Dasatinib enhances antitumor activity of paclitaxel in ovarian cancer through Src signaling

Xiao,Juan; Xu,Manman; Hou,Teng; Huang,Yongwen; Yang,Chenlu; Li,Jundong

doi:10.3892/mmr.2015.3784

Dasatinib enhances antitumor activity of paclitaxel in ovarian cancer through Src signaling

Authors:
- Juan Xiao
- Manman Xu
- Teng Hou
- Yongwen Huang
- Chenlu Yang
- Jundong Li
View Affiliations

Affiliations: Department of Gynecology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China, Department of Obstetrics and Gynecology, The First Affiliated Hospital, Sun Yat‑sen University, Guangzhou, Guangdong 510080, P.R. China
Published online on: May 14, 2015 https://doi.org/10.3892/mmr.2015.3784
Pages: 3249-3256
Copyright: © Xiao et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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

Src family tyrosine kinase (SFK) activation is associated with ovarian cancer progression. Therefore, SFKs are targets for the development of potential treatments of ovarian cancer. Dasatinib is a tyrosine kinase inhibitor that targets SFK activity, and is used for the treatment of B cell and Abelson lymphomas. At the present time, the potential effect of dasatinib on ovarian cancer is not clear. The aim of the present study was to investigate the antitumor activity of dasatinib, alone and in combination with paclitaxel, in ovarian cancer in vitro and in vivo. In the present study, the expression of Src and phospho‑Src-Y416 (p‑Src) was measured in six ovarian cancer cell lines using western blotting and immunohistochemistry. In addition, cell viability and apoptosis were measured using an MTT assay and annexin V‑fluorescein isothiocyanate staining. An ovarian cancer murine xenograft model was established, in order to evaluate the antitumor effect of dasatinib alone and in combination with paclitaxel in ovarian cancer. High levels of p‑Src protein expression were observed in all cell lines, as compared with healthy cells, which indicated activation of the Src signaling pathway. p‑Src expression increased in ovarian cancer cells following paclitaxel treatment. Dasatinib treatment demonstrated anti‑ovarian cancer properties, by downregulating p‑Src expression and by inducing cancer cell apoptosis. Combined treatment with dasatinib and paclitaxel markedly inhibited proliferation and promoted apoptosis of ovarian cancer cells, compared with control cells. Combined dasatinib and paclitaxel treatment exhibited antitumor activities in vivo and in vitro (combination indices, 0.25‑0.93 and 0.31‑0.75; and tumor growth inhibitory rates, 76.7% and 58.5%, in A2780 and HO8910 cell lines, respectively), compared with paclitaxel treatment alone. Dasatinib monotherapy demonstrated anti‑ovarian cancer activities. The effects of dasatinib and paclitaxel treatments on ovarian cancer cells appeared to be mediated by the Src pathway.

View Figures

View References

1	Jelovac D and Armstrong DK: Recent progress in the diagnosis and treatment of ovarian cancer. CA Cancer J Clin. 61:183–203. 2011. View Article : Google Scholar : PubMed/NCBI
2	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2012. CA Cancer J Clin. 62:10–29. 2012. View Article : Google Scholar : PubMed/NCBI
3	Shah NP, Tran C, Lee FY, Chen P, Norris D and Sawyers CL: Overriding imatinib resistance with a novel ABL kinase inhibitor. Science. 305:399–401. 2004. View Article : Google Scholar : PubMed/NCBI
4	Yeatman TJ: A renaissance for SRC. Nat Rev Cancer. 4:470–480. 2004. View Article : Google Scholar : PubMed/NCBI
5	Brunton VG and Frame MC: Src and focal adhesion kinase as therapeutic targets in cancer. Curr Opin Pharmacol. 8:427–432. 2008. View Article : Google Scholar : PubMed/NCBI
6	Wheeler DL, Iida M and Dunn EF: The role of Src in solid tumors. Oncologist. 14:667–678. 2009. View Article : Google Scholar : PubMed/NCBI
7	Summy JM and Gallick GE: Src family kinases in tumor progression and metastasis. Cancer Metastasis Rev. 22:337–358. 2003. View Article : Google Scholar : PubMed/NCBI
8	Dehm SM and Bonham K: SRC gene expression in human cancer: The role of transcriptional activation. Biochem Cell Biol. 82:263–274. 2004. View Article : Google Scholar : PubMed/NCBI
9	Morgan L, Nicholson RI and Hiscox S: SRC as a therapeutic target in breast cancer. Endocr Metab Immune Disord Drug Targets. 8:273–278. 2008. View Article : Google Scholar : PubMed/NCBI
10	Lutz MP, Esser IB, Flossmann-Kast BBM, et al: Overexpression and activation of the tyrosine kinase Src in human pancreatic carcinoma. Biochem Biophys Res Commun. 243:503–508. 1998. View Article : Google Scholar : PubMed/NCBI
11	Budde RJ, Ke S and Levin VA: Activity of pp60c-src in 60 different cell lines derived from human tumors. Cancer Biochem Biophys. 14:171–175. 1994.PubMed/NCBI
12	Wiener JR, Windham TC, Estrella VC, et al: Activated SRC protein tyrosine kinase is overexpressed in late-stage human ovarian cancers. Gynecol Oncol. 88:73–79. 2003. View Article : Google Scholar
13	Huang YW, Chen C, Xu MM, Li JD, Xiao J and Zhu XF: Expression of c-Src and phospho-Src in epithelial ovarian carcinoma. Mol Cell Biochem. 376:73–79. 2013. View Article : Google Scholar : PubMed/NCBI
14	Lombardo LJ, Lee FY, Chen P, et al: Discovery of N-(2- chloro- 6- methyl- phenyl)- 2-(6-(4-(2- hydroxyethyl)-piperazin - 1- yl)- 2- methylpyrimidin- 4- ylamino)thiazole- 5- carboxamide (BMS- 354825), a dual Src/Abl kinase inhibitor with potent antitumor activity in preclinical assays. J Med Chem. 47:6658–6661. 2004. View Article : Google Scholar : PubMed/NCBI
15	Gnoni A, Marech I, Silvestris N, Vacca A and Lorusso V: Dasatinib: an anti-tumour agent via Src inhibition. Curr Drug Targets. 12:563–578. 2011. View Article : Google Scholar : PubMed/NCBI
16	Nam S, Kim D, Cheng JQ, et al: Action of the Src family kinase inhibitor, dasatinib (BMS-354825), on human prostate cancer cells. Cancer Res. 65:9185–9189. 2005. View Article : Google Scholar : PubMed/NCBI
17	Johnson FM, Saigal B, Talpaz M and Donato NJ: Dasatinib (BMS-354825) tyrosine kinase inhibitor suppresses invasion and induces cell cycle arrest and apoptosis of head and neck squamous cell carcinoma and non-small cell lung cancer cells. Clin Cancer Res. 11:6924–6932. 2005. View Article : Google Scholar : PubMed/NCBI
18	Ceppi P, Papotti M, Monica V, et al: Effects of Src kinase inhibition induced by dasatinib in non-small cell lung cancer cell lines treated with cisplatin. Mol Cancer Ther. 8:3066–3074. 2009. View Article : Google Scholar : PubMed/NCBI
19	Tsao AS, He D, Saigal B, et al: Inhibition of c-Src expression and activation in malignant pleural mesothelioma tissues leads to apoptosis, cell cycle arrest, and decreased migration and invasion. Mol Cancer Ther. 6:1962–1972. 2007. View Article : Google Scholar : PubMed/NCBI
20	Trevino JG, Summy JM, Lesslie DP, et al: Inhibition of SRC expression and activity inhibits tumor progression and metastasis of human pancreatic adenocarcinoma cells in an orthotopic nude mouse model. Am J Pathol. 168:962–972. 2006. View Article : Google Scholar : PubMed/NCBI
21	Shor AC, Keschman EA, Lee FY, et al: Dasatinib inhibits migration and invasion in diverse human sarcoma cell lines and induces apoptosis in bone sarcoma cells dependent on SRC kinase for survival. Cancer Res. 67:2800–2808. 2007. View Article : Google Scholar : PubMed/NCBI
22	Konecny GE, Glas R, Dering J, et al: Activity of the multikinase inhibitor dasatinib against ovarian cancer cells. Br J Cancer. 101:1699–1708. 2009. View Article : Google Scholar : PubMed/NCBI
23	Teoh D, Ayeni TA, Rubatt JM, Adams DJ, Grace L and Starr MD: Dasatinib (BMS-35482) has synergistic activity with paclitaxel and carboplatin in ovarian cancer cells. Gynecol Oncol. 121:187–192. 2011. View Article : Google Scholar : PubMed/NCBI
24	Deng R, Tang J, Xia LP, et al: ExcisaninA, a diterpenoid compound purified from Isodon MacrocalyxinD, induces tumor cells apoptosis and suppresses tumor growth through inhibition of PKB/AKT kinase activity and blockade of its signal pathway. Mol Cancer Ther. 8:873–882. 2009. View Article : Google Scholar : PubMed/NCBI
25	Le XF, Mao W, Lu Z, Carter BZ and Bast RC Jr: Dasatinib induces autophagic cell death in human ovarian cancer. Cancer. 116:4980–4990. 2010. View Article : Google Scholar : PubMed/NCBI
26	Vitali R, Mancini C, Cesi V, et al: Activity of tyrosine kinase inhibitor Dasatinib in neuroblastoma cells in vitro and in orthotopic mouse model. Int J Cancer. 125:2547–2555. 2009. View Article : Google Scholar : PubMed/NCBI
27	Kim LC, Rix U and Haura EB: Dasatinib in solid tumors. Expert Opin Investig Drugs. 19:415–425. 2010. View Article : Google Scholar : PubMed/NCBI
28	Mayer EL and Krop IE: Advances in targeting SRC in the treatment of breast cancer and other solid malignancies. Clin Cancer Res. 16:3526–3532. 2010. View Article : Google Scholar : PubMed/NCBI
29	Yezhelyev MV, Koehl G, Guba M, et al: Inhibition of SRC tyrosine kinase as treatment for human pancreatic cancer growing orthotopically in nude mice. Clin Cancer Res. 10:8028–8036. 2004. View Article : Google Scholar : PubMed/NCBI
30	Le XF and Bast RC Jr: Src family kinases and paclitaxel sensitivity. Cancer Biol Ther. 12:260–269. 2011. View Article : Google Scholar : PubMed/NCBI
31	George JA, Chen T and Taylor CC: SRC tyrosine kinase and multidrug resistance protein-1 inhibitions act independently but cooperatively to restore paclitaxel sensitivity to paclitaxel-resistant ovarian cancer cells. Cancer Res. 65:10381–10388. 2005. View Article : Google Scholar : PubMed/NCBI
32	Chen T, Pengetnze Y and Taylor CC: Src inhibition enhances paclitaxel cytotoxicity in ovarian cancer cells by caspase-9-independent activation of caspase-3. Mol Cancer Ther. 4:217–224. 2005.PubMed/NCBI
33	Agarwal R and Kaye SB: Ovarian cancer: strategies for overcoming resistance to chemotherapy. Nat Rev Cancer. 3:502–516. 2003. View Article : Google Scholar : PubMed/NCBI
34	Le XF, Mao W, He G, et al: The role of p27(Kip1) in dasatinib-enhanced paclitaxel cytotoxicity in human ovarian cancer cells. J Natl Cancer Inst. 103:1403–1422. 2011. View Article : Google Scholar : PubMed/NCBI
35	Han LY, Landen CN, Trevino JG, et al: Antiangiogenic and antitumor effects of SRC inhibition in ovarian carcinoma. Cancer Res. 66:8633–8639. 2006. View Article : Google Scholar : PubMed/NCBI
36	Kim HS, Han HD, Armaiz-Pena GN, et al: Functional roles of Src and Fgr in ovarian carcinoma. Clin Cancer Res. 17:1713–1721. 2011. View Article : Google Scholar : PubMed/NCBI
37	Kopetz S, Lesslie DP, Dallas NA, et al: Synergistic activity of the SRC family kinase inhibitor dasatinib and oxaliplatin in colon carcinoma cells is mediated by oxidative stress. Cancer Res. 69:3842–3849. 2009. View Article : Google Scholar : PubMed/NCBI