and molecular mechanisms aspects linking obesity and cancer. Arq Bras Endocrinol Metabol. 53:213–226. 2009. View Article : Google Scholar : PubMed/NCBI
9	O'Neil E and Kolch W: Conferring apccificity on the ubiquitous Ras/MEK signaling pathway. Br J Cancer. 90:283–288. 2004. View Article : Google Scholar : PubMed/NCBI
10	Steelman LS, Abrams SL, Whelan J, Bertrand FE, Ludwig DE, Bäsecke J, Libra M, Stivala F, Milella M, Tafuri A, et al: Contributions of the Raf/MEK/ERK, PI3K/PTEN/Akt/mTOR and Jak/STAT pathways to leukemia. Leukemia. 22:686–707. 2008. View Article : Google Scholar : PubMed/NCBI
11	Cheung KL, Lee JH, Shu L, Kim JH, Sacks DB and Kong AN: The Ras GTPase-activating-like protein IQGAPI mediates Nrf2 protein activation via the mitogen-activated protein kinase/extracellular signal regulated kinase (ERK) kinase (MEK)-ERK pathway. J Biol Chem. 288:22378–22386. 2013. View Article : Google Scholar : PubMed/NCBI
12	Bai Y, Cui W, Xin Y, Miao X, Barati MT, Zhang C, Chen Q, Tan Y, Cui T, Zheng Y and Cai L: Prevention by sulforaphane of diabetic cardiomyopathy is associated with up-regulation of Nrf2 expression transcription activation. J Mol Cell Cardiol. 57:82–95. 2013. View Article : Google Scholar : PubMed/NCBI
13	Muslin AJ: MAPK signalling in cardiovascular health and disease: Molecular mechanisms and therapeutic targets. Clin Sci (Lond). 115:203–218. 2008. View Article : Google Scholar : PubMed/NCBI
14	Guruvayoorappan C and Kuttan G: Amentoflavone inhibits experimental tumor metastasis through a regulatory mechanism involving MMP-2, MMP-9, prolyl hydroxylase, lysyl oxidase, VEGF, ERK-1, ERK-2, STAT-1, nm23 and cytokines in lung tissues of C57BL/6 mice. Immunopharmacol Immunotoxicol. 30:711–727. 2008. View Article : Google Scholar : PubMed/NCBI
15	Wang J, Kuiatse I, Lee AV, Pan J, Giuliano A and Cui X: Sustained c-Jun-NH2-kinase activity promotes epithelial mesenchymal transition, invasion, and survival of breast cancer cells by regulating extracellular signal-regulated kinase activation. Mol Cancer Res. 8:266–277. 2010. View Article : Google Scholar : PubMed/NCBI
16	Chatziioannou AF: PET scanners dedicated to molecular imaging of small animal models. Mol Imaging Biol. 4:47–63. 2002. View Article : Google Scholar : PubMed/NCBI
17	Kosugi C, Saito N, Murakami K, Ochiai A, Koda K, Ono M, Sugito M, Ito M, Oda K, Seike K and Miyazaki M: Positron emission tomography for preoperative staging in patients with locally advanced or metastatic colorectal adenocarcinoma in lymphnode metastasis. Hepatogastroentero logy. 55:398–402. 2008.
18	Nahas CS, Akhurst T, Yeung H, Leibold T, Riedel E, Markowitz AJ, Minsky BD, Paty PB, Weiser MR, Temple LK, et al: Positron emission tomography detection of distant metastatic or synchronous disease in patients with locally advanced rectal cancer receiving preoperative chemoradiation. Ann Surg Oncol. 15:704–711. 2008. View Article : Google Scholar : PubMed/NCBI
19	Meerovitch K, Bergeron F, Leblond L, Grouix B, Poirier C, Bubenik M, Chan L, Gourdeau H, Bowlin T and Attardo G: A novel RGD antagonist that targets both alphavbeta3 and alpha5beta1 induces apoptosis of angiogenic endothelial cells on type I collagen. Vascul Pharmacol. 40:77–89. 2003. View Article : Google Scholar : PubMed/NCBI
20	Jianliang You, Liuyong Zhou and Ming Xu: Clinical research of the treatment of advanced gastric cancer using Chinese herbal medicine WD-3. Hubei J Traditional Chinese Med. 26:8–9. 2004.
21	Zhou LY, Shan ZZ and You JL: Clinical observation on treatment of colonic cancer with combined treatment of chemotherapy and chinese herbal medicine. Chin J Integr Med. 15:107–111. 2009. View Article : Google Scholar : PubMed/NCBI
22	Watanabe H, Kanzaki H, Narukawa S, Inoue T, Katsuragawa H, Kaneko Y and Mori T: Bcl 2 and Fas expression in eutopic and ectopic human endometrium during the menstrual cycle in relation to endometrial cell apoptosis. Am J Obstet Gynecol. 176:360–368. 1997. View Article : Google Scholar : PubMed/NCBI
23	Zehorai E, Yao Z, Plotnikov A and Seger R: The subcellular localization of MEK and ERK-a novel nuclear translocation signal (NTS) paves a way to the nucleus. Mol Cell Endocrinol. 314:213–220. 2010. View Article : Google Scholar : PubMed/NCBI
24	Sasaki Y, Nishina T, Yasui H, Goto M, Muro K, Tsuji A, Koizumi W, Toh Y, Hara T and Miyata Y: Phase II trial of nanoparticle albumin-bound paclitaxel as second-line chemotherapy for unresectable or recurrent gastric cancer. Cancer Sci. 105:812–817. 2014. View Article : Google Scholar : PubMed/NCBI
25	Böger C, Warneke VS, Behrens HM, Kalthoff H, Goodman SL, Becker T and Röcken C: Integrins αvβ3 and αvβ5 as prognostic, diagnostic, and therapeutic targets in gastric cancer. Gastric Cancer. 18:784–795. 2015. View Article : Google Scholar : PubMed/NCBI
26	Friedland JC, Lee MH and Boettiger D: Mechanically activated integrin switch controls alpha5beta1 function. Science. 323:642–644. 2009. View Article : Google Scholar : PubMed/NCBI