Growth inhibitory effect of the Src inhibitor dasatinib in combination with anticancer agents on uterine cervical adenocarcinoma cells

Takiguchi,Eri; Nishimura,Masato; Mineda,Ayuka; Kawakita,Takako; Abe,Akiko; Irahara,Minoru

doi:10.3892/etm.2017.5061

Growth inhibitory effect of the Src inhibitor dasatinib in combination with anticancer agents on uterine cervical adenocarcinoma cells

Authors:
- Eri Takiguchi
- Masato Nishimura
- Ayuka Mineda
- Takako Kawakita
- Akiko Abe
- Minoru Irahara
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Affiliations: Department of Obstetrics and Gynecology, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan
Published online on: August 28, 2017 https://doi.org/10.3892/etm.2017.5061
Pages: 4293-4299
Copyright: © Takiguchi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Uterine cervical adenocarcinoma has a poor clinical prognosis when compared with squamous cell carcinoma. Therefore, the development of new treatment strategies for uterine cervical adenocarcinoma is necessary. Src is a proto‑oncogene that is important in cancer progression. Dasatinib is a Src inhibitor that has been reported to be effective when used in combination with anticancer drugs. The present study aimed to confirm Src expression in human cervical adenocarcinoma cell lines and to determine the mechanism underlying the inhibitory effect of dasatinib on Src signaling in vitro. Western blot analysis was performed to investigate Src expression in cervical adenocarcinoma cell lines (HeLa and TCO‑2 cells). The cells were cultured for 48 h with the addition of different concentrations of anticancer drugs (paclitaxel or oxaliplatin). Viable cell count was measured using a colorimetric (WST‑1) assay. The concentrations of anticancer agents were fixed according to the results obtained, and the same experiments were performed using the drugs in combination with dasatinib at various concentrations to determine the concentrations that significantly affected the number of viable cells. The presence or absence of apoptosis was investigated using a caspase‑3/7 assay. Signal transduction in each cell line was examined using western blotting. Src was activated in the two cell lines, and cell proliferation was significantly suppressed by each anticancer drug in combination with 10 µM dasatinib. Caspase‑3/7 activity was also increased and Src signaling was suppressed by each anticancer drug in combination with dasatinib. In conclusion, Src is overexpressed in cervical adenocarcinoma cell lines, and dasatinib inhibits intracellular Src signaling and causes apoptosis. The results of the present study suggest that Src may be targeted in novel therapeutic strategies for cervical adenocarcinoma.

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1	The Editorial Board of the Cancer Statistics in Japan: Cancer Statistics in Japan. 2014.
2	Fujiwara K, Monk B and Devouassoux-Shisheboran M: Adenocarcinoma of the uterine cervix: Why is it different? Curr Oncol Rep. 16:4162014. View Article : Google Scholar : PubMed/NCBI
3	NCNN Guideline: NCCN Clinical Practice Guidelines in Oncology, cervical cancer. 2016.
4	Gien LT, Beauchemin MC and Thomas G: Adenocarcinoma: A unique cervical cancer. Gynecol Oncol. 116:140–146. 2010. View Article : Google Scholar : PubMed/NCBI
5	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
6	Summy JM and Gallick GE: Treatment for advanced tumors: SRC reclaims center stage. Clin Cancer Res. 12:1398–1401. 2006. View Article : Google Scholar : PubMed/NCBI
7	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
8	Schott AF, Barlow WE, Van Poznak CH, Hayes DF, Moinpour CM, Lew DL, Dy PA, Keller ET, Keller JM and Hortobagyi GN: Phase II studies of two different schedules of dasatinib in bone metastasis predominant metastatic breast cancer: SWOG S0622. Breast Cancer Res Treat. 159:87–95. 2016. View Article : Google Scholar : PubMed/NCBI
9	Fornier MN, Morris PG, Abbruzzi A, D'Andrea G, Gilewski T, Bromberg J, Dang C, Dickler M, Modi S, Seidman AG, et al: A phase I study of dasatinib and weekly paclitaxel for metastatic breast cancer. Ann Oncol. 22:2575–2581. 2011. View Article : Google Scholar : PubMed/NCBI
10	Araujo JC, Mathew P, Armstrong AJ, Braud EL, Posadas E, Lonberg M, Gallick GE, Trudel GC, Paliwal P, Agrawal S and Logothetis CJ: Dasatinib combined with docetaxel for castration-resistant prostate cancer: Results from a phase 1–2 study. Cancer. 118:63–71. 2012. View Article : Google Scholar : PubMed/NCBI
11	Araujo JC, Trudel GC, Saad F, Armstrong AJ, Yu EY, Bellmunt J, Wilding G, McCaffrey J, Serrano SV, Matveev VB, et al: Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): A randomised, double-blind phase 3 trial. Lancet Oncol. 14:1307–1316. 2013. View Article : Google Scholar : PubMed/NCBI
12	Chee CE, Krishnamurthi S, Nock CJ, Meropol NJ, Gibbons J, Fu P, Bokar J, Teston L, O'Brien T, Gudena J, et al: Phase II study of dasatinib (BMS-354825) in patients with metastatic adenocarcinoma of the pancreas. Oncologist. 18:1091–1092. 2013. View Article : Google Scholar : PubMed/NCBI
13	Sharma MR, Wroblewski K, Polite BN, Knost JA, Wallace JA, Modi S, Sleckman BG, Taber D, Vokes EE, Stadler WM and Kindler HL: Dasatinib in previously treated metastatic colorectal cancer: A phase II trial of the University of Chicago Phase II Consortium. Invest New Drugs. 30:1211–1215. 2012. View Article : Google Scholar : PubMed/NCBI
14	Gold K, Lee J, Harun N, Tang X, Price J, Kawedia JD, Tran HT, Erasmus JJ, Blumenschein GR and William WN: A phase I/II study combining erlotinib and dasatinib for non-small cell lung cancer. Oncologist. 19:1040–1041. 2014. View Article : Google Scholar : PubMed/NCBI
15	Schilder RJ, Brady WE, Lankes HA, Fiorica JV, Shahin MS, Zhou XC, Mannel R, Pathak HB, Hu W, Alpaugh K, et al: Phase II evaluation of dasatinib in the treatment of recurrent or persistent epithelial ovarian or primary peritoneal carcinoma: A gynecologic oncology group study. Gynecol Oncol. 127:70–74. 2012. View Article : Google Scholar : PubMed/NCBI
16	Secord AA, Teoh DK, Barry WT, Yu M, Broadwater G, Havrilesky LJ, Lee PS, Berchuck A, Lancaster J and Wenham RM: A phase I trial of dasatinib, a Src-family kinase inhibitor, in combination with paclitaxel and carboplatin in patients with advanced or recurrent ovarian cancer. Clin Cancer Res. 18:5489–5498. 2013. View Article : Google Scholar
17	Hong DS, Choe DH, Naing A, Wheler JJ, Falchook GS, Piha-Paul S, Moulder SL, George GC, Choe JM, Strauss LC, et al: A phase 1 study of gemcitabine combined with dasatinib in patients with advanced solid tumors. Invest New Drugs. 31:918–926. 2013. View Article : Google Scholar : PubMed/NCBI
18	Matsuo K, Nishimura M, Bottsford-Miller JN, Huang J, Komurov K, Armaiz-Pena GN, Shahzad MM, Stone RL, Roh JW, Sanguino AM, et al: Targeting Src in mucinous ovarian carcinoma. Clin Cancer Res. 17:5367–5378. 2011. View Article : Google Scholar : PubMed/NCBI
19	Pengetnze Y, Steed M, Roby KF, Terranova PF and Taylor CC: Src tyrosine kinase promotes survival and resistance to chemotherapeutics in a mouse ovarian cancer cell line. Biochem Biophys Res Commun. 309:377–383. 2003. View Article : Google Scholar : PubMed/NCBI
20	Xiao J, Xu M, Hou T, Huang Y, Yang C and Li J: Dasatinib enhances antitumor activity of paclitaxel in ovarian cancer through Src signaling. Mol Med Rep. 12:3249–3256. 2015. View Article : Google Scholar : PubMed/NCBI
21	Teoh D, Ayeni TA, Rubatt JM, Adams DJ, Grace L, Starr MD, Barry WT, Berchuck A, Murphy SK and Secord AA: 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
22	Liu T, Hu W, Dalton HJ, Choi HJ, Huang J, Kang Y, Pradeep S, Miyake T, Song JH, Wen Y, et al: Targeting Src and tubulin in mucinous ovarian carcinoma. Clin Cancer Res. 19:6532–6543. 2013. View Article : Google Scholar : PubMed/NCBI
23	Kong L, Deng Z, Zhao Y, Wang Y, Sarkar FH and Zhan Y: Down-regulation of phospho-non-receptor Src tyrosine kinases contributes to growth inhibition of cervical cancer cells. Med Oncol. 28:1495–1506. 2011. View Article : Google Scholar : PubMed/NCBI
24	Kong L, Deng Z, Shen H and Zhang Y: Src family kinase inhibitor PP2 efficiently inhibits cervical cancer cell proliferation through down-regulating phospho-Src-Y416 and phospho-EGFR-Y1173. Mol Cell Biochem. 348:11–19. 2011. View Article : Google Scholar : PubMed/NCBI