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Article Open Access

UNBS5162 induces growth inhibition and apoptosis via inhibiting PI3K/AKT/mTOR pathway in triple negative breast cancer MDA‑MB‑231 cells

  • Authors:
    • Xin Yue
    • Mingzhong Li
    • Dongxiang Chen
    • Zhenghua Xu
    • Shengrong Sun
  • View Affiliations / Copyright

    Affiliations: Department of Breast and Thyroid Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China, Department of Surgical Oncology, The First People's Hospital of Jingzhou City, Jingzhou, Hubei 434000, P.R. China
    Copyright: © Yue et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 3921-3928
    |
    Published online on: September 3, 2018
       https://doi.org/10.3892/etm.2018.6675
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Abstract

UNBS5162, a naphthalimide derivative, has a strong anticancer effect and low clinical hematological toxicity. UNBS5162 has been shown to have an anticancer effect in numerous cancer types, except triple negative breast cancer (TNBC). To explore this issue, TNBC MDA‑MB‑231 cells were selected, and the effect of UNBS5162 on their growth, proliferation and motility regulation was investigated in vitro. The results showed that UNBS5162 significantly inhibited the proliferation, migration and invasion of TNBC cells. In addition, the level of pro‑apoptosis protein Bcl‑2‑associated X protein and active caspase‑3 increased, but apotptosis regulator BCL‑2 decreased in MDA‑MB‑231 cells after UNBS5162 treatment, which demonstrated UNBS5162 treatment triggered cell apoptosis. Moreover, UNBS5162 reduced the phosphorylation levels of AKT serine/threonine kinase (AKT), mechanistic target of rapamycin kinase (mTOR), P70S6 kinase and eukaryotic translation initiation factor 4E‑binding protein 1 in the phosphatidylinositol 3‑kinase/AKT/mTOR (PAM) signaling pathway, which plays a critical role in cell proliferation, and apoptosis. Altogether, the results of the present study suggest that UNBS5162 effectively induces the growth inhibition and apoptosis of TNBC cells through regulation of the PAM pathway, which may be a candidate target for TNBC treatment.
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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 

Torre LA, Siegel RL, Ward EM and Jemal A: Global cancer incidence and mortality rates and trends-an update. Cancer Epidemiol Biomarkers Prev. 25:16–27. 2016. View Article : Google Scholar : PubMed/NCBI

3 

Cancer Genome Atlas Network: Comprehensive molecular portraits of human breast tumours. Nature. 490:61–70. 2012. View Article : Google Scholar : PubMed/NCBI

4 

Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, et al: Molecular portraits of human breast tumours. Nature. 406:747–752. 2000. View Article : Google Scholar : PubMed/NCBI

5 

Sørlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, et al: Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 98:10869–10874. 2001. View Article : Google Scholar : PubMed/NCBI

6 

Sorlie T, Tibshirani R, Parker J, Hastie T, Marron JS, Nobel A, Deng S, Johnsen H, Pesich R, Geisler S, et al: Repeated observation of breast tumor subtypes in independent gene expression data sets. Proc Natl Acad Sci USA. 100:8418–8423. 2003. View Article : Google Scholar : PubMed/NCBI

7 

Foulkes WD, Smith IE and Reis-Filho JS: Triple-negative breast cancer. N Engl J Med. 363:1938–1948. 2010. View Article : Google Scholar : PubMed/NCBI

8 

Loi S, Pommey S, Haibe-Kains B, Beavis PA, Darcy PK, Smyth MJ and Stagg J: CD73 promotes anthracycline resistance and poor prognosis in triple negative breast cancer. Proc Natl Acad Sci USA. 110:11091–11096. 2013. View Article : Google Scholar : PubMed/NCBI

9 

Coates AS, Winer EP, Goldhirsch A, Gelber RD, Gnant M, Piccart-Gebhart M, Thürlimann B and Senn HJ: Panel Members: Tailoring therapies-improving the management of early breast cancer: St gallen international expert consensus on the primary therapy of early breast cancer 2015. Ann Oncol. 26:1533–1546. 2015. View Article : Google Scholar : PubMed/NCBI

10 

Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thürlimann B and Senn HJ: 10th St. Gallen conference: Progress and promise: Highlights of the international expert consensus on the primary therapy of early breast cancer 2007. Ann Oncol. 18:1133–1144. 2007. View Article : Google Scholar : PubMed/NCBI

11 

Banda M, Speyer CL, Semma SN, Osual KO, Kounalakis N, Torres Torres KE, Barnard NJ, Kim HJ, Sloane BF, Miller FR, et al: Metabotropic glutamate receptor-1 contributes to progression in triple negative breast cancer. PLoS One. 9:e811262014. View Article : Google Scholar : PubMed/NCBI

12 

Pal SK, Childs BH and Pegram M: Triple negative breast cancer: Unmet medical needs. Breast Cancer Res Treat. 125:627–636. 2011. View Article : Google Scholar : PubMed/NCBI

13 

Lehmann BD and Pietenpol JA: Clinical implications of molecular heterogeneity in triple negative breast cancer. Breast. 24 Suppl 2:S36–S40. 2015. View Article : Google Scholar : PubMed/NCBI

14 

Perou CM: Molecular stratification of triple-negative breast cancers. Oncologist. 16 Suppl 1:S61–S70. 2011. View Article : Google Scholar

15 

Juvekar A, Burga LN, Hu H, Lunsford EP, Ibrahim YH, Balmañà J, Rajendran A, Papa A, Spencer K, Lyssiotis CA, et al: Combining a PI3K inhibitor with a PARP inhibitor provides an effective therapy for BRCA1-related breast cancer. Cancer Discov. 2:1048–1063. 2012. View Article : Google Scholar : PubMed/NCBI

16 

Braña MF and Ramos A: Naphthalimides as anti-cancer agents: Synthesis and biological activity. Curr Med Chem Anticancer Agents. 1:237–255. 2001. View Article : Google Scholar : PubMed/NCBI

17 

Costanza ME, Berry D, Henderson IC, Ratain MJ, Wu K, Shapiro C, Duggan D, Kalra J, Berkowitz I and Lyss AP: Amonafide: An active agent in the treatment of previously untreated advanced breast cancer-a cancer and leukemia group B study (CALGB 8642). Clin Cancer Res. 1:699–704. 1995.PubMed/NCBI

18 

Scheithauer W, Dittrich C, Kornek G, Haider K, Linkesch W, Gisslinger H and Depisch D: Phase II study of amonafide in advanced breast cancer. Breast Cancer Res Treat. 20:63–67. 1991. View Article : Google Scholar : PubMed/NCBI

19 

Kuhn JG, Burris HA III, Jones SF, Hein DE, Willcutt NT, Greco FA, Thompson DS, Meluch AA, Schwartz RS and Brown DM: Phase I/II dose-escalation trial of amonafide for treatment of advanced solid tumors: Genotyping to optimize dose based on polymorphic metabolism. J Clin Oncol. 25:25032007.

20 

Ratain MJ, Mick R, Berezin F, Janisch L, Schilsky RL, Williams SF and Smiddy J: Paradoxical relationship between acetylator phenotype and amonafide toxicity. Clin Pharmacol Ther. 50:573–579. 1991. View Article : Google Scholar : PubMed/NCBI

21 

Ingrassia L, Lefranc F, Kiss R and Mijatovic T: Naphthalimides and azonafides as promising anti-cancer agents. Curr Med Chem. 16:1192–1213. 2009. View Article : Google Scholar : PubMed/NCBI

22 

Lv M and Xu H: Overview of naphthalimide analogs as anticancer agents. Curr Med Chem. 16:4797–4813. 2009. View Article : Google Scholar : PubMed/NCBI

23 

Mijatovic T, Mahieu T, Bruyère C, De Nève N, Dewelle J, Simon G, Dehoux MJ, van der Aar E, Haibe-Kains B, Bontempi G, et al: UNBS5162, a novel naphthalimide that decreases CXCL chemokine expression in experimental prostate cancers. Neoplasia. 10:573–586. 2008. View Article : Google Scholar : PubMed/NCBI

24 

Mahadevan D, Northfelt DW, Chalasani P, Rensvold D, Kurtin S, Von Hoff DD, Borad MJ and Tibes R: Phase I trial of UNBS5162, a novel naphthalimide in patients with advanced solid tumors or lymphoma. Int J Clin Oncol. 18:934–941. 2013. View Article : Google Scholar : PubMed/NCBI

25 

Balkwill F: Cancer and the chemokine network. Nat Rev Cancer. 4:540–550. 2004. View Article : Google Scholar : PubMed/NCBI

26 

Fernandez EJ and Lolis E: Structure, function, and inhibition of chemokines. Annu Rev Pharmacol Toxicol. 42:469–499. 2002. View Article : Google Scholar : PubMed/NCBI

27 

Liu P, Cheng H, Roberts TM and Zhao JJ: Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 8:627–644. 2009. View Article : Google Scholar : PubMed/NCBI

28 

Massihnia D, Galvano A, Fanale D, Perez A, Castiglia M, Incorvaia L, Listì A, Rizzo S, Cicero G, Bazan V, et al: Triple negative breast cancer: shedding light onto the role of pi3k/akt/mtor pathway. Oncotarget. 7:60712–60722. 2016. View Article : Google Scholar : PubMed/NCBI

29 

Blanchard Z, Paul BT, Craft B and Elshamy WM: BRCA1-IRIS inactivation overcomes paclitaxel resistance in triple negative breast cancers. Breast Cancer Res. 17:52015. View Article : Google Scholar : PubMed/NCBI

30 

Krammer PH: CD95's deadly mission in the immune system. Nature. 407:789–795. 2000. View Article : Google Scholar : PubMed/NCBI

31 

Lo AC, Woo TT, Wong RL and Wong D: Apoptosis and other cell death mechanisms after retinal detachment: Implications for photoreceptor rescue. Ophthalmologica. 226 Suppl 1:S10–S17. 2011. View Article : Google Scholar

32 

Krammer PH, Arnold R and Lavrik IN: Life and death in peripheral T cells. Nat Rev Immunol. 7:532–542. 2007. View Article : Google Scholar : PubMed/NCBI

33 

King D, Yeomanson D and Bryant HE: PI3King the lock: Targeting the PI3K/Akt/mTOR pathway as a novel therapeutic strategy in neuroblastoma. J Pediatr Hematol Oncol. 37:245–251. 2015. View Article : Google Scholar : PubMed/NCBI

34 

Man HY, Wang Q, Lu WY, Ju W, Ahmadian G, Liu L, D'Souza S, Wong TP, Taghibiglou C, Lu J, et al: Activation of PI3-kinase is required for AMPA receptor insertion during LTP of mEPSCs in cultured hippocampal neurons. Neuron. 38:611–624. 2003. View Article : Google Scholar : PubMed/NCBI

35 

Rafalski VA and Brunet A: Energy metabolism in adult neural stem cell fate. Prog Neurobiol. 93:182–203. 2011. View Article : Google Scholar : PubMed/NCBI

36 

Rozengurt E, Soares HP and Sinnet-Smith J: Suppression of feedback loops mediated by PI3K/mTOR induces multiple overactivation of compensatory pathways: An unintended consequence leading to drug resistance. Mol Cancer Ther. 13:2477–2488. 2014. View Article : Google Scholar : PubMed/NCBI

37 

Courtney KD, Corcoran RB and Engelman JA: The PI3K pathway as drug target in human cancer. J Clin Oncol. 28:1075–1083. 2010. View Article : Google Scholar : PubMed/NCBI

38 

Ayub A, Yip WK and Seow HF: Dual treatments targeting IGF-1R, PI3K, mTORC or MEK synergize to inhibit cell growth, induce apoptosis, and arrest cell cycle at G1 phase in MDA-MB-231 cell line. Biomed Pharmacother. 75:40–50. 2015. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Yue X, Li M, Chen D, Xu Z and Sun S: UNBS5162 induces growth inhibition and apoptosis via inhibiting PI3K/AKT/mTOR pathway in triple negative breast cancer MDA‑MB‑231 cells. Exp Ther Med 16: 3921-3928, 2018.
APA
Yue, X., Li, M., Chen, D., Xu, Z., & Sun, S. (2018). UNBS5162 induces growth inhibition and apoptosis via inhibiting PI3K/AKT/mTOR pathway in triple negative breast cancer MDA‑MB‑231 cells. Experimental and Therapeutic Medicine, 16, 3921-3928. https://doi.org/10.3892/etm.2018.6675
MLA
Yue, X., Li, M., Chen, D., Xu, Z., Sun, S."UNBS5162 induces growth inhibition and apoptosis via inhibiting PI3K/AKT/mTOR pathway in triple negative breast cancer MDA‑MB‑231 cells". Experimental and Therapeutic Medicine 16.5 (2018): 3921-3928.
Chicago
Yue, X., Li, M., Chen, D., Xu, Z., Sun, S."UNBS5162 induces growth inhibition and apoptosis via inhibiting PI3K/AKT/mTOR pathway in triple negative breast cancer MDA‑MB‑231 cells". Experimental and Therapeutic Medicine 16, no. 5 (2018): 3921-3928. https://doi.org/10.3892/etm.2018.6675
Copy and paste a formatted citation
x
Spandidos Publications style
Yue X, Li M, Chen D, Xu Z and Sun S: UNBS5162 induces growth inhibition and apoptosis via inhibiting PI3K/AKT/mTOR pathway in triple negative breast cancer MDA‑MB‑231 cells. Exp Ther Med 16: 3921-3928, 2018.
APA
Yue, X., Li, M., Chen, D., Xu, Z., & Sun, S. (2018). UNBS5162 induces growth inhibition and apoptosis via inhibiting PI3K/AKT/mTOR pathway in triple negative breast cancer MDA‑MB‑231 cells. Experimental and Therapeutic Medicine, 16, 3921-3928. https://doi.org/10.3892/etm.2018.6675
MLA
Yue, X., Li, M., Chen, D., Xu, Z., Sun, S."UNBS5162 induces growth inhibition and apoptosis via inhibiting PI3K/AKT/mTOR pathway in triple negative breast cancer MDA‑MB‑231 cells". Experimental and Therapeutic Medicine 16.5 (2018): 3921-3928.
Chicago
Yue, X., Li, M., Chen, D., Xu, Z., Sun, S."UNBS5162 induces growth inhibition and apoptosis via inhibiting PI3K/AKT/mTOR pathway in triple negative breast cancer MDA‑MB‑231 cells". Experimental and Therapeutic Medicine 16, no. 5 (2018): 3921-3928. https://doi.org/10.3892/etm.2018.6675
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