Breast cancer cells evade paclitaxel-induced cell death by developing resistance to dasatinib

Jeong,Yun‑Ji; Kang,Jong  Soon; Lee,Su  In; So,Dong  Min; Yun,Jieun; Baek,Ji  Young; Kim,Sang  Kyum; Lee,Kiho; Park,Song‑Kyu

doi:10.3892/ol.2016.4852

Breast cancer cells evade paclitaxel-induced cell death by developing resistance to dasatinib

Authors:
- Yun‑Ji Jeong
- Jong Soon Kang
- Su In Lee
- Dong Min So
- Jieun Yun
- Ji Young Baek
- Sang Kyum Kim
- Kiho Lee
- Song‑Kyu Park
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Affiliations: College of Pharmacy, Korea University, Sejong 30019, Republic of Korea, Bioevaluation Center, Korea Institute of Bioscience and Biotechnology, Ochang 28116, Republic of Korea, College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea
Published online on: July 13, 2016 https://doi.org/10.3892/ol.2016.4852
Pages: 2153-2158

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Abstract

Triple negative breast cancer (TNBC), which does not express the progesterone, estrogen, or HER2/neu receptor, is aggressive and difficult to treat. Paclitaxel, a tubulin stabilizing agent, is one of the most frequently prescribed anticancer agents for breast cancers, including TNBC. Residual disease that occurs due to resistance or partial resistance of cancer cells in a tumor against anticancer agents is the most important issue in oncology. In the present study, when MDA‑MB‑231 cells, a TNBC cell line, were treated with 30 µM paclitaxel, a slightly higher concentration than its GI50 value, for 6 days, a small number of cells with different morphologies survived. Among the surviving cells, small round cells were isolated, cloned, and named MDA‑MB‑231‑JYJ cells. MDA‑MB‑231‑JYJ cells were observed to be highly proliferative and tumorigenic. In addition, signal transduction molecules involved in proliferation, survival, malignancy, or stemness of cancer cells, such as c‑Src, c‑Met, Notch 1, c‑Myc, Sox2, Oct3/4, Nanog, and E‑cadherin were highly expressed or activated. While further study is required, MDA‑MB‑231‑JYJ cells appear to have some of the characteristics of cancer precursor cells. Although MDA‑MB‑231‑JYJ cells were isolated from the cells that survived in the continuous presence of paclitaxel, they were not resistant to paclitaxel but developed resistance to dasatinib, a Bcr‑Abl and Src kinase family inhibitor. The activated state of Src and Notch 1, and the expression levels of c‑Myc and cyclins in MDA‑MB‑231‑JYJ cells were less affected than MDA‑MB‑231 cells by the treatment of dasatinib, which may explain the resistance of MDA‑MB‑231‑JYJ cells to dasatinib. These results suggest that cancer cells that become resistant to dasatinib during the process of paclitaxel therapy in patients may appear, and caution is required in the design of clinical trials using these two agents.

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1	Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI
2	Crown J, O'Leary M and Ooi WS: Docetaxel and paclitaxel in the treatment of breast cancer: A review of clinical experience. Oncologist. 9(Suppl 2): S24–S32. 2004. View Article : Google Scholar
3	Gradishar WJ: Taxanes for the treatment of metastatic breast cancer. Breast Cancer (Auckl). 6:159–171. 2012.PubMed/NCBI
4	Galletti E, Magnani M, Renzulli ML and Botta M: Paclitaxel and docetaxel resistance: Molecular mechanisms and development of new generation taxanes. ChemMedChem. 2:920–942. 2007. View Article : Google Scholar : PubMed/NCBI
5	Krishna R and Mayer LD: Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur J Pharm Sci. 11:265–283. 2000. View Article : Google Scholar : PubMed/NCBI
6	Orr GA, Verdier-Pinard P, McDaid H and Horwitz SB: Mechanisms of Taxol resistance related to microtubules. Oncogene. 22:7280–7295. 2003. View Article : Google Scholar : PubMed/NCBI
7	Zasadil LM, Andersen KA, Yeum D, Rocque GB, Wilke LG, Tevaarwerk AJ, Raines RT, Burkard ME and Weaver BA: Cytotoxicity of paclitaxel in breast cancer is due to chromosome missegregation on multipolar spindles. Sci Transl Med. 6:229ra432014. View Article : Google Scholar : PubMed/NCBI
8	Kim HM, Lim J, Park SK, Kang JS, Lee K, Lee CW, Lee KH, Yun MJ, Yang KH, Han G, et al: Antitumor activity of cytokine-induced killer cells against human lung cancer. Int Immunopharmacol. 7:1802–1807. 2007. View Article : Google Scholar : PubMed/NCBI
9	Kang MR, Park SK, Lee CW, Cho IJ, Jo YN, Yang JW, Kim JA, Yun J, Lee KH, Kwon HJ, et al: Widdrol induces apoptosis via activation of AMP-activated protein kinase in colon cancer cells. Oncol Rep. 27:1407–1412. 2012.PubMed/NCBI
10	Krishan A: Rapid flow cytofluorometric analysis of mammalian cell cycle by propidium iodide staining. J Cell Biol. 66:188–193. 1975. View Article : Google Scholar : PubMed/NCBI
11	Kang MR, Kang JS, Yang JW, Kim BG, Kim JA, Jo YN, Lee K, Lee CW, Lee KH, Yun J, et al: Gene expression profiling of KBH-A42, a novel histone deacetylase inhibitor, in human leukemia and bladder cancer cell lines. Oncol Lett. 3:113–118. 2012.PubMed/NCBI
12	Li L, Zhao F, Lu J, Li T, Yang H, Wu C and Liu Y: Notch-1 signaling promotes the malignant features of human breast cancer through NF-kB activation. PLoS One. 9:e959122014. View Article : Google Scholar : PubMed/NCBI
13	Meacham CE and Morrison SJ: Tumour heterogeneity and cancer cell plasticity. Nature. 501:328–337. 2013. View Article : Google Scholar : PubMed/NCBI
14	Burrell RA, McGranahan N, Bartek J and Swanton C: The causes and consequences of genetic heterogeneity in cancer evolution. Nature. 501:338–345. 2013. View Article : Google Scholar : PubMed/NCBI
15	Croce MV, Colussi AG, Price MR and Segal-Eiras A: Identification and characterization of different subpopulations in a human lung adenocarcinoma cell line (A549). Pathol Oncol Res. 5:197–204. 1999. View Article : Google Scholar : PubMed/NCBI
16	Stockholm D, Benchaouir R, Picot J, Rameau P, Neildez TM, Landini G, Laplace-Builhé C and Paldi A: The origin of phenotypic heterogeneity in a clonal cell population in vitro. PLoS One. 2:e3942007. View Article : Google Scholar : PubMed/NCBI
17	Marupudi NI, Han JE, Li KW, Renard VM, Tyler BM and Brem H: Paclitaxel: A review of adverse toxicities and novel delivery strategies. Expert Opin Drug Saf. 6:609–621. 2007. View Article : Google Scholar : PubMed/NCBI
18	Gherardi E, Birchmeier W, Birchmeier C and Vande Woude G: Targeting MET in cancer: Rationale and progress. Nat Rev Cancer. 12:89–103. 2012. View Article : Google Scholar : PubMed/NCBI
19	Zhang S and Yu D: Targeting Src family kinases in anti-cancer therapies: Turning promise into triumph. Trends Pharmacol Sci. 33:122–128. 2012. View Article : Google Scholar : PubMed/NCBI
20	Li D, Masiero M, Banham AH and Harris AL: The notch ligand JAGGED1 as a target for anti-tumor therapy. Front Oncol. 4:2542014. View Article : Google Scholar : PubMed/NCBI
21	Lu Z and Xu S: ERK1/2 MAP kinases in cell survival and apoptosis. IUBMB Life. 58:621–631. 2006. View Article : Google Scholar : PubMed/NCBI
22	Xu N, Lao Y, Zhang Y and Gillespie DA: Akt: A double-edged sword in cell proliferation and genome stability. J Oncol. 2012:9517242012. View Article : Google Scholar : PubMed/NCBI
23	Tirino V, Desiderio V, Paino F, De Rosa A, Papaccio F, La Noce M, Laino L, De Francesco F and Papaccio G: Cancer stem cells in solid tumors: An overview and new approaches for their isolation and characterization. FASEB J. 27:13–24. 2013. View Article : Google Scholar : PubMed/NCBI
24	Ling GQ, Chen DB, Wang BQ and Zhang LS: Expression of the pluripotency markers Oct3/4, Nanog and Sox2 in human breast cancer cell lines. Oncol Lett. 4:1264–1268. 2012.PubMed/NCBI
25	Klonisch T, Wiechec E, Hombach-Klonisch S, Ande SR, Wesselborg S, Schulze-Osthoff K and Los M: Cancer stem cell markers in common cancers-therapeutic implications. Trends Mol Med. 14:450–460. 2008. View Article : Google Scholar : PubMed/NCBI
26	Borst P: Cancer drug pan-resistance: Pumps, cancer stem cells, quiescence, epithelial to mesenchymal transition, blocked cell death pathways, persisters or what? Open Biol. 2:1200662012. View Article : Google Scholar : PubMed/NCBI
27	Röyttä M, Laine KM and Härkönen P: Morphological studies on the effect of taxol on cultured human prostatic cancer cells. Prostate. 11:95–106. 1987. View Article : Google Scholar : PubMed/NCBI
28	Talpaz M, Shah NP, Kantarjian H, Donato N, Nicoll J, Paquette R, Cortes J, O'Brien S, Nicaise C, Bleickardt E, et al: Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med. 354:2531–2541. 2006. View Article : Google Scholar : PubMed/NCBI
29	Steinberg M: Dasatinib: A tyrosine kinase inhibitor for the treatment of chronic myelogenous leukemia and philadelphia chromosome-positive acute lymphoblastic leukemia. Clin Ther. 29:2289–2308. 2007. View Article : Google Scholar : PubMed/NCBI