Antitumour effects of Yangzheng Xiaoji in human osteosarcoma: The pivotal role of focal adhesion kinase signalling

Jiang,Wen   G.; Ye,Lin; Ji,Ke; Ruge,Fiona; Wu,Yiling; Gao,Yong; Ji,Jiafu; Mason,Malcolm  D.

doi:10.3892/or.2013.2586

Antitumour effects of Yangzheng Xiaoji in human osteosarcoma: The pivotal role of focal adhesion kinase signalling

Authors:
- Wen G. Jiang
- Lin Ye
- Ke Ji
- Fiona Ruge
- Yiling Wu
- Yong Gao
- Jiafu Ji
- Malcolm D. Mason
View Affiliations

Affiliations: Cardiff University-Peking University School of Oncology Joint Institute, Cardiff CF14 4XN, UK, Yiling Medical Research Institute Tianshan Dajie, Shijiazhuang, Hebei, P.R. China
Published online on: July 3, 2013 https://doi.org/10.3892/or.2013.2586
Pages: 1405-1413

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 present study examined, in vitro and in vivo, the potential antitumour effects of Yangzheng Xiaoji (YZXJ), a traditional Chinese medical formula used in cancer treatment, on osteosarcoma, a tumour type recently found to be sensitive to YZXJ. The human osteosarcoma cell line MG63 was used in cell-matrix adhesion and cell growth assays. The same cell line was used in an in vivo tumour model by establishing subcutaneous osteosarcoma xenografts. Oral and intraperitoneal routes were used to deliver the YZXJ extract. The effect of YZXJ on the activation of focal adhesion kinase (FAK) and paxillin was evaluated by immunofluorescence methods. It was found that YZXJ exhibited a significant inhibitory effect on cell-matrix adhesion as demonstrated by a cell-based assay and electric cell-substrate impedance sensing (ECIS) analysis. The effect was observed together with a reduction in phospho-FAK and phospho-paxillin in the cells when treated with YZXJ. In the in vivo tumour model, YZXJ was found to significantly inhibit the growth of osteosarcoma with a sustained effect observed when YZXJ was delivered intraperitoneally. YZXJ sensitized cells to the effect of FAK inhibitor in vitro and in vivo. It is concluded that Yangzheng Xiaoji plays a significant role in cell-matrix adhesion and tumour growth, likely by inhibiting the activation of the FAK pathway. The therapeutic role of Yangzheng Xiaoji in osteosarcoma warrants further investigation.

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	Dorfman HA and Czerniak B: Bone cancers. Cancer. 75(Suppl 1): S203–S210. 1995. View Article : Google Scholar
3	Hayden JB and Hoang BH: Osteosarcoma: basic science and clinical implications. Orthop Clin North Am. 37:1–7. 2006. View Article : Google Scholar : PubMed/NCBI
4	Wachtel M and Schäfer BW: Targets for cancer therapy in childhood sarcomas. Cancer Treat Rev. 36:318–327. 2010. View Article : Google Scholar : PubMed/NCBI
5	Kubo T, Piperdi S, Rosenblum J, Antonescu CR, Chen W, Kim HS, Huvos AG, Sowers R, Meyers PA, Healey JH and Gorlick R: Platelet-derived growth factor receptor as a prognostic marker and a therapeutic target for imatinib mesylate therapy in osteosarcoma. Cancer. 112:2119–2129. 2008. View Article : Google Scholar : PubMed/NCBI
6	Ferrari S and Palmerini E: Adjuvant and neoadjuvant combination chemotherapy for osteogenic sarcoma. Curr Opin Oncol. 19:341–346. 2007. View Article : Google Scholar : PubMed/NCBI
7	Jiang WG, Ye L, Ji K, Frewer N, Ji J and Mason MD: Inhibitory effects of Yangzheng Xiaoji on angiogenesis and the role of the focal adhesion kinase pathway. Int J Oncol. 41:1635–1642. 2012.
8	Ye L, Ji K, Frewer N, Ji J and Jiang WG: Impact of Yangzheng Xiaoji on the adhesion and migration of human cancer cells: the role of the AKT signalling pathway. Anticancer Res. 32:2537–2543. 2012.
9	Zhang SY, Gu CH, Gao XD and Wu YL: A random, double-blinded and multicentre study of chemotherapy assisted Yangzheng Xiaoji capsule on treating primary hepatic carcinoma. Chin J Diffic Compl Case. 8:461–464. 2009.
10	Wang QL, Xuo CM, Wu XP, Li YX and Bi XJ: Treatment of atypical gastric dysplasia using Yangzheng Xiaoji. Chin J Diffic Compl Case. 7:38–39. 2009.
11	Ye Li, Ji K, Ji JF, Hargest R and Jiang WG: Application of electric cell-substrate impedance sensing in evaluation of traditional medicine on the cellular functions of gastric and colorectal cancer cells. Cancer Metastasis Biol Treat. 17:195–202. 2012.
12	Jiang WG, Hiscox S, Hallett MB, Scott C, Horrobin DF and Puntis MC: Inhibition of hepatocyte growth factor-induced motility and in vitro invasion and motility of human colon cancer cells by gamma-linolenic acid. Br J Cancer. 71:744–752. 1995. View Article : Google Scholar : PubMed/NCBI
13	Giaever I and Keese CR: Micromotion of mammalian cells measured electrically. Proc Natl Acad Sci USA. 88:7896–7900. 1991. View Article : Google Scholar : PubMed/NCBI
14	Keese CR, Wegener J, Walker SR and Giaever I: Electrical wound-healing assay for cells in vitro. Proc Natl Acad Sci USA. 101:1554–1559. 2004. View Article : Google Scholar : PubMed/NCBI
15	Jiang WG, Martin TA, Lewis-Russell JM, Douglas-Jones A, Ye L and Mansel RE: Eplin-alpha expression in human breast cancer, the impact on cellular migration and clinical outcome. Mol Cancer. 7:712008. View Article : Google Scholar : PubMed/NCBI
16	Davies G, Mason MD, Martin TA, Parr C, Watkins G, Lane J, Matsumoto K, Nakamura T and Jiang WG: The HGF/SF antagonist NK4 reverses fibroblast- and HGF-induced prostate tumor growth and angiogenesis in vivo. Int J Cancer. 106:348–354. 2003. View Article : Google Scholar : PubMed/NCBI
17	Ye L, Martin TA, Parr C, Harrison GM, Mansel RE and Jiang WG: Biphasic effects of 17-β-estradiol on expression of occludin and transendothelial resistance and paracellular permeability in human vascular endothelial cells. J Cell Physiol. 196:362–369. 2003.
18	Gilmore AP and Romer LH: Inhibition of focal adhesion kinase (FAK) signaling in focal adhesions decreases cell motility and proliferation. Mol Biol Cell. 7:1209–1224. 1996. View Article : Google Scholar : PubMed/NCBI
19	Chen JY, Tang YA, Huang SM, Juan HF, Wu LW, Sun YC, Wang SC, Wu KW, Balraj G, Chang TT, Li WS, Cheng HC and Wang YC: A novel sialyltransferase inhibitor suppresses FAK/paxillin signaling and cancer angiogenesis and metastasis pathways. Cancer Res. 71:473–483. 2011. View Article : Google Scholar : PubMed/NCBI
20	Stokes JB, Adair SJ, Slack-Davis JK, Walters DM, Tilghman RW, Hershey ED, Lowrey B, Thomas KS, Bouton AH, Hwang RF, Stelow EB, Parsons JT and Bauer TW: Inhibition of focal adhesion kinase by PF-562,271 inhibits the growth and metastasis of pancreatic cancer concomitant with altering the tumor microenvironment. Mol Cancer Ther. 10:2135–2145. 2011. View Article : Google Scholar : PubMed/NCBI
21	Halder J, Lin YG, Merritt WM, Spannuth WA, Nick AM, Honda T, Kamat AA, Han LY, Kim TJ, Lu C, Tari AM, Bornmann W, Fernandez A, Lopez-Berestein G and Sood AK: Therapeutic efficacy of a novel focal adhesion kinase inhibitor TAE226 in ovarian carcinoma. Cancer Res. 67:10976–10983. 2007. View Article : Google Scholar : PubMed/NCBI
22	Infante JR, Camidge DR, Mileshkin LR, Chen EX, Hicks RJ, Rischin D, Fingert H, Pierce KJ, Xu H, Roberts WG, Shreeve SM, Burris HA and Siu LL: Safety, pharmacokinetic, and pharmacodynamic phase I dose-escalation trial of PF-00562271, an inhibitor of focal adhesion kinase, in advanced solid tumors. J Clin Oncol. 30:1527–1533. 2012. View Article : Google Scholar : PubMed/NCBI
23	Soria JC, Plummer R, Ranson M, Gan H, Arkenau HT, Zalcman G, Blagden S, Evans TRJ, Peddareddigari V, Mazumdar J, Murray S, Gidson D, Fleming RA, Auger K and Millward M: Loss of the tumor suppressor merlin as a potential predictive biomarker of clinical activity for the oral, focal adhesion kinase (FAK) inhibitor GSK_2256098 in pts with recurrent mesothelioma. Eur J Cancer. 48(Suppl 6): S1882012. View Article : Google Scholar
24	Ritter J and Bielack SS: Osteosarcoma. Ann Oncol. 21(Suppl 7): vii320–vii325. 2010. View Article : Google Scholar : PubMed/NCBI
25	Anninga JK, Gelderblom H, Fiocco M, Kroep JR, Taminiau AH, Hogendoorn PC and Egeler RM: Chemotherapeutic adjuvant treatment for osteosarcoma: where do we stand? Eur J Cancer. 47:2431–2445. 2011. View Article : Google Scholar : PubMed/NCBI
26	Jaffe N: Osteosarcoma: review of the past, impact on the future. The American experience. Cancer Treat Res. 152:239–262. 2009. View Article : Google Scholar : PubMed/NCBI