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Cytotoxic effects of natural and semisynthetic cucurbitacins on lung cancer cell line A549

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Summary

Cucurbitacins and their derivatives are triterpenoids that are found in various plant families, and are known for their pharmacological and biological activities, including anti-cancer effects. Lung cancer represents a major public health problem, with non-small-cell lung cancer (NSCLC) being the most frequent and aggressive type of lung cancer. The objective of this work was to evaluate four cucurbitacins (CUCs) for their cytotoxic activity, effects on apoptosis induction, cell cycle progression, anti-migratory, and anti-invasive effects on the human NSCLC cell line (A549 cells). Our findings showed that these CUCs could suppress human NSCLC cell growth in vitro through their effects on the PI3Kinase and MAPK pathways, which lead to programmed cell death induction, as well as inhibition of cell migration and cell invasion. Additionally, these effects culminate in apoptosis induction and G2/M cell cycle arrest by modulating cyclin B1 expression, and in the mitigation of strategic steps of lung cancer metastasis, including migration and invasion of A549 cells. These results suggest that two natural (DDCB and CB) and two novel semisynthetic derivatives of cucurbitacin B (ACB and DBCB) could be considered as promising compounds with antitumor potential.

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References

  1. Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65(1):5–29. doi:10.3322/caac.21254

    Article  PubMed  Google Scholar 

  2. Koh PK, Faivre-Finn C, Blackhall FH, De Ruysscher D (2012) Targeted agents in non-small cell lung cancer (NSCLC): clinical developments and rationale for the combination with thoracic radiotherapy. Cancer Treat Rev 38(6):626–640. doi:10.1016/j.ctrv.2011.11.003

    Article  PubMed  Google Scholar 

  3. Reck M, Heigener DF, Mok T, Soria JC, Rabe KF (2013) Management of non-small-cell lung cancer: recent developments. Lancet 382(9893):709–719. doi:10.1016/S0140-6736(13)61502-0

    Article  CAS  PubMed  Google Scholar 

  4. Perlikos F, Harrington KJ, Syrigos KN (2013) Key molecular mechanisms in lung cancer invasion and metastasis: a comprehensive review. Crit Rev Oncol Hematol 87(1):1–11. doi:10.1016/j.critrevonc.2012.12.007

    Article  PubMed  Google Scholar 

  5. Neuzillet C, Tijeras-Raballand A, de Mestier L, Cros J, Faivre S, Raymond E (2014) MEK in cancer and cancer therapy. Pharmacol Ther 141(2):160–171. doi:10.1016/j.pharmthera.2013.10.001

    Article  CAS  PubMed  Google Scholar 

  6. Holmes D (2011) PI3K pathway inhibitors approach junction. Nat Rev Drug Discov 10(8):563–564. doi:10.1038/nrd3527

    Article  CAS  PubMed  Google Scholar 

  7. Newman DJ, Giddings L-A (2014) Natural products as leads to antitumor drugs. Phytochem Rev 13(1):123–137. doi:10.1007/s11101-013-9292-6

    Article  CAS  Google Scholar 

  8. Chen X, Bao J, Guo J, Ding Q, Lu J, Huang M, Wang Y (2012) Biological activities and potential molecular targets of cucurbitacins: a focus on cancer. Anti-Cancer Drugs 23(8):777–787. doi:10.1097/CAD.0b013e3283541384

    Article  CAS  PubMed  Google Scholar 

  9. Rios JL, Andujar I, Escandell JM, Giner RM, Recio MC (2012) Cucurbitacins as inducers of cell death and a rich source of potential anticancer compounds. Curr Pharm Des 18(12):1663–1676

    Article  CAS  PubMed  Google Scholar 

  10. Lee DH, Iwanski GB, Thoennissen NH (2010) Cucurbitacin: ancient compound shedding new light on cancer treatment. Sci World J 10:413–418. doi:10.1100/tsw.2010.44

    Article  CAS  Google Scholar 

  11. Lang KL, da Rosa Guimarães T, Rocha Machado V, Zimmermann LA, Silva IT, Teixeira MR, Durán FJ, Palermo JA, Simões CMO, Caro MSB, Schenkel EP (2011) New cytotoxic cucurbitacins from Wilbrandia ebracteata cogn. Planta Med 77(EFirst):1648–1651. doi:10.1055/s-0030-1270962

    Article  CAS  PubMed  Google Scholar 

  12. Silva IT, Teixeira MR, Lang KL, Guimaraes TR, Dudek SE, Duran FJ, Ludwig S, Caro MS, Schenkel EP, Simoes CM (2013) Proliferative inhibition and apoptotic mechanism on human non-small-cell lung cancer (A549 Cells) of a novel cucurbitacin from Wilbrandia ebracteata cogn. Int J Cancer Res 9:54–68

    Article  Google Scholar 

  13. Lang KL, Silva IT, Zimmermann LA, Machado VR, Teixeira MR, Lapuh MI, Galetti MA, Palermo JA, Cabrera GM, Bernardes LS, Simoes CM, Schenkel EP, Caro MS, Duran FJ (2012) Synthesis and cytotoxic activity evaluation of dihydrocucurbitacin B and cucurbitacin B derivatives. Bioorg Med Chem 20(9):3016–3030. doi:10.1016/j.bmc.2012.03.001

    Article  CAS  PubMed  Google Scholar 

  14. Lang KL, Silva IT, Machado VR, Zimmermann LA, Caro MS, Simoes CM, Schenkel EP, Duran FJ, Bernardes LS, de Melo EB (2014) Multivariate SAR and QSAR of cucurbitacin derivatives as cytotoxic compounds in a human lung adenocarcinoma cell line. J Mol Graph Model 48:70–79. doi:10.1016/j.jmgm.2013.12.004

    Article  CAS  PubMed  Google Scholar 

  15. Silva IT, Carvalho A, Lang KL, Dudek SE, Masemann D, Duran FJ, Caro MS, Rapp UR, Wixler V, Schenkel EP, Simoes CM, Ludwig S (2015) In vitro and in vivo antitumor activity of a novel semisynthetic derivative of cucurbitacin B. PLoS ONE 10(2):e0117794. doi:10.1371/journal.pone.0117794

    Article  PubMed  PubMed Central  Google Scholar 

  16. Marostica LL, Silva IT, Kratz JM, Persich L, Geller FC, Lang KL, Caro MS, Duran FJ, Schenkel EP, Simoes CM (2015) Synergistic antiproliferative effects of a new cucurbitacin B derivative and chemotherapy drugs on lung cancer cell line A549. Chem Res Toxicol 28(10):1949–1960. doi:10.1021/acs.chemrestox.5b00153

    Article  CAS  PubMed  Google Scholar 

  17. Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65(1–2):55–63

    Article  CAS  PubMed  Google Scholar 

  18. Riccardi C, Nicoletti I (2006) Analysis of apoptosis by propidium iodide staining and flow cytometry. Nat Protoc 1(3):1458–1461. doi:10.1038/nprot.2006.238

    Article  CAS  PubMed  Google Scholar 

  19. Geller FC, Teixeira MR, Pereira ABD, Dourado LPA, Souza DG, Braga FC, Simões CMO (2015) Evaluation of the wound healing properties of Hancornia speciosa leaves. Phytother Res. doi:10.1002/ptr.5438

    PubMed  Google Scholar 

  20. Selinummi J, Seppala J, Yli-Harja O, Puhakka JA (2005) Software for quantification of labeled bacteria from digital microscope images by automated image analysis. BioTechniques 39(6):859–863. doi:10.2144/000112018

    Article  CAS  PubMed  Google Scholar 

  21. Vermeulen K, Van Bockstaele DR, Berneman ZN (2003) The cell cycle: a review of regulation, deregulation and therapeutic targets in cancer. Cell Prolif 36(3):131–149. doi:10.1046/j.1365-2184.2003.00266.x

    Article  CAS  PubMed  Google Scholar 

  22. Lee BY, Timpson P, Horvath LG, Daly RJ (2015) FAK signaling in human cancer as a target for therapeutics. Pharmacol Ther 146:132–149. doi:10.1016/j.pharmthera.2014.10.001

    Article  CAS  PubMed  Google Scholar 

  23. Tai Y-L, Chen L-C, Shen T-L (2015) Emerging roles of focal adhesion kinase in cancer. BioMed Res Int 2015:13. doi:10.1155/2015/690690

    Google Scholar 

  24. Chung SO, Kim YJ, Park SU (2015) An updated review of cucurbitacins and their biological and pharmacological activities. EXCLI J 14:562–566. doi:10.17179/excli2015-283

    PubMed  PubMed Central  Google Scholar 

  25. Alghasham AA (2013) Cucurbitacins - a promising target for cancer therapy. Int J Health Sci (Qassim) 7(1):77–89. doi:10.12816/0006025

    Article  Google Scholar 

  26. Zhang M, Bian ZG, Zhang Y, Wang JH, Kan L, Wang X, Niu HY, He P (2014) Cucurbitacin B inhibits proliferation and induces apoptosis via STAT3 pathway inhibition in A549 lung cancer cells. Mol Med Rep 10(6):2905–2911. doi:10.3892/mmr.2014.2581

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Feng H, Zang L, Zhao ZX, Kan QC (2014) Cucurbitacin-E inhibits multiple cancer cells proliferation through attenuation of Wnt/beta-catenin signaling. Cancer Biother Radiopharm 29(5):210–214. doi:10.1089/cbr.2014.1614

    Article  CAS  PubMed  Google Scholar 

  28. Guo J, Wu G, Bao J, Hao W, Lu J, Chen X (2014) Cucurbitacin B induced ATM-mediated DNA damage causes G2/M cell cycle arrest in a ROS-dependent manner. PLoS ONE 9(2):e88140. doi:10.1371/journal.pone.0088140

    Article  PubMed  PubMed Central  Google Scholar 

  29. Shukla S, Khan S, Kumar S, Sinha S, Farhan M, Bora HK, Maurya R, Meeran SM (2015) Cucurbitacin B alters the expression of tumor-related genes by epigenetic modifications in NSCLC and inhibits NNK-induced lung tumorigenesis. Cancer Prev Res (Phila) 8(6):552–562. doi:10.1158/1940-6207.CAPR-14-0286

    Article  CAS  Google Scholar 

  30. Kapoor S (2013) Cucurbitacin B and its rapidly emerging role in the management of systemic malignancies besides lung carcinomas. Cancer Biother Radiopharm 28(4):359. doi:10.1089/cbr.2012.1373

    Article  PubMed  Google Scholar 

  31. Jacquot C, Rousseau B, Carbonnelle D, Chinou I, Malleter M, Tomasoni C, Roussakis C (2014) Cucurbitacin-D-induced CDK1 mRNA up-regulation causes proliferation arrest of a non-small cell lung carcinoma cell line (NSCLC-N6). Anticancer Res 34(9):4797–4806

    CAS  PubMed  Google Scholar 

  32. LoPiccolo J, Blumenthal GM, Bernstein WB, Dennis PA (2008) Targeting the PI3K/Akt/mTOR pathway: effective combinations and clinical considerations. Drug Resist Updat 11(1–2):32–50. doi:10.1016/j.drup.2007.11.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Fang JY, Richardson BC (2005) The MAPK signalling pathways and colorectal cancer. Lancet Oncol 6(5):322–327. doi:10.1016/S1470-2045(05)70168-6

    Article  CAS  PubMed  Google Scholar 

  34. Ciuffreda L, McCubrey JA, Milella M (2009) Signaling intermediates (PI3K/PTEN/AKT/mTOR and RAF/MEK/ERK pathways) as therapeutic targets for anti-cancer and anti-angiogenesis treatments. Curr Signal Transduction Ther 4(2):130–143. doi:10.2174/157436209788167466

    Article  CAS  Google Scholar 

  35. Altomare DA, Testa JR (2005) Perturbations of the AKT signaling pathway in human cancer. Oncogene 24(50):7455–7464. doi:10.1038/sj.onc.1209085

    Article  CAS  PubMed  Google Scholar 

  36. McIlwain DR, Berger T, Mak TW (2013) Caspase functions in cell death and disease. Cold Spring Harb Perspect Biol 5(4):a008656. doi:10.1101/cshperspect.a008656

    Article  PubMed  PubMed Central  Google Scholar 

  37. Wan L, Pantel K, Kang Y (2013) Tumor metastasis: moving new biological insights into the clinic. Nat Med 19(11):1450–1464. doi:10.1038/nm.3391

    Article  CAS  PubMed  Google Scholar 

  38. Donadio A, Remedi M, Susperreguy S, Frede S, Gilardoni M, Tang Y, Pellizas C, Yan L (2008) Extracellular matrix metalloproteinase inducer (EMMPRIN) and matrix metalloproteinases (MMPs) as regulators of tumor–host interaction in a spontaneous metastasis model in rats. Histochem Cell Biol 130(6):1155–1164. doi:10.1007/s00418-008-0496-6

    Article  CAS  PubMed  Google Scholar 

  39. Valster A, Tran NL, Nakada M, Berens ME, Chan AY, Symons M (2005) Cell migration and invasion assays. Methods 37(2):208–215. doi:10.1016/j.ymeth.2005.08.001

    Article  CAS  PubMed  Google Scholar 

  40. Zhang T, Li J, Dong Y, Zhai D, Lai L, Dai F, Deng H, Chen Y, Liu M, Yi Z (2012) Cucurbitacin E inhibits breast tumor metastasis by suppressing cell migration and invasion. Breast Cancer Res Treat 135(2):445–458. doi:10.1007/s10549-012-2175-5

    Article  CAS  PubMed  Google Scholar 

  41. Zhou X, Yang J, Wang Y, Li W, Li-Ling J, Deng Y, Zhang M (2012) Cucurbitacin B inhibits 12-O-tetradecanoylphorbol 13-acetate-induced invasion and migration of human hepatoma cells through inactivating mitogen-activated protein kinase and PI3K/Akt signal transduction pathways. Hepatol Res 42(4):401–411. doi:10.1111/j.1872-034X.2011.00933.x

    Article  CAS  PubMed  Google Scholar 

  42. Wu X, Gan B, Yoo Y, Guan JL (2005) FAK-mediated src phosphorylation of endophilin A2 inhibits endocytosis of MT1-MMP and promotes ECM degradation. Dev Cell 9(2):185–196. doi:10.1016/j.devcel.2005.06.006

    Article  CAS  PubMed  Google Scholar 

  43. Mehlen P, Puisieux A (2006) Metastasis: a question of life or death. Nat Rev Cancer 6(6):449–458. doi:10.1038/nrc1886

    Article  CAS  PubMed  Google Scholar 

  44. Lee SO, Jeong YJ, Im HG, Kim CH, Chang YC, Lee IS (2007) Silibinin suppresses PMA-induced MMP-9 expression by blocking the AP-1 activation via MAPK signaling pathways in MCF-7 human breast carcinoma cells. Biochem Biophys Res Commun 354(1):165–171. doi:10.1016/j.bbrc.2006.12.181

    Article  CAS  PubMed  Google Scholar 

  45. Hour T, Wu L, Chung C, Tsuzuki Y (2012) Antitumor effects of the novel quinazolinone MJ-33: Inhibition of metastasis through the MAPK, AKT, NF-kB and AP-1 signaling pathways in DU145 human prostate cancer cells. Int J Oncol 41(4):1513–1519. doi:10.3892/ijo.2012.1560

    CAS  PubMed  Google Scholar 

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Acknowledgments

We acknowledge the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq, MCTI, Brazil), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, MEC, Brazil), Fundação de Apoio à Pesquisa e Inovação do Estado de Santa Catarina (FAPESC, State of Santa Catarina, Brazil), Consejo Nacional de Investigaciones Cientifícas y Tecnicas (CONICET, Argentina), Agencia Nacional de Promocion Cientifíca y Tecnologica (ANPCyT, Argentina) and UBA (Universidad de Buenos Aires, Argentina) for the financial support (grant numbers 472979/2011-6 and 2671/2012-9 from CNPq and PRONEX/FAPESC, respectively) as well as for our research fellowships.

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Authors and Affiliations

  1. Departamento de Ciências Farmacêuticas, CIF, CCS, Universidade Federal de Santa Catarina (UFSC), Campus Universitário Trindade, Florianópolis, 88040-900, SC, Brazil

    Izabella Thaís Silva, Fabiana Cristina Geller, Lara Persich, Eloir Paulo Schenkel & Cláudia Maria Oliveira Simões

  2. Department of Chemistry, Universidade Federal de Santa Catarina, Florianópolis, SC, Brazil

    Karen Luise Lang & Miguel Soriano Balparda Caro

  3. UMYMFOR – Department of Organic Chemistry, Universidad de Buenos Aires, Buenos Aires, Argentina

    Fernando Javier Durán

  4. Institute of Molecular Virology, Center of Molecular Biology of Inflammation, Westfaelische-Wilhelms-University, Muenster, Germany

    Sabine Eva Dudek & Stephan Ludwig

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  1. Izabella Thaís Silva
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  2. Fabiana Cristina Geller
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  3. Lara Persich
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  4. Sabine Eva Dudek
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  5. Karen Luise Lang
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  6. Miguel Soriano Balparda Caro
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  7. Fernando Javier Durán
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  8. Eloir Paulo Schenkel
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  9. Stephan Ludwig
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  10. Cláudia Maria Oliveira Simões
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Correspondence to Cláudia Maria Oliveira Simões.

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Silva, I.T., Geller, F.C., Persich, L. et al. Cytotoxic effects of natural and semisynthetic cucurbitacins on lung cancer cell line A549. Invest New Drugs 34, 139–148 (2016). https://doi.org/10.1007/s10637-015-0317-4

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