Novel multi‑kinase inhibitor, T03 inhibits Taxol‑resistant breast cancer

Li,Yan; Liu,Chunxia; Tang,Ke; Chen,Yan; Tian,Kang; Feng,Zhiqiang; Chen,Jindong

doi:10.3892/mmr.2017.8179

Novel multi‑kinase inhibitor, T03 inhibits Taxol‑resistant breast cancer

Authors:
- Yan Li
- Chunxia Liu
- Ke Tang
- Yan Chen
- Kang Tian
- Zhiqiang Feng
- Jindong Chen
View Affiliations

Affiliations: Department of Pharmacology, State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China, Department of Synthetic Medicinal Chemistry, Beijing Key Laboratory of Active Substance Discovery and Drugability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, P.R. China, Department of Urology, University of Rochester Medical Center, Rochester, NY 14642, USA
Published online on: November 28, 2017 https://doi.org/10.3892/mmr.2017.8179
Pages: 2373-2383
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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

Activation of kinase-associated signaling pathways is one of the leading causes of various malignant phenotypes in breast tumors. Strategies of drug discovery and development have investigated approaches to target the inhibition of protein kinase signaling. In the current study, the anti‑tumor activities of a novel multi‑kinase inhibitor, T03 were evaluated in breast cancer. T03 inhibited Taxol‑resistant breast cancer cell proliferation and induced cell cycle arrest and apoptosis in vitro and in vivo. The current results demonstrated that T03 downregulated c‑Raf, platelet‑derived growth factor receptor‑β and other kinases, thus inhibited Raf/mitogen‑activated protein kinase kinase/extracellular signal‑regulated kinase and Akt/mechanistic target of rapamycin survival pathways in MCF‑7 and MCF‑7/Taxol xenograft tumors. At a dose of 100 mg/kg, T03 inhibited tumor growth by 62.90 and 59.98% in tumor weight in MX‑1 and MX‑1/T xenograft models, respectively and by 62.60 and 60.22% in MCF‑7 and MCF‑7/T tumors, respectively. These data indicate that the novel multi‑kinase inhibitor, T03, may present as a potential compound to develop novel treatments against breast cancer and Taxol‑resistant breast tumors.

View Figures

View References

1	Reese JM, Suman VJ, Subramaniam M, Wu X, Negron V, Gingery A, Pitel KS, Shah SS, Cunliffe HE, McCullough AE, et al: ERβ1: Characterization, prognosis, and evaluation of treatment strategies in ERα-positive and -negative breast cancer. BMC Cancer. 14:7492014. View Article : Google Scholar : PubMed/NCBI
2	Nahta R, Hortobágyi GN and Esteva FJ: Growth factor receptors in breast cancer: Potential for therapeutic intervention. Oncologist. 8:5–17. 2003. View Article : Google Scholar : PubMed/NCBI
3	Vlahovic G and Crawford J: Activation of tyrosine kinases in cancer. Oncologist. 8:531–538. 2003. View Article : Google Scholar : PubMed/NCBI
4	Niehoff P, Mundhenke C, Kimmig B and Maas N: Breast irradiation with brachytherapy: Approved techniques and new concepts. Minerva Ginecol. 59:377–386. 2007.PubMed/NCBI
5	Hubbard SR: Juxtamembrane autoinhibition in receptor tyrosine kinases. Nat Rev Mol Cell Biol. 5:464–471. 2004. View Article : Google Scholar : PubMed/NCBI
6	Shchemelinin I, Sefc L and Necas E: Protein kinase inhibitors. Folia Biol (Praha). 52:137–148. 2006.PubMed/NCBI
7	Weigel MT, Meinhold-Heerlein I, Bauerschlag DO, Schem C, Bauer M, Jonat W, Maass N and Mundhenke C: Combination of imatinib and vinorelbine enhances cell growth inhibition in breast cancer cells via PDGFR beta signalling. Cancer Lett. 273:70–79. 2009. View Article : Google Scholar : PubMed/NCBI
8	Weigel MT, Banerjee S, Arnedos M, Salter J, A'Hern R, Dowsett M and Martin LA: Enhanced expression of the PDGFR/Abl signaling pathway in aromatase inhibitor-resistant breast cancer. Ann Oncol. 24:126–133. 2013. View Article : Google Scholar : PubMed/NCBI
9	Lin HJ, Hsieh FC, Song H and Lin J: Elevated phosphorylation and activation of PDK-1/AKT pathway in human breast cancer. Br J Cancer. 93:1372–1381. 2005. View Article : Google Scholar : PubMed/NCBI
10	Weigel MT, Dahmke L, Schem C, Bauerschlag DO, Weber K, Niehoff P, Bauer M, Strauss A, Jonat W, Maass N and Mundhenke C: In vitro effects of imatinib mesylate on radiosensitivity and chemosensitivity of breast cancer cells. BMC Cancer. 10:4122010. View Article : Google Scholar : PubMed/NCBI
11	Sridhar SS, Hedley D and Siu LL: Raf kinase as a target for anticancer therapeutics. Mol Cancer Ther. 4:677–685. 2005. View Article : Google Scholar : PubMed/NCBI
12	Li Z, Min W and Gou J: Knockdown of cyclophilin A reverses paclitaxel resistance in human endometrial cancer cells via suppression of MAPK kinase pathways. Cancer Chemother Pharmacol. 72:1001–1011. 2013. View Article : Google Scholar : PubMed/NCBI
13	Gong Y, He H, Liu H, Zhang C, Zhao W and Shao RG: Phosphorylation of myofibrillogenesis regulator-1 activates the MAPK signaling pathway and induces proliferation and migration in human breast cancer MCF7 cells. FEBS Lett. 588:2903–2910. 2014. View Article : Google Scholar : PubMed/NCBI
14	Hashimoto K, Tsuda H, Koizumi F, Shimizu C, Yonemori K, Ando M, Kodaira M, Yunokawa M, Fujiwara Y and Tamura K: Activated PI3K/AKT and MAPK pathways are potential good prognostic markers in node-positive, triple-negative breast cancer. Ann Oncol. 25:1973–1979. 2014. View Article : Google Scholar : PubMed/NCBI
15	Heckler MM, Thakor H, Schafer CC and Riggins RB: ERK/MAPK regulates ERRγ expression, transcriptional activity and receptor-mediated tamoxifen resistance in ER+ breast cancer. FEBS J. 281:2431–2442. 2014. View Article : Google Scholar : PubMed/NCBI
16	Im NK, Jang WJ, Jeong CH and Jeong GS: Delphinidin suppresses PMA-induced MMP-9 expression by blocking the NF-κB activation through MAPK signaling pathways in MCF-7 human breast carcinoma cells. J Med Food. 17:855–861. 2014. View Article : Google Scholar : PubMed/NCBI
17	Saini KS, Loi S, de Azambuja E, Metzger-Filho O, Saini ML, Ignatiadis M, Dancey JE and Piccart-Gebhart MJ: Targeting the PI3K/AKT/mTOR and Raf/MEK/ERK pathways in the treatment of breast cancer. Cancer Treat Rev. 39:935–946. 2013. View Article : Google Scholar : PubMed/NCBI
18	Lu J, Tan M, Huang WC, Li P, Guo H, Tseng LM, Su XH, Yang WT, Treekitkarnmongkol W, Andreeff M, et al: Mitotic deregulation by survivin in ErbB2-overexpressing breast cancer cells contributes to Taxol resistance. Clin Cancer Res. 15:1326–3134. 2009. View Article : Google Scholar : PubMed/NCBI
19	Li Y, Tang K, Zhang H, Zhang Y, Zhou W and Chen X: Function of Aurora kinase A in Taxol-resistant breast cancer and its correlation with P-gp. Mol Med Rep. 4:739–746. 2011.PubMed/NCBI
20	Wilhelm SM, Carter C, Tang L, Wilkie D, McNabola A, Rong H, Chen C, Zhang X, Vincent P, McHugh M, et al: BAY 43–9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res. 64:7099–7109. 2004. View Article : Google Scholar : PubMed/NCBI
21	Li Y, Zhang ZF, Chen J, Huang D, Ding Y, Tan MH, Qian CN, Resau JH, Kim H and Teh BT: VX680/MK-0457, a potent and selective Aurora kinase inhibitor, targets both tumor and endothelial cells in clear cell renal cell carcinoma. Am J Transl Res. 2:296–308. 2010.PubMed/NCBI
22	Reynolds TH IV, Bodine SC and Lawrence JC Jr: Control of Ser2448 phosphorylation in the mammalian target of rapamycin by insulin and skeletal muscle load. J Biol Chem. 277:17657–17662. 2002. View Article : Google Scholar : PubMed/NCBI
23	Salmond RJ, Emery J, Okkenhaug K and Zamoyska R: MAPK, phosphatidylinositol 3-kinase, and mammalian target of rapamycin pathways converge at the level of ribosomal protein S6 phosphorylation to control metabolic signaling in CD8 T cells. J Immunol. 183:7388–7397. 2009. View Article : Google Scholar : PubMed/NCBI
24	Biran A, Brownstein M, Haklai R and Kloog Y: Downregulation of survivin and aurora A by histone deacetylase and RAS inhibitors: A new drug combination for cancer therapy. Int J Cancer. 128:691–701. 2011. View Article : Google Scholar : PubMed/NCBI
25	Kim BK, Lee JW, Park PJ, Shin YS, Lee WY, Lee KA, Ye S, Hyun H, Kang KN, Yeo D, et al: The multiplex bead array approach to identifying serum biomarkers associated with breast cancer. Breast Cancer Res. 11:R222009. View Article : Google Scholar : PubMed/NCBI
26	de Jong JS, van Diest PJ, van der Valk P and Baak JP: Expression of growth factors, growth-inhibiting factors, and their receptors in invasive breast cancer. II: Correlations with proliferation and angiogenesis. J Pathol. 184:53–57. 1998. View Article : Google Scholar : PubMed/NCBI
27	Lev DC, Kim SJ, Onn A, Stone V, Nam DH, Yazici S, Fidler IJ and Price JE: Inhibition of platelet-derived growth factor receptor signaling restricts the growth of human breast cancer in the bone of nude mice. Clin Cancer Res. 11:306–314. 2005.PubMed/NCBI
28	Klos KS, Wyszomierski SL, Sun M, Tan M, Zhou X, Li P, Yang W, Yin G, Hittelman WN and Yu D: ErbB2 increases vascular endothelial growth factor protein synthesis via activation of mammalian target of rapamycin/p70S6K leading to increased angiogenesis and spontaneous metastasis of human breast cancer cells. Cancer Res. 66:2028–2037. 2006. View Article : Google Scholar : PubMed/NCBI
29	Wen XF, Yang G, Mao W, Thornton A, Liu J, Bast RC Jr and Le XF: HER2 signaling modulates the equilibrium between pro- and antiangiogenic factors via distinct pathways: Implications for HER2-targeted antibody therapy. Oncogene. 25:6986–6996. 2006. View Article : Google Scholar : PubMed/NCBI
30	Seymour L and Bezwoda WR: Positive immunostaining for platelet derived growth factor (PDGF) is an adverse prognostic factor in patients with advanced breast cancer. Breast Cancer Res Treat. 32:229–233. 1994. View Article : Google Scholar : PubMed/NCBI
31	Blagosklonny MV and Fojo T: Molecular effects of paclitaxel: Myths and reality (a critical review). Int J Cancer. 83:151–156. 1999. View Article : Google Scholar : PubMed/NCBI
32	Langley RR, Fan D, Tsan RZ, Rebhun R, He J, Kim SJ and Fidler IJ: Activation of the platelet-derived growth factor-receptor enhances survival of murine bone endothelial cells. Cancer Res. 64:3727–3730. 2004. View Article : Google Scholar : PubMed/NCBI
33	Sambade MJ, Camp JT, Kimple RJ, Sartor CI and Shields JM: Mechanism of lapatinib-mediated radiosensitization of breast cancer cells is primarily by inhibition of the Raf>MEK>ERK mitogen-activated protein kinase cascade and radiosensitization of lapatinib-resistant cells restored by direct inhibition of MEK. Radiother Oncol 93: 639–644, 2009. Radiother Oncol 93: 639–644, 2009. 93: 639–644, 2009:639-644, 2009–644, 2009. 2009.
34	Frogne T, Benjaminsen RV, Sonne-Hansen K, Sorensen BS, Nexo E, Laenkholm AV, Rasmussen LM, Riese DJ II, de Cremoux P, Stenvang J and Lykkesfeldt AE: Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant. Breast Cancer Res Treat. 114:263–275. 2009. View Article : Google Scholar : PubMed/NCBI
35	Lian WJ, Liu G, Liu YJ, Zhao ZW, Yi T and Zhou HY: Downregulation of BMP6 enhances cell proliferation and chemoresistance via activation of the ERK signaling pathway in breast cancer. Oncol Rep. 30:193–200. 2013. View Article : Google Scholar : PubMed/NCBI
36	Sokolosky M, Chappell WH, Stadelman K, Abrams SL, Davis NM, Steelman LS and McCubrey JA: Inhibition of GSK-3β activity can result in drug and hormonal resistance and alter sensitivity to targeted therapy in MCF-7 breast cancer cells. Cell Cycle. 13:820–833. 2014. View Article : Google Scholar : PubMed/NCBI
37	D'Assoro AB, Liu T, Quatraro C, Amato A, Opyrchal M, Leontovich A, Ikeda Y, Ohmine S, Lingle W, Suman V, et al: The mitotic kinase Aurora-a promotes distant metastases by inducing epithelial-to-mesenchymal transition in ERα(+) breast cancer cells. Oncogene. 33:599–610. 2014. View Article : Google Scholar : PubMed/NCBI
38	Anand S, Penrhyn-Lowe S and Venkitaraman AR: AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol. Cancer Cell. 3:51–62. 2003. View Article : Google Scholar : PubMed/NCBI
39	Kwiatkowski N, Deng X, Wang J, Tan L, Villa F, Santaguida S, Huang HC, Mitchison T, Musacchio A and Gray N: Selective aurora kinase inhibitors identified using a taxol-induced checkpoint sensitivity screen. ACS Chem Biol. 7:185–196. 2012. View Article : Google Scholar : PubMed/NCBI
40	Horowitz JC, Lee DY, Waghray M, Keshamouni VG, Thomas PE, Zhang H, Cui Z and Thannickal VJ: Activation of the pro-survival phosphatidylinositol 3-kinase/AKT pathway by transforming growth factor-beta1 in mesenchymal cells is mediated by p38 MAPK-dependent induction of an autocrine growth factor. J Biol Chem. 279:1359–1367. 2004. View Article : Google Scholar : PubMed/NCBI
41	Arany I, Faisal A, Nagamine Y and Safirstein RL: p66shc inhibits pro-survival epidermal growth factor receptor/ERK signaling during severe oxidative stress in mouse renal proximal tubule cells. J Biol Chem. 283:6110–6117. 2008. View Article : Google Scholar : PubMed/NCBI