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A thiopyran derivative with low murine toxicity with therapeutic potential on lung cancer acting through a NF-κB mediated apoptosis-to-pyroptosis switch

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Abstract

Pyroptosis is a novel manner of cell death that can be mediated by chemotherapy drugs. The awareness of pyroptosis is significantly increasing in the fields of anti-tumor research and chemotherapy drugs. Invoking the occurrence of pyroptosis is an attractive prospect for the treatment of lung cancer. Here, the compound L61H10 was obtained as a thiopyran derivative to compare its activity with curcumin. It was indicated that L61H10 exhibited good anti-tumor activity both in vitro and in vivo via the switch of apoptosis-to-pyroptosis, which was associated with the NF-κB signaling pathway. In addition, L61H10 had no obvious side effects both in vitro and in vivo. In brief, L61H10 is shown to be a potential anti-lung cancer agent and research on its anti-tumor mechanism provides new information for chemotherapy drug research.

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References

  1. Aggarwal A, Lewison G, Idir S et al (2016) The state of lung cancer research: a global analysis. J Thorac Oncol 11:1040–1050

    Article  Google Scholar 

  2. Navani N, Nankivell M, Lawrence DR et al (2015) Lung cancer diagnosis and staging with endobronchial ultrasound-guided transbronchial needle aspiration compared with conventional approaches: an open-label, pragmatic, randomised controlled trial. Lancet Respir Med 3:282–289

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hardy D, Liu CC, Cormier JN, Xia R, Du XL (2010) Cardiac toxicity in association with chemotherapy and radiation therapy in a large cohort of older patients with non-small-cell lung cancer. Ann Oncol 21:1825–1833

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Gridelli C, Sacco PC (2016) Novel cytotoxic drugs in advanced nonsmall cell lung cancer. Curr Opin Oncol 28:110–114

    Article  CAS  PubMed  Google Scholar 

  5. Heavey S, Godwin P, Baird AM et al (2014) Strategic targeting of the PI3K-NFkappaB axis in cisplatin-resistant NSCLC. Cancer Biol Ther 15:1367–1377

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gronberg BH, Sundstrom S, Kaasa S et al (2010) Influence of comorbidity on survival, toxicity and health-related quality of life in patients with advanced non-small-cell lung cancer receiving platinum-doublet chemotherapy. Eur J Cancer 46:2225–2234

    Article  CAS  PubMed  Google Scholar 

  7. Man SM, Karki R, Kanneganti TD (2017) Molecular mechanisms and functions of pyroptosis, inflammatory caspases and inflammasomes in infectious diseases. Immunol Rev 277:61–75

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shi J, Gao W, Shao F (2017) Pyroptosis: gasdermin-mediated programmed necrotic cell death. Trends Biochem Sci 42:245–254

    Article  CAS  Google Scholar 

  9. Wang YP, Gao WQ, Shi XY et al (2017) Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 547:99–103

    Article  CAS  Google Scholar 

  10. Zhao CG, Liu ZG, Liang G (2013) Promising curcumin-based drug design: mono-carbonyl analogues of curcumin (MACs). Curr Pharm Design 19:2114–2135

    CAS  Google Scholar 

  11. Wu JZ, Zhang YL, Cai YP et al (2013) Discovery and evaluation of piperid-4-one-containing mono-carbonyl analogs of curcumin as anti-inflammatory agents. Bioorg Med Chem 21:3058–3065

    Article  CAS  PubMed  Google Scholar 

  12. Zhou DY, Zhang K, Conney AH et al (2013) Synthesis and evaluation of curcumin-related compounds containing benzyl piperidone for their effects on human cancer cells. Chem Pharm Bull 61:1149–1155

    Article  CAS  PubMed  Google Scholar 

  13. Shyam H, Singh N, Kaushik S, Sharma R, Balapure AK (2017) Centchroman induces redox-dependent apoptosis and cell-cycle arrest in human endometrial cancer cells. Apoptosis 22:570–584

    Article  CAS  PubMed  Google Scholar 

  14. Furusawa Y, Yamanouchi Y, Iizumi T et al (2017) Checkpoint kinase 2 is dispensable for regulation of the p53 response but is required for G2/M arrest and cell survival in cells with p53 defects under heat stress. Apoptosis 22:1225–1234

    Article  CAS  PubMed  Google Scholar 

  15. Fink SL, Cookson BT (2005) Apoptosis, pyroptosis, and necrosis: mechanistic description of dead and dying eukaryotic cells. Infect Immun 73:1907–1916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Guo B, Zhai D, Cabezas E et al (2003) Humanin peptide suppresses apoptosis by interfering with Bax activation. Nature 423:456–461

    Article  CAS  PubMed  Google Scholar 

  17. Wong KK, Jacks T, Dranoff G (2010) NF-kappaB fans the flames of lung carcinogenesis. Cancer Prev Res 3:403–405

    Article  CAS  Google Scholar 

  18. Chen WS, Li Z, Bai L, Lin Y (2012) NF-kappaB, a mediator for lung carcinogenesis and a target for lung cancer prevention and therapy. Front Biosci 16:1172–1185

    Article  Google Scholar 

  19. Kasinski AL, Du Y, Thomas SL et al (2008) Inhibition of IkappaB kinase-nuclear factor-kappaB signaling pathway by 3,5-bis(2-flurobenzylidene)piperidin-4-one (EF24), a novel monoketone analog of curcumin. Mol Pharmacol 74:654–661

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Liu ZJ, Gan L, Xu YT et al (2017) Melatonin alleviates inflammasome-induced pyroptosis through inhibiting NF-kappaB/GSDMD signal in mice adipose tissue. J Pineal Res 63:e12414–e12430

    Article  CAS  Google Scholar 

  21. Kesavardhana S, Kanneganti TD (2017) Mechanisms governing inflammasome activation, assembly and pyroptosis induction. Int Immunol 29:201–210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Onen HI, Yilmaz A, Alp E et al (2015) EF24 and RAD001 potentiates the anticancer effect of platinum-based agents in human malignant pleural mesothelioma (MSTO-211H) cells and protects nonmalignant mesothelial (MET-5A) cells. Hum Exp Toxicol 34:117–126

    Article  CAS  PubMed  Google Scholar 

  23. Li R, Zhang LM, Sun WB (2017) Erythropoietin rescues primary rat cortical neurons from pyroptosis and apoptosis via Erk1/2-Nrf2/Bach1 signal pathway. Brain Res Bull 130:236–244

    Article  CAS  PubMed  Google Scholar 

  24. Brandstetter C, Patt J, Holz FG, Krohne TU (2016) Inflammasome priming increases retinal pigment epithelial cell susceptibility to lipofuscin phototoxicity by changing the cell death mechanism from apoptosis to pyroptosis. J Photochem Photobiol B 161:177–183

    Article  CAS  PubMed  Google Scholar 

  25. Wu XX, Zhang HY, Qi W et al (2018) Nicotine promotes atherosclerosis via ROS-NLRP3-mediated endothelial cell pyroptosis. Cell Death Dis 9:171–182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kim JY, Paton JC, Briles DE, Rhee DK, Pyo S (2015) Streptococcus pneumoniae induces pyroptosis through the regulation of autophagy in murine microglia. Oncotarget 6:44161–44178

    PubMed  PubMed Central  Google Scholar 

  27. Wang YB, Yin B, Li DN, Wang GJ, Han XD, Sun XJ (2018) GSDME mediates caspase-3-dependent pyroptosis in gastric cancer. Biochem Biophys Res Commun 495:1418–1425

    Article  CAS  PubMed  Google Scholar 

  28. Olivier E, Dutot M, Regazzetti A, Laprevote O, Rat P (2017) 25-Hydroxycholesterol induces both P2X7-dependent pyroptosis and caspase-dependent apoptosis in human skin model: new insights into degenerative pathways. Chem Phys Lipids 207:171–178

    Article  CAS  PubMed  Google Scholar 

  29. Cheng KT, Xiong SQ, Ye ZM et al (2017) Caspase-11-mediated endothelial pyroptosis underlies endotoxemia-induced lung injury. J Clin Invest 127:4124–4135

    Article  PubMed  PubMed Central  Google Scholar 

  30. Cerqueira DM, Pereira MS, Silva AL, Cunha LD, Zamboni DS (2015) Caspase-1 but not caspase-11 is required for NLRC4-mediated pyroptosis and restriction of infection by flagellated legionella species in mouse macrophages and in vivo. J Immunol 195:2303–2311

    Article  CAS  PubMed  Google Scholar 

  31. Yang JR, Yao FH, Zhang JG et al (2014) Ischemia-reperfusion induces renal tubule pyroptosis via the CHOP-caspase-11 pathway. Am J Physiol Renal Physiol 306:F75–F84

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Zhejiang Province Natural Science Fund of China (Grant Nos. LY15H280014, LY17H160059, LY19H130001), Technology Foundation for Medical Science of Zhejiang Province (2015KYA1506), the National Natural Science Foundation of China (Grant Nos. 81272462), the Opening Project of Zhejiang Provincial Top Key Discipline of Pharmaceutical Sciences.

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Author notes

  1. Liping Chen and Bixia Weng have contributed equally to this work.

Authors and Affiliations

  1. Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

    Liping Chen, Bixia Weng, Huimin Li, Haonan Wang, Qian Li, Xiaoyan Wei, Chengxi Jiang, Renyu Lin & Jianzhang Wu

  2. Department of Pharmaceutical Sciences, Tonglu First Peoples Hospital, Hangzhou, 311500, Zhejiang, China

    Bixia Weng

  3. Department of Periodontics, Hospital & School of Stomatology, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

    Huimin Li & Hui Deng

  4. Department of Pharmacy, Zhejiang Cancer Hospital, Hangzhou, 310022, Zhejiang, China

    Xiaoyan Wei

  5. School of Pharmacy, Xi’an Jiaotong University, Xi’an, 710049, Shanxi, China

    Sicen Wang

  6. Department of Otorhinolaryngology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China

    Renyu Lin

Authors
  1. Liping Chen
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  2. Bixia Weng
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Corresponding authors

Correspondence to Renyu Lin or Jianzhang Wu.

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Chen, L., Weng, B., Li, H. et al. A thiopyran derivative with low murine toxicity with therapeutic potential on lung cancer acting through a NF-κB mediated apoptosis-to-pyroptosis switch. Apoptosis 24, 74–82 (2019). https://doi.org/10.1007/s10495-018-1499-y

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  • DOI: https://doi.org/10.1007/s10495-018-1499-y

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