Advertisement

A preclinical evaluation of thiostrepton, a natural antibiotic, in nasopharyngeal carcinoma

  • Yen-Bin Hsu
  • Ming-Chin Lan
  • Yu-Lun Kuo
  • Chi-Ying F. HuangEmail author
  • Ming-Ying LanEmail author
PRECLINICAL STUDIES
  • 38 Downloads

Summary

Background Thiostrepton, a natural antibiotic, has recently been shown to be a potential anticancer drug for certain cancers, but its study in nasopharyngeal carcinoma (NPC) is still limited. The aims of this study were to investigate the anticancer effect of thiostrepton on NPC cells and to explore its underlying mechanism. Methods The effects of thiostrepton on the proliferation, migration, and invasion of NPC cells were investigated by a WST-1 assay, wound healing assay, and cell invasion assay, respectively. Microarrays were conducted and further analyzed by Ingenuity Pathways Analysis (IPA) to determine the molecular mechanism by which thiostrepton affects NPC cells. Results Our results showed that thiostrepton reduced NPC cell viability in a dose-dependent manner. Thiostrepton inhibited the migration and invasion of NPC cells in wound healing and cell invasion assays. The microarray data analyzed by IPA indicated the top 5 ingenuity canonical pathways, which were unfolded protein response, NRF2-mediated oxidative stress response, retinoate biosynthesis I, choline biosynthesis III, and pancreatic adenocarcinoma signaling. Conclusion Thiostrepton effectively suppressed NPC cell proliferation, migration, and invasion, likely by several mechanisms. Thiostrepton may be a potential therapeutic agent for treating NPC in the future.

Keywords

Nasopharyngeal carcinoma Thiostrepton Anticancer drug Microarray 

Notes

Acknowledgements

The authors thank Clinical Research Core Laboratory at Taipei Veterans General Hospital for the facility support.

Funding

This research was supported by grants from the Taipei Veterans General Hospital (V105-B–022 and V108C-088), and Ministry of Science and Technology, Taiwan (MOST 106–2314-B-075-035-MY3 and MOST 107–2320-B-010-040-MY3).

Compliance with ethical standards

Conflict of interest

All the authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human participants or animals.

References

  1. 1.
    Tang LL, Chen WQ, Xue WQ, He YQ, Zheng RS, Zeng YX, Jia WH (2016) Global trends in incidence and mortality of nasopharyngeal carcinoma. Cancer Lett 374:22–30CrossRefGoogle Scholar
  2. 2.
    Lu JJ, Cooper JS, Lee AWM (2010) Nasopharyngeal cancer: multidisciplinary management (medical radiology/radiation oncology). Springer–Verlag Berlin and Heidelberg GmbH & Co. KG, BerlinCrossRefGoogle Scholar
  3. 3.
    Chou J, Lin YC, Kim J, You L, Xu Z, He B, Jablons DM (2008) Nasopharyngeal carcinoma-- review of the molecular mechanisms of tumorigenesis. Head Neck 30:946–963CrossRefGoogle Scholar
  4. 4.
    Lan MY, Chen CL, Lin KT, Lee SA, Yang WL et al (2010) From NPC therapeutic target identification to potential treatment strategy. Mol Cancer Ther 9:2511–2523CrossRefGoogle Scholar
  5. 5.
    Lan MY, Yang WL, Lin KT, Lin JC, Shann YJ, Ho CY, Huang CY (2014) Using computational strategies to predict potential drugs for nasopharyngeal carcinoma. Head Neck 36:1398–1407Google Scholar
  6. 6.
    Wang SF, Zheng QF, Wang JF, Zhao ZX, Li QY, Yu Y, Wang R, Liu W (2015) Target-oriented design and biosynthesis of Thiostrepton-derived thiopeptide antibiotics with improved pharmaceutical properties. Org Chem Front 2:106–109CrossRefGoogle Scholar
  7. 7.
    Rosendahl G, Douthwaite S (1994) The antibiotics micrococcin and thiostrepton interact directly with 23S rRNA nucleotides 1067A and 1095A. Nucleic Acids Res 22:357–363CrossRefGoogle Scholar
  8. 8.
    NCATS Inxight: Drugs (2018) THIOSTREPTON HR4S203Y18. https://drugs.ncats.io/drug/HR4S203Y18. Accessed 26 Mar 2019
  9. 9.
    Kwok JM, Myatt SS, Marson CM, Coombes RC, Constantinidou D, Lam EW (2008) Thiostrepton selectively targets breast cancer cells through inhibition of forkhead box M1 expression. Mol Cancer Ther 7:2022–2032CrossRefGoogle Scholar
  10. 10.
    Bhat UG, Halasi M, Gartel AL (2009) FoxM1 is a general target for proteasome inhibitors. PLoS One 4:e6593CrossRefGoogle Scholar
  11. 11.
    Bhat UG, Halasi M, Gartel AL (2009) Thiazole antibiotics target FoxM1 and induce apoptosis in human cancer cells. PLoS One 4:e5592CrossRefGoogle Scholar
  12. 12.
    Pandit B, Bhat UG, Gartel AL (2011) Proteasome inhibitory activity of thiazole antibiotics. Cancer Biol Ther 11:43–47CrossRefGoogle Scholar
  13. 13.
    Pandit B, Gartel AL (2011) Proteasome inhibitors induce p53-independent apoptosis in human cancer cells. Am J Pathol 178:355–360CrossRefGoogle Scholar
  14. 14.
    Ju SY, Huang CY, Huang WC, Su Y (2015) Identification of thiostrepton as a novel therapeutic agent that targets human colon cancer stem cells. Cell Death Dis 6:e1801CrossRefGoogle Scholar
  15. 15.
    Hasanov E, Chen G, Chowdhury P, Weldon J, Ding Z, Jonasch E, Sen S, Walker CL, Dere R (2017) Ubiquitination and regulation of AURKA identifies a hypoxia-independent E3 ligase activity of VHL. Oncogene 36:3450–3463CrossRefGoogle Scholar
  16. 16.
    Chiu WT, Huang YF, Tsai HY, Chen CC, Chang CH, Huang SC, Hsu KF, Chou CY (2015) FOXM1 confers to epithelial-mesenchymal transition, stemness and chemoresistance in epithelial ovarian carcinoma cells. Oncotarget 6:2349–2365Google Scholar
  17. 17.
    Jiang L, Wang P, Chen L, Chen H (2014) Down-regulation of FoxM1 by thiostrepton or small interfering RNA inhibits proliferation, transformation ability and angiogenesis, and induces apoptosis of nasopharyngeal carcinoma cells. Int J Clin Exp Pathol 7:5450–5460Google Scholar
  18. 18.
    Jiang L, Wang P, Chen H (2014) Overexpression of FOXM1 is associated with metastases of nasopharyngeal carcinoma. Ups J Med Sci 119:324–332CrossRefGoogle Scholar
  19. 19.
    Yu C, Chen L, Yie L, Wei L, Wen T et al (2015) Targeting FoxM1 inhibits proliferation, invasion and migration of nasopharyngeal carcinoma through the epithelial-to-mesenchymal transition pathway. Oncol Rep 33:2402–2410CrossRefGoogle Scholar
  20. 20.
    Chen H, Yang C, Yu L, Xie L, Hu J, Zeng L, Tan Y (2012) Adenovirus-mediated RNA interference targeting FOXM1 transcription factor suppresses cell proliferation and tumor growth of nasopharyngeal carcinoma. J Gene Med 14:231–240CrossRefGoogle Scholar
  21. 21.
    Huang PY, Li Y, Luo DH, Hou X, Zeng TT, Li MQ, Mai HQ, Zhang L (2015) Expression of Aurora-B and FOXM1 predict poor survival in patients with nasopharyngeal carcinoma. Strahlenther Onkol 191:649–655CrossRefGoogle Scholar
  22. 22.
    Lin CT, Wong CI, Chan WY, Tzung KW, Ho JK, Hsu MM, Chuang SM (1990) Establishment and characterization of two nasopharyngeal carcinoma cell lines. Lab Investig 62:713–724Google Scholar
  23. 23.
    Lin CT, Chan WY, Chen W, Huang HM, Wu HC, Hsu MM, Chuang SM, Wang CC (1993) Characterization of seven newly established nasopharyngeal carcinoma cell lines. Lab Investig 68:716–727Google Scholar
  24. 24.
    Katoh M, Katoh M (2004) Human FOX gene family (review). Int J Oncol 25:1495–1500Google Scholar
  25. 25.
    Park HJ, Carr JR, Wang Z, Nogueira V, Hay N, Tyner AL, Lau LF, Costa RH, Raychaudhuri P (2009) FoxM1, a critical regulator of oxidative stress during oncogenesis. EMBO J 28:2908–2918CrossRefGoogle Scholar
  26. 26.
    Halasi M, Gartel AL (2009) A novel mode of FoxM1 regulation: positive auto-regulatory loop. Cell Cycle 8:1966–1967CrossRefGoogle Scholar
  27. 27.
    Myatt SS, Lam EW (2007) The emerging roles of forkhead box (Fox) proteins in cancer. Nat Rev Cancer 7:847–859CrossRefGoogle Scholar
  28. 28.
    Kalinichenko VV, Major ML, Wang X, Petrovic V, Kuechle J, Yoder HM, Dennewitz MB, Shin B, Datta A, Raychaudhuri P, Costa RH (2004) Foxm1b transcription factor is essential for development of hepatocellular carcinomas and is negatively regulated by the p19ARF tumor suppressor. Genes Dev 18:830–850CrossRefGoogle Scholar
  29. 29.
    Wonsey DR, Follettie MT (2005) Loss of the forkhead transcription factor FoxM1 causes centrosome amplification and mitotic catastrophe. Cancer Res 65:5181–5189CrossRefGoogle Scholar
  30. 30.
    Kim IM, Ackerson T, Ramakrishna S, Tretiakova M, Wang IC, Kalin TV, Major ML, Gusarova GA, Yoder HM, Costa RH, Kalinichenko VV (2006) The Forkhead Box m1 transcription factor stimulates the proliferation of tumor cells during development of lung cancer. Cancer Res 66:2153–2161CrossRefGoogle Scholar
  31. 31.
    Kalin TV, Wang IC, Ackerson TJ, Major ML, Detrisac CJ, Kalinichenko VV, Lyubimov A, Costa RH (2006) Increased levels of the FoxM1 transcription factor accelerate development and progression of prostate carcinomas in both TRAMP and LADY transgenic mice. Cancer Res 66:1712–1720CrossRefGoogle Scholar
  32. 32.
    Chan DW, Yu SY, Chiu PM, Yao KM, Liu VW, Cheung ANY, Ngan HYS (2008) Over-expression of FOXM1 transcription factor is associated with cervical cancer progression and pathogenesis. J Pathol 215:245–252CrossRefGoogle Scholar
  33. 33.
    Westhoff GL, Chen Y, Teng NNH (2017) Targeting Foxm1 improves cytotoxicity of paclitaxel and cisplatinum in platinum-resistant ovarian Cancer. Int J Gynecol Cancer 27:887–894CrossRefGoogle Scholar
  34. 34.
    Douard R, Moutereau S, Pernet P, Chimingqi M, Allory Y, Manivet P, Conti M, Vaubourdolle M, Cugnenc PH, Loric S (2006) Sonic hedgehog-dependent proliferation in a series of patients with colorectal cancer. Surgery 139:665–670CrossRefGoogle Scholar
  35. 35.
    Liu M, Dai B, Kang SH, Ban K, Huang FJ, Lang FF, Aldape KD, Xie TX, Pelloski CE, Xie K, Sawaya R, Huang S (2006) FoxM1B is overexpressed in human glioblastomas and critically regulates the tumorigenicity of glioma cells. Cancer Res 66:3593–3602CrossRefGoogle Scholar
  36. 36.
    Zhu H (2014) Targeting forkhead box transcription factors FOXM1 and FOXO in leukemia (review). Oncol Rep 32:1327–1334CrossRefGoogle Scholar
  37. 37.
    Wang JY, Jia XH, Xing HY, Li YJ, Fan WW et al (2015) Inhibition of Forkhead box protein M1 by thiostrepton increases chemosensitivity to doxorubicin in T-cell acute lymphoblastic leukemia. Mol Med Rep 12:1457–1464CrossRefGoogle Scholar
  38. 38.
    Gemenetzidis E, Bose A, Riaz AM, Chaplin T, Young BD, Ali M, Sugden D, Thurlow JK, Cheong SC, Teo SH, Wan H, Waseem A, Parkinson EK, Fortune F, Teh MT (2009) FOXM1 upregulation is an early event in human squamous cell carcinoma and it is enhanced by nicotine during malignant transformation. PLoS One 4:e4849CrossRefGoogle Scholar
  39. 39.
    Jiang L, Wu X, Wang P, Wen T, Yu C, Wei L, Chen H (2015) Targeting FoxM1 by thiostrepton inhibits growth and induces apoptosis of laryngeal squamous cell carcinoma. J Cancer Res Clin Oncol 141:971–981CrossRefGoogle Scholar
  40. 40.
    Qiao S, Lamore SD, Cabello CM, Lesson JL, Muñoz-Rodriguez JL, Wondrak GT (2012) Thiostrepton is an inducer of oxidative and proteotoxic stress that impairs viability of human melanoma cells but not primary melanocytes. Biochem Pharmacol 83:1229–1240CrossRefGoogle Scholar
  41. 41.
    Sandu C, Chandramouli N, Glickman JF, Molina H, Kuo CL, Kukushkin N, Goldberg AL, Steller H (2015) Thiostrepton interacts covalently with Rpt subunits of the 19S proteasome and proteasome substrates. J Cell Mol Med 19:2181–2192CrossRefGoogle Scholar
  42. 42.
    Qureshi AA, Zuvanich EG, Khan DA, Mushtaq S, Silswal N, Qureshi N (2018) Proteasome inhibitors modulate anticancer and anti-proliferative properties via NF-kB signaling, and ubiquitin-proteasome pathways in cancer cell lines of different organs. Lipids Health Dis 17:62CrossRefGoogle Scholar
  43. 43.
    Verfaillie T, Salazar M, Velasco G, Agostinis P (2010) Linking ER stress to autophagy: potential implications for Cancer therapy. Int J Cell Biol 2010:930509CrossRefGoogle Scholar
  44. 44.
    Bhat TA, Chaudhary AK, Kumar S, O'Malley J, Inigo JR et al (2017) Endoplasmic reticulum-mediated unfolded protein response and mitochondrial apoptosis in cancer. Biochim Biophys Acta Rev Cancer 1867:58–66CrossRefGoogle Scholar
  45. 45.
    Nuhn P, Künzli BM, Hennig R, Mitkus T, Ramanauskas T et al (2009) Heme oxygenase-1 and its metabolites affect pancreatic tumor growth in vivo. Mol Cancer 8:37CrossRefGoogle Scholar
  46. 46.
    Jo EJ, Park SJ, Kim BC (2016) Propyl gallate sensitizes human lung cancer cells to cisplatin-induced apoptosis by targeting heme oxygenase-1 for TRC8-mediated degradation. Eur J Pharmacol 788:321–327CrossRefGoogle Scholar
  47. 47.
    Jang HJ, Hong EM, Kim M, Kim JH, Jang J, Park SW, Byun HW, Koh DH, Choi MH, Kae SH, Lee J (2016) Simvastatin induces heme oxygenase-1 via NF-E2-related factor 2 (Nrf2) activation through ERK and PI3K/Akt pathway in colon cancer. Oncotarget 7:46219–46229Google Scholar
  48. 48.
    Han L, Jiang J, Ma Q, Wu Z, Wang Z (2018) The inhibition of heme oxygenase-1 enhances the chemosensitivity and suppresses the proliferation of pancreatic cancer cells through the SHH signaling pathway. Int J Oncol 52:2101–2109Google Scholar
  49. 49.
    Shiiba M, Yamagami H, Yamamoto A, Minakawa Y, Okamoto A, Kasamatsu A, Sakamoto Y, Uzawa K, Takiguchi Y, Tanzawa H (2017) Mefenamic acid enhances anticancer drug sensitivity via inhibition of aldo-keto reductase 1C enzyme activity. Oncol Rep 37:2025–2032CrossRefGoogle Scholar
  50. 50.
    Yin J, Liu H, Liu Z, Owzar K, Han Y, Su L, Wei Y, Hung RJ, Brhane Y, McLaughlin J, Brennan P, Bickeboeller H, Rosenberger A, Houlston RS, Caporaso N, Landi MT, Heinrich J, Risch A, Christiani DC, Amos CI, Wei Q (2017) Pathway-analysis of published genome-wide association studies of lung cancer: a potential role for the CYP4F3 locus. Mol Carcinog 56:1663–1672CrossRefGoogle Scholar
  51. 51.
    Park EM, Lim YS, Ahn BY, Hwang SB (2015) Interacts with nonstructural 4B and regulates hepatitis C virus propagation. PLoS One 10:e0132839CrossRefGoogle Scholar
  52. 52.
    Zhou S, Shen Y, Zheng M, Wang L, Che R, Hu W, Li P (2017) DNA methylation of METTL7A gene body regulates its transcriptional level in thyroid cancer. Oncotarget 8:34652–34660Google Scholar
  53. 53.
    Schön S, Flierman I, Ofner A, Stahringer A, Holdt LM, Kolligs FT, Herbst A (2014) β-catenin regulates NF-κB activity via TNFRSF19 in colorectal cancer cells. Int J Cancer 135:1800–1811CrossRefGoogle Scholar
  54. 54.
    Loftus JC, Dhruv H, Tuncali S, Kloss J, Yang Z, Schumacher CA, Cao B, Williams BO, Eschbacher JM, Ross JTD, Tran NL (2013) TROY (TNFRSF19) promotes glioblastoma survival signaling and therapeutic resistance. Mol Cancer Res 11:865–874CrossRefGoogle Scholar
  55. 55.
    Wang M, Gartel AL (2011) Micelle-encapsulated thiostrepton as an effective nanomedicine for inhibiting tumor growth and for suppressing FOXM1 in human xenografts. Mol Cancer Ther 10:2287–2297CrossRefGoogle Scholar
  56. 56.
    Halasi M, Schraufnagel DP, Gartel AL (2009) Wild-type p53 protects normal cells against apoptosis induced by thiostrepton. Cell Cycle 8:2850–2851CrossRefGoogle Scholar
  57. 57.
    Wang M, Gartel AL (2012) Combination with bortezomib enhances the antitumor effects of nanoparticle-encapsulated thiostrepton. Cancer Biol Ther 13:184–189CrossRefGoogle Scholar
  58. 58.
    Halasi M, Zhao H, Dahari H, Bhat UG, Gonzalez EB, Lyubimo AV, Tonetti DA, Gartel AL (2010) Thiazole antibiotics against breast cancer. Cell Cycle 9:1214–1217CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Otolaryngology-Head and Neck SurgeryTaipei Veterans General HospitalTaipeiTaiwan
  2. 2.Institute of Clinical MedicineNational Yang-Ming UniversityTaipeiTaiwan
  3. 3.Department of Otolaryngology-Head and Neck Surgery, Buddhist Tzu Chi Medical FoundationTaipei Tzu Chi HospitalNew Taipei CityTaiwan
  4. 4.School of MedicineTzu Chi UniversityHualienTaiwan
  5. 5.Biotools, Co., LtdNew Taipei CityTaiwan
  6. 6.Institute of Biopharmaceutical SciencesNational Yang-Ming UniversityTaipeiTaiwan
  7. 7.School of MedicineNational Yang-Ming UniversityTaipeiTaiwan

Personalised recommendations