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Article

A novel small inhibitor, LLL12, targets STAT3 in non‑small cell lung cancer in vitro and in vivo

  • Authors:
    • Yanli Nie
    • Yuanyuan Li
    • Sheng Hu
  • View Affiliations / Copyright

    Affiliations: Department of Gastrointestinal Medical Oncology, Hubei Province Cancer Hospital, Wuhan, Hubei 430079, P.R. China, College of Chemistry, Central China Normal University, Wuhan, Hubei 430079, P.R. China
  • Pages: 5349-5354
    |
    Published online on: August 3, 2018
       https://doi.org/10.3892/ol.2018.9262
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Abstract

Lung cancer is the leading cause of cancer‑associated mortality worldwide. Despite the development of novel molecular therapies, the prognosis for patients with locally advanced or metastatic lung cancer remains poor. Therefore, the identification of novel therapeutic approaches is required. In numerous types of cancer, the constitutive activation of signal transducer and activator of transcription 3 (STAT3) signaling serves as a potent therapeutic target. The present study aimed to characterize the suppressive role of LLL12, a STAT3 small molecule inhibitor, in lung cancer cell proliferation and tumor growth. The mechanism of STAT3 signaling modulation by LLL12 was also investigated. The antitumor activity of LLL12 was revealed to take place via inhibition of lung cancer cell proliferation and migration in vitro. High and low doses of LLL12 significantly reduced tumor volume and weight in xenograft mice compared with that in the control group. Furthermore, LLL12 was demonstrated to reduce the level of STAT3 phosphorylation. These results suggested that LLL12 inhibited the proliferation and migration of A549 cells, and the increase in tumor volume in nude mice with lung cancer. This may be associated with the inhibitory effect of STAT3 phosphorylation and the expression of STAT3. The results of the present study suggest that constitutive STAT3 signaling is required for lung cancer cell survival and migration, and tumor growth in vivo. It is also indicated that LLL12 has clinical potential as a novel targeted therapy.
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1 

Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI

2 

Pao W and Girard N: New driver mutations in non-small-cell lung cancer. Lancet Oncol. 12:175–180. 2011. View Article : Google Scholar : PubMed/NCBI

3 

Reka AK, Goswami MT, Krishnapuram R, Standiford TJ and Keshamouni VG: Molecular cross-regulation between PPAR-γ and other signaling pathways: Implications for lung cancer therapy. Lung Cancer. 72:154–159. 2011. View Article : Google Scholar : PubMed/NCBI

4 

Haura EB, Turkson J and Jove R: Mechanisms of disease: Insights into the emerging role of signal transducers and activators of transcription in cancer. Nat Clin Pract Oncol. 2:315–324. 2005. View Article : Google Scholar : PubMed/NCBI

5 

Kamran MZ, Patil P and Gude RP: Role of STAT3 in cancer metastasis and translational advances. BioMed Res Int. 2013:4218212013. View Article : Google Scholar : PubMed/NCBI

6 

Jatiani SS, Baker SJ, Silverman LR and Reddy EP: Jak/STAT pathways in cytokine signaling and myeloproliferative disorders: Approaches for targeted therapies. Genes Cancer. 1:979–993. 2010. View Article : Google Scholar : PubMed/NCBI

7 

Yu H and Jove R: The STATs of cancer—new molecular targets come of age. Nat Rev Cancer. 4:97–105. 2004. View Article : Google Scholar : PubMed/NCBI

8 

Looyenga BD, Hutchings D, Cherni I, Kingsley C, Weiss GJ and Mackeigan JP: STAT3 is activated by JAK2 independent of key oncogenic driver mutations in non-small cell lung carcinoma. PloS One. 7:e308202012. View Article : Google Scholar : PubMed/NCBI

9 

Xie TX, Wei D, Liu M, Gao AC, Ali-Osman F, Sawaya R and Huang S: Stat3 activation regulates the expression of matrix metalloproteinase-2 and tumor invasion and metastasis. Oncogene. 23:3550–3560. 2004. View Article : Google Scholar : PubMed/NCBI

10 

Yu H, Pardoll D and Jove R: STATs in cancer inflammation and immunity: A leading role for STAT3. Nat Rev Cancer. 9:798–809. 2009. View Article : Google Scholar : PubMed/NCBI

11 

Carpenter RL and Lo HW: STAT3 target genes relevant to human cancers. Cancers (Basel). 6:897–925. 2014. View Article : Google Scholar : PubMed/NCBI

12 

Debnath B, Xu S and Neamati N: Small molecule inhibitors of signal transducer and activator of transcription 3 (Stat3) protein. J Med Chem. 55:6645–6668. 2012. View Article : Google Scholar : PubMed/NCBI

13 

Masciocchi D, Gelain A, Villa S, Meneghetti F and Barlocco D: Signal transducer and activator of transcription 3 (STAT3): A promising target for anticancer therapy. Future Med Chem. 3:567–597. 2011. View Article : Google Scholar : PubMed/NCBI

14 

Hedvat M, Huszar D, Herrmann A, Gozgit JM, Schroeder A, Sheehy A, Buettner R, Proia D, Kowolik CM, Xin H, et al: The JAK2 inhibitor AZD1480 potently blocks Stat3 signaling and oncogenesis in solid tumors. Cancer Cell. 16:487–497. 2009. View Article : Google Scholar : PubMed/NCBI

15 

Sen M, Thomas SM, Kim S, Yeh JI, Ferris RL, Johnson JT, Duvvuri U, Lee J, Sahu N, Joyce S, et al: First-in-human trial of a STAT3 decoy oligonucleotide in head and neck tumors: Implications for cancer therapy. Cancer Discov. 2:694–705. 2012. View Article : Google Scholar : PubMed/NCBI

16 

Alas S and Bonavida B: Inhibition of constitutive STAT3 activity sensitizes resistant non-Hodgkin's lymphoma and multiple myeloma to chemotherapeutic drug-mediated apoptosis. Clin Cancer Res. 9:316–326. 2003.PubMed/NCBI

17 

Sledz CA and Williams BR: RNA interference in biology and disease. Blood. 106:787–794. 2005. View Article : Google Scholar : PubMed/NCBI

18 

Stein CA: The experimental use of antisense oligonucleotides: A guide for the perplexed. J Clin Invest. 108:641–644. 2001. View Article : Google Scholar : PubMed/NCBI

19 

Lin L, Hutzen B, Li PK, Ball S, Zuo M, DeAngelis S, Foust E, Sobo M, Friedman L, Bhasin D, et al: A novel small molecule, LLL12, inhibits STAT3 phosphorylation and activities and exhibits potent growth-suppressive activity in human cancer cells. Neoplasia. 12:39–50. 2010. View Article : Google Scholar : PubMed/NCBI

20 

Liu A, Liu Y, Li PK, Li C and Lin J: LLL12 inhibits endogenous and exogenous interleukin-6-induced STAT3 phosphorylation in human pancreatic cancer cells. Anticancer Res. 31:2029–2035. 2011.PubMed/NCBI

21 

Zuo M, Li C, Lin J and Javle M: LLL12, a novel small inhibitor targeting STAT3 for hepatocellular carcinoma therapy. Oncotarget. 6:10940–10949. 2015. View Article : Google Scholar : PubMed/NCBI

22 

Mankan AK and Greten FR: Inhibiting signal transducer and activator of transcription 3: Rationality and rationale design of inhibitors. Exp Opin Investig Drugs. 20:1263–1275. 2011. View Article : Google Scholar

23 

Bid HK, Oswald D, Li C, London CA, Lin J and Houghton PJ: Anti-angiogenic activity of a small molecule STAT3 inhibitor LLL12. PloS One. 7:e355132012. View Article : Google Scholar : PubMed/NCBI

24 

Bishop JL, Thaper D and Zoubeidi A: The multifaceted roles of STAT3 signaling in the progression of prostate cancer. Cancers (Basel). 6:829–859. 2014. View Article : Google Scholar : PubMed/NCBI

25 

Morikawa T, Baba Y, Yamauchi M, Kuchiba A, Nosho K, Shima K, Tanaka N, Huttenhower C, Frank DA, Fuchs CS and Ogino S: STAT3 expression, molecular features, inflammation patterns, and prognosis in a database of 724 colorectal cancers. Clin Cancer Res. 17:1452–1462. 2011. View Article : Google Scholar : PubMed/NCBI

26 

Lin L, Liu A, Peng Z, Lin HJ, Li PK, Li C and Lin J: STAT3 is necessary for proliferation and survival in colon cancer-initiating cells. Cancer Res. 71:7226–7237. 2011. View Article : Google Scholar : PubMed/NCBI

27 

Xiong H, Du W, Wang JL, Wang YC, Tang JT, Hong J and Fang JY: Constitutive activation of STAT3 is predictive of poor prognosis in human gastric cancer. J Mol Med(Berl). 90:1037–1046. 2012. View Article : Google Scholar : PubMed/NCBI

28 

Ryu K, Choy E, Yang C, Susa M, Hornicek FJ, Mankin H and Duan Z: Activation of signal transducer and activator of transcription 3 (Stat3) pathway in osteosarcoma cells and overexpression of phosphorylated-Stat3 correlates with poor prognosis. J Orthopaed Res. 28:971–978. 2010.

29 

Schoppmann SF, Jesch B, Friedrich J, Jomrich G, Maroske F and Birner P: Phosphorylation of signal transducer and activator of transcription 3 (STAT3) correlates with Her-2 status, carbonic anhydrase 9 expression and prognosis in esophageal cancer. Clin Exp Metastasis. 29:615–624. 2012. View Article : Google Scholar : PubMed/NCBI

30 

Ball S, Li C, Li PK and Lin J: The small molecule, LLL12, inhibits STAT3 phosphorylation and induces apoptosis in medulloblastoma and glioblastoma cells. PloS One. 6:e188202011. View Article : Google Scholar : PubMed/NCBI

31 

Lin L, Benson DM Jr, DeAngelis S, Bakan CE, Li PK, Li C and Lin J: A small molecule, LLL12 inhibits constitutive STAT3 and IL-6-induced STAT3 signaling and exhibits potent growth suppressive activity in human multiple myeloma cells. Int J Cancer. 130:1459–1469. 2012. View Article : Google Scholar : PubMed/NCBI

32 

Onimoe GI, Liu A, Lin L, Wei CC, Schwartz EB, Bhasin D, Li C, Fuchs JR, Li PK, Houghton P, et al: Small molecules, LLL12 and FLLL32, inhibit STAT3 and exhibit potent growth suppressive activity in osteosarcoma cells and tumor growth in mice. Invest New Drugs. 30:916–926. 2012. View Article : Google Scholar : PubMed/NCBI

33 

Couto JI, Bear MD, Lin J, Pennel M, Kulp SK, Kisseberth WC and London CA: Biologic activity of the novel small molecule STAT3 inhibitor LLL12 against canine osteosarcoma cell lines. BMC Vet Res. 8:2442012. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Nie Y, Li Y and Hu S: A novel small inhibitor, LLL12, targets STAT3 in non‑small cell lung cancer in vitro and in vivo. Oncol Lett 16: 5349-5354, 2018.
APA
Nie, Y., Li, Y., & Hu, S. (2018). A novel small inhibitor, LLL12, targets STAT3 in non‑small cell lung cancer in vitro and in vivo. Oncology Letters, 16, 5349-5354. https://doi.org/10.3892/ol.2018.9262
MLA
Nie, Y., Li, Y., Hu, S."A novel small inhibitor, LLL12, targets STAT3 in non‑small cell lung cancer in vitro and in vivo". Oncology Letters 16.4 (2018): 5349-5354.
Chicago
Nie, Y., Li, Y., Hu, S."A novel small inhibitor, LLL12, targets STAT3 in non‑small cell lung cancer in vitro and in vivo". Oncology Letters 16, no. 4 (2018): 5349-5354. https://doi.org/10.3892/ol.2018.9262
Copy and paste a formatted citation
x
Spandidos Publications style
Nie Y, Li Y and Hu S: A novel small inhibitor, LLL12, targets STAT3 in non‑small cell lung cancer in vitro and in vivo. Oncol Lett 16: 5349-5354, 2018.
APA
Nie, Y., Li, Y., & Hu, S. (2018). A novel small inhibitor, LLL12, targets STAT3 in non‑small cell lung cancer in vitro and in vivo. Oncology Letters, 16, 5349-5354. https://doi.org/10.3892/ol.2018.9262
MLA
Nie, Y., Li, Y., Hu, S."A novel small inhibitor, LLL12, targets STAT3 in non‑small cell lung cancer in vitro and in vivo". Oncology Letters 16.4 (2018): 5349-5354.
Chicago
Nie, Y., Li, Y., Hu, S."A novel small inhibitor, LLL12, targets STAT3 in non‑small cell lung cancer in vitro and in vivo". Oncology Letters 16, no. 4 (2018): 5349-5354. https://doi.org/10.3892/ol.2018.9262
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