Imatinib mesylate induces mitochondria-dependent apoptosis and inhibits invasion of human pigmented villonodular synovitis fibroblast-like synovial cells

Chen,Kang; Ren,Qiao; Han,Xiao-Rui; Zhang,Xiao-Nan; Wei,Bo; Bai,Xi-Zhuang

doi:10.3892/or.2015.4350

Imatinib mesylate induces mitochondria-dependent apoptosis and inhibits invasion of human pigmented villonodular synovitis fibroblast-like synovial cells

Authors:
- Kang Chen
- Qiao Ren
- Xiao-Rui Han
- Xiao-Nan Zhang
- Bo Wei
- Xi-Zhuang Bai
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Affiliations: Department of Orthopedics, The First Affiliated Hospital of China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China, Department of Medicine, Benxi Central Hospital, Benxi, Liaoning 117000, P.R. China, Department of Sports Medicine and Joint Surgery, The First Affiliated Hospital of China Medical University, Heping, Shenyang, Liaoning 110001, P.R. China
Published online on: October 26, 2015 https://doi.org/10.3892/or.2015.4350
Pages: 197-204

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Abstract

Pigmented villonodular synovitis (PVNS) is a rare sarcoma-like disorder characterized by synovial lesions proliferation and invasion to articular cartilage for which no effective treatments are available. Imatinib mesylate (IM) is known to exert antitumor activity in some tumors, but its effects on PVNS fibroblast-like synoviocytes (PVNS-FLS) and the specific mechanism involved remain to be established. In the present study, the in vitro effects of IM on cell proliferation and survival rates were investigated in PVNS-FLS. Apoptosis induction was assessed via acridine orange/ethidium bromide (AO)/(EB) and Annexin V/PI staining as well as western blotting. The invasion ability of PVNS-FLS was evaluated by Transwell invasion chambers. IM significantly inhibited survival and invasion ability of PVNS-FLS in a dose- and time‑dependent manner. The drug-treated cell groups exhibited markedly higher apoptosis, which was blocked upon pretreatment with the specific caspase-9 inhibitor Z-LEHD-FMK. Expression of cleaved caspase-9 was significantly increased and the Bcl-2 family and caspase-3 were activated following treatment with IM. Our results collectively demonstrated that IM has a strong antiproliferative effect on PVNS-FLS in vitro, attributable to induction of mitochondrial-dependent apoptosis in association with activation of caspase-9/-3 and the Bcl-2/Bax family, and exhibits significant inhibition on the invasion ability of PVNS-FLS, suggesting that IM may be useful as a novel treatment of this disease.

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1	Blay JY, El Sayadi H, Thiesse P, Garret J and Ray-Coquard I: Complete response to imatinib in relapsing pigmented villonodular synovitis/tenosynovial giant cell tumor (PVNS/TGCT). Ann Oncol. 19:821–822. 2008. View Article : Google Scholar : PubMed/NCBI
2	Gu HF, Zhang SJ, Zhao C, Chen Y and Bi Q: A comparison of open and arthroscopic surgery for treatment of diffuse pigmented villonodular synovitis of the knee. Knee Surg Sports Traumatol Arthrosc. 22:2830–2836. 2014. View Article : Google Scholar : PubMed/NCBI
3	Ottaviani S, Ayral X, Dougados M and Gossec L: Pigmented villonodular synovitis: A retrospective single-center study of 122 cases and review of the literature. Semin Arthritis Rheum. 40:539–546. 2011. View Article : Google Scholar
4	Lavrador JP, Oliveira E, Gil N, Francisco AF and Livraghi S: C1-C2 pigmented villonodular synovitis and clear cell carcinoma: Unexpected presentation of a rare disease and a review of the literature. Eur Spine J. 24(Suppl 4): S465–S471. 2015. View Article : Google Scholar
5	Myers BW, Masi AT and Feigenbaum SL: Pigmented villo-nodular synovitis and tenosynovitis: A clinical epidemiologic study of 166 cases and literature review. Medicine. 59:223–238. 1980.
6	West RB, Rubin BP, Miller MA, Subramanian S, Kaygusuz G, Montgomery K, Zhu S, Marinelli RJ, De Luca A, Downs-Kelly E, et al: A landscape effect in tenosynovial giant-cell tumor from activation of CSF1 expression by a translocation in a minority of tumor cells. Proc Natl Acad Sci USA. 103:690–695. 2006. View Article : Google Scholar : PubMed/NCBI
7	Nassar WA, Bassiony AA and Elghazaly HA: Treatment of diffuse pigmented villonodular synovitis of the knee with combined surgical and radiosynovectomy. HSS J. 5:19–23. 2009. View Article : Google Scholar :
8	Fiocco U, Sfriso P, Lunardi F, Pagnin E, Oliviero F, Scagliori E, Cozzi L, Vezzù M, Molena B, Scanu A, et al: Molecular pathways involved in synovial cell inflammation and tumoral proliferation in diffuse pigmented villonodular synovitis. Autoimmun Rev. 9:780–784. 2010. View Article : Google Scholar : PubMed/NCBI
9	Bertoni F, Unni KK, Beabout JW and Sim FH: Malignant giant cell tumor of the tendon sheaths and joints (malignant pigmented villonodular synovitis). Am J Surg Pathol. 21:153–163. 1997. View Article : Google Scholar : PubMed/NCBI
10	Imakiire N, Fujino T, Morii T, Honya K, Mochizuki K, Satomi K and Fujioka Y: Malignant pigmented villonodular synovitis in the knee - report of a case with rapid clinical progression. Open Orthop J. 5:13–16. 2011. View Article : Google Scholar : PubMed/NCBI
11	Kaneko K, Nakahara D, Tobe M, Iwase H, Inoue Y, Ohbayashi O and Kurosawa H: Pigmented villonodular synovitis of the ankle in an adolescent. Int Orthop. 24:234–237. 2000. View Article : Google Scholar : PubMed/NCBI
12	Park G, Kim YS, Kim JH, Lee SW, Song SY, Choi EK, Yi SY and Ahn SD: Low-dose external beam radiotherapy as a postoperative treatment for patients with diffuse pigmented villonodular synovitis of the knee: 4 recurrences in 23 patients followed for mean 9 years. Acta Orthop. 83:256–260. 2012. View Article : Google Scholar : PubMed/NCBI
13	Snoots WM, Watkins D, Dockery D, Mennel R and Cheek BS: Pigmented villonodular synovitis responsive to imatinib therapy. Proc. 24:134–138. 2011.
14	Ray RA, Morton CC, Lipinski KK, Corson JM and Fletcher JA: Cytogenetic evidence of clonality in a case of pigmented villonodular synovitis. Cancer. 67:121–125. 1991. View Article : Google Scholar : PubMed/NCBI
15	Chen WM, Wu PK and Liu CL: Simultaneous anterior and posterior synovectomies for treating diffuse pigmented villonodular synovitis. Clin Orthop Relat Res. 470:1755–1762. 2012. View Article : Google Scholar : PubMed/NCBI
16	Nakahara H, Matsuda S, Harimaya K, Sakamoto A, Matsumoto Y, Okazaki K, Tashiro Y and Iwamoto Y: Clinical results of open synovectomy for treatment of diffuse pigmented villonodular synovitis of the knee: Case series and review of literature. Knee. 19:684–687. 2012. View Article : Google Scholar : PubMed/NCBI
17	Nishida Y, Tsukushi S, Nakashima H, Sugiura H, Yamada Y, Urakawa H, Arai E and Ishiguro N: Osteochondral destruction in pigmented villonodular synovitis during the clinical course. J Rheumatol. 39:345–351. 2012. View Article : Google Scholar
18	Liu XY, Yang YF, Wu CT, Xiao FJ, Zhang QW, Ma XN, Li QF, Yan J, Wang H and Wang LS: Spred2 is involved in imatinib-induced cytotoxicity in chronic myeloid leukemia cells. Biochem Biophys Res Commun. 393:637–642. 2010. View Article : Google Scholar : PubMed/NCBI
19	Cassier PA, Gelderblom H, Stacchiotti S, Thomas D, Maki RG, Kroep JR, van der graaf WT, Italiano A, Seddon B, Dômont J, et al: Efficacy of imatinib mesylate for the treatment of locally advanced and/or metastatic tenosynovial giant cell tumor/pigmented villonodular synovitis. Cancer. 118:1649–1655. 2012. View Article : Google Scholar
20	Ravi V, Wang WL and Lewis VO: Treatment of tenosynovial giant cell tumor and pigmented villonodular synovitis. Curr Opin Oncol. 23:361–366. 2011. View Article : Google Scholar : PubMed/NCBI
21	Stacchiotti S, Crippa F, Messina A, Pilotti S, Gronchi A, Blay JY and Casali PG: Response to imatinib in villonodular pigmented synovitis (PVNS) resistant to nilotinib. Clin Sarcoma Res. 3:82013. View Article : Google Scholar : PubMed/NCBI
22	Zimmermann T, Kunisch E, Pfeiffer R, Hirth A, Stahl HD, Sack U, Laube A, Liesaus E, Roth A, Palombo-Kinne E, et al: Isolation and characterization of rheumatoid arthritis synovial fibroblasts from primary culture - primary culture cells markedly differ from fourth-passage cells. Arthritis Res. 3:72–76. 2001. View Article : Google Scholar :
23	Wessel D and Flügge UI: A method for the quantitative recovery of protein in dilute solution in the presence of detergents and lipids. Anal Biochem. 138:141–143. 1984. View Article : Google Scholar : PubMed/NCBI
24	Granowitz SP, D'Antonio J and Mankin HL: The pathogenesis and long-term end results of pigmented villonodular synovitis. Clin Orthop Relat Res. 114:335–351. 1976.PubMed/NCBI
25	Schwartz HS, Unni KK and Pritchard DJ: Pigmented villonodular synovitis. A retrospective review of affected large joints. Clin Orthop Relat Res. 247:243–255. 1989.PubMed/NCBI
26	Tyler WK, Vidal AF, Williams RJ and Healey JH: Pigmented villonodular synovitis. J Am Acad Orthop Surg. 14:376–385. 2006.PubMed/NCBI
27	Dines JS, DeBerardino TM, Wells JL, Dodson CC, Shindle M, DiCarlo EF and Warren RF: Long-term follow-up of surgically treated localized pigmented villonodular synovitis of the knee. Arthroscopy. 23:930–937. 2007. View Article : Google Scholar : PubMed/NCBI
28	Guilhot F: Indications for imatinib mesylate therapy and clinical management. Oncologist. 9:271–281. 2004. View Article : Google Scholar : PubMed/NCBI
29	Sawyers CL: Imatinib GIST keeps finding new indications: Successful treatment of dermatofibrosarcoma protuberans by targeted inhibition of the platelet-derived growth factor receptor. J Clin Oncol. 20:3568–3569. 2002.PubMed/NCBI
30	Du Y, Wang K, Fang H, Li J, Xiao D, Zheng P, Chen Y, Fan H, Pan X, Zhao C, et al: Coordination of intrinsic, extrinsic, and endoplasmic reticulum-mediated apoptosis by imatinib mesylate combined with arsenic trioxide in chronic myeloid leukemia. Blood. 107:1582–1590. 2006. View Article : Google Scholar
31	Hu Q, Wu D, Chen W, Yan Z, Yan C, He T, Liang Q and Shi Y: Molecular determinants of caspase-9 activation by the Apaf-1 apoptosome. Proc Natl Acad Sci USA. 111:16254–16261. 2014. View Article : Google Scholar : PubMed/NCBI
32	Jin Z and El-Deiry WS: Overview of cell death signaling pathways. Cancer Biol Ther. 4:139–163. 2005. View Article : Google Scholar : PubMed/NCBI
33	Luo X, Budihardjo I, Zou H, Slaughter C and Wang X: Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell. 94:481–490. 1998. View Article : Google Scholar : PubMed/NCBI
34	Mutlu A, Gyulkhandanyan AV, Freedman J and Leytin V: Activation of caspases-9, -3 and -8 in human platelets triggered by BH3-only mimetic ABT-737 and calcium ionophore A23187: Caspase-8 is activated via bypass of the death receptors. Br J Haematol. 159:565–571. 2012.PubMed/NCBI