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Cypripedin, a phenanthrenequinone from Dendrobium densiflorum, sensitizes non-small cell lung cancer H460 cells to cisplatin-mediated apoptosis

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A Correction to this article was published on 13 March 2018

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Abstract

The life-threatening potential of lung cancer has increased over the years due to its acquisition of chemotherapeutic resistance, especially to cisplatin, a first-line therapy. In response to this development, researchers have turned their attention to several compounds derived from natural origins, including cypripedin (CYP), a phenanthrenequinone substance extracted from Dendrobium densiflorum. The aim of the present study was to investigate the ability of CYP to induce apoptosis and enhance cisplatin-mediated death of human lung cancer NCI-H460 cells using cell viability and apoptosis assays. The induction of apoptosis by CYP was observed at a concentration of > 50 μM with the appearance of morphological changes, including DNA condensation and chromatin fragmentation. Together with, CYP was able to activate caspase-3 and downregulate the anti-apoptotic proteins Bcl-2 and Bcl-xL. Also, a non-cytotoxic dose of CYP synergistically potentiated the effect of cisplatin in non-small cell lung cancer line H460 cells, which clearly exhibited the apoptotic phenotype. Western blot analysis revealed that the underlying mechanism involved the downregulation of anti-apoptotic Bcl-xL, whereas the levels of other apoptotic regulatory proteins were not altered. This study provides interesting information on the potent effect of CYP as a chemotherapeutic sensitizer that could be further developed to improve the clinical outcomes of lung cancer patients.

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Change history

  • 13 March 2018

    In original publication of the article, unfortunately one of the author names was published incorrectly as “Boonchu Sritularuk”. The correct name is “Boonchoo Sritularak”.

References

  1. Miller KD, Siegel RL, Lin CC (2016) Cancer treatment and survivorship statistics. CA Cancer J Clin 66:271–289

    Article  PubMed  Google Scholar 

  2. Ettinger DS, Akerley W, Borghaei H (2012) Non-small cell lung cancer. J Natl Compr Canc Netw 10:1236–1271

    Article  CAS  PubMed  Google Scholar 

  3. Siddik ZH (2003) Cisplatin: mode of cytotoxic action and molecular basis of resistance. Oncogene 22:7265–7279

    Article  CAS  PubMed  Google Scholar 

  4. Florea AM, Büsselberg D (2011) Cisplatin as an anti-tumor drug: cellular mechanisms of activity, drug resistance and induced side effects. Cancers 3:1351–1371

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Oosterwijk JGV, Herpers B, Meijer D, Briaire-de BIH, Cleton-Jansen AM, Gelderblom H, van de Water B, Bovee JV (2012) Restoration of chemosensitivity for doxorubicin and cisplatin in chondrosarcoma in vitro: BCL-2 family members cause chemoresistance. Ann Oncol 23:1617–1626

    Article  PubMed  Google Scholar 

  6. Kumar Biswas S, Huang J, Persaud S, Basu A (2004) Down-regulation of Bcl-2 is associated with cisplatin resistance in human small cell lung cancer H69 cells. Mol Cancer Ther 3:327–334

    CAS  PubMed  Google Scholar 

  7. Nishioka T, Luo LY, Shen L, Mariyannis A, Dai W, Chen C (2014) Nicotine increases the resistance of lung cancer cells to cisplatin through enhancing Bcl-2 stability. Br J Cancer 110:1785–1792

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Leisching G, Loos B, Botha M, Engelbrecht A-M (2015) Bcl-2 confers survival in cisplatin treated cervical cancer cells: circumventing cisplatin dose-dependent toxicity and resistance. J Transl Med 13:328

    Article  PubMed  PubMed Central  Google Scholar 

  9. Chen HC, Kanai M, Inoue-Yamauchi A, Tu HC, Huang Y, Ren D, Ganesan YT (2015) An interconnected hierarchical model of cell death regulation by the BCL-2 family. Nat Cell Biol 17:1270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Williams MM, Lee L, Hicks DJ, Joly MM, Elion D, Rahman B, Estrada MV (2017) Key survival factor, Mcl-1, correlates with sensitivity to combined Bcl-2/Bcl-xL blockade. Mol Cancer Res 15:259–268

    Article  CAS  PubMed  Google Scholar 

  11. Brotin E, Meryet-Figuière M, Simonin K, Duval RE, Villedieu M, Leroy-Dudal J, Poulain L (2010) Bcl-xL and Mcl-1 constitute pertinent targets in ovarian carcinoma and their concomitant inhibition is sufficient to induce apoptosis. Int J Cancer 126:885–895

    CAS  PubMed  Google Scholar 

  12. Chen XM, Dong HL, Hu KX, Sun ZR, Chen J, Guo SX (2010) Diversity and antimicrobial and plant-growth-promoting activities of endophytic fungi in Dendrobium loddigesii Rolfe. J Plant Growth Regul 29:328–337

    Article  Google Scholar 

  13. Simmler C, Antheaume C, Lobstein A (2010) Antioxidant biomarkers from Vanda coerulea stems reduce irradiated HaCaT PGE-2 production as a result of COX-2 inhibition. PLoS ONE 5:e13713

    Article  PubMed  PubMed Central  Google Scholar 

  14. Lin TH, Chang SJ, Chen CC, Wang JP, Tsao LT (2001) Two phenanthraquinones from Dendrobium moniliforme. J Nat Prod 64:1084–1086

    Article  CAS  PubMed  Google Scholar 

  15. Unahabhokha T, Chanvorachote P, Pongrakhananon V (2016) The attenuation of epithelial to mesenchymal transition and induction of anoikis by gigantol in human lung cancer H460 cells. Tumour Biol 37:8633–8641

    Article  CAS  PubMed  Google Scholar 

  16. Charoenrungruang S, Chanvorachote P, Sritularak B, Pongrakhananon V (2014) Gigantol, a bibenzyl from Dendrobium draconis, inhibits the migratory behavior of non-small cell lung cancer cells. J Nat Prod 77:1359–1366

    Article  CAS  PubMed  Google Scholar 

  17. Busaranon K, Plaimee P, Sritularak B, Chanvorachote P (2016) Moscatilin inhibits epithelial-to-mesenchymal transition and sensitizes anoikis in human lung cancer H460 cells. J Nat Med 70:18–27

    Article  CAS  PubMed  Google Scholar 

  18. Toyooka T, Shinmen T, Aarts JM, Ibuki Y (2012) Dual effects of N-acetyl-l-cysteine dependent on NQO1 activity: suppressive or promotive of 9, 10-phenanthrenequinone-induced toxicity. Toxicol Appl Pharmacol 264:404–412

    Article  CAS  PubMed  Google Scholar 

  19. Matsunaga T, Kamiya T, Sumi D, Kumagai Y, Kalyanaraman B, Hara A (2008) l-Xylulose reductase is involved in 9, 10-phenanthrenequinone-induced apoptosis in human T lymphoma cells. Free Radic Biol Med 44:1191–1202

    Article  CAS  PubMed  Google Scholar 

  20. Matsunaga T, Arakaki M, Kamiya T, Endo S, El-Kabbani O, Hara A (2009) Involvement of an aldo-keto reductase (AKR1C3) in redox cycling of 9, 10-phenanthrenequinone leading to apoptosis in human endothelial cells. Chem Biol Interact 181:52–60

    Article  CAS  PubMed  Google Scholar 

  21. Saibu M, Sagar S, Green I, Ameer F, Meyer M (2014) Evaluating the cytotoxic effects of novel quinone compounds. Anticancer Res 34:4077–4086

    CAS  PubMed  Google Scholar 

  22. Foucquier J, Guedj M (2015) Analysis of drug combinations: current methodological landscape. Pharmacol Res Perspect 3:e00149

    Article  PubMed  PubMed Central  Google Scholar 

  23. Srinual S, Chanvorachote P, Pongrakhananon V (2017) Suppression of cancer stem-like phenotypes in NCI-H460 lung cancer cells by vanillin through an Akt-dependent pathway. Int J Oncol 50:1341–1351

    Article  CAS  PubMed  Google Scholar 

  24. Reed JC (2000) Mechanisms of apoptosis. Am J Pathol 157:1415–1430

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Wong RS (2011) Apoptosis in cancer: from pathogenesis to treatment. J Exp Clin Cancer Res 30:87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. O’Brien MA, Kirby R (2008) Apoptosis: a review of pro-apoptotic and anti-apoptotic pathways and dysregulation in disease. J Vet Emerg Crit Care 18:572–585

    Article  Google Scholar 

  27. Fischer U, Schulze-Osthoff K (2005) New approaches and therapeutics targeting apoptosis in disease. Pharmacol Rev 57:187–215

    Article  CAS  PubMed  Google Scholar 

  28. Porter AG, Jänicke RU (1999) Emerging roles of caspase-3 in apoptosis. Cell Death Differ 6(2):99–104

    Article  CAS  PubMed  Google Scholar 

  29. Dasari S, Tchounwou PB (2014) Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol 740:364–378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Henkels KM, Turchi JJ (1999) Cisplatin-induced apoptosis proceeds by caspase-3-dependent and-independent pathways in cisplatin-resistant and-sensitive human ovarian cancer cell lines. Cancer Res 59:3077–3083

    CAS  PubMed  Google Scholar 

  31. Brozovic A, Ambriovic-Ristov A, Osmak M (2010) The relationship between cisplatin-induced reactive oxygen species, glutathione, and BCL-2 and resistance to cisplatin. Crit Rev Toxicol 40:347–359

    Article  CAS  PubMed  Google Scholar 

  32. Saad SY, Najjar TA, Alashari M (2004) Role of non-selective adenosine receptor blockade and phosphodiesterase inhibition in cisplatin-induced nephrogonadal toxicity in rats. Clin Exp Pharmacol Physiol 31:862–867

    Article  CAS  PubMed  Google Scholar 

  33. Gupta SC, Hevia D, Patchva S, Park B, Koh W, Aggarwal BB (2012) Upsides and downsides of reactive oxygen species for cancer: the roles of reactive oxygen species in tumorigenesis, prevention, and therapy. Antioxid Redox Signal 16:1295–1322

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fuertes MA, Alonso C, Pérez JM (2003) Biochemical modulation of cisplatin mechanisms of action: enhancement of antitumor activity and circumvention of drug resistance. Chem Rev 103:645–662

    Article  CAS  PubMed  Google Scholar 

  35. Sirichanchuen B, Pengsuparp T, Chanvorachote P (2012) Long-term cisplatin exposure impairs autophagy and causes cisplatin resistance in human lung cancer cells. Mol Cell Biochem 364:11–18

    Article  CAS  PubMed  Google Scholar 

  36. Pabla N, Dong Z (2008) Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int 73:994–1007

    Article  CAS  PubMed  Google Scholar 

  37. Johnson SW, Perez RP, Godwin AK, Yeung AT, Handel LM, Ozols RF, Hamilton TC (1994) Role of platinum-DNA adduct formation and removal in cisplatin resistance in human ovarian cancer cell lines. Biochem Pharmacol 47:689–697

    Article  CAS  PubMed  Google Scholar 

  38. Matsumoto M, Nakajima W, Seike M, Gemma A, Tanaka N (2016) Cisplatin-induced apoptosis in non-small-cell lung cancer cells is dependent on Bax- and Bak-induction pathway and synergistically activated by BH3-mimetic ABT-263 in p53 wild-type and mutant cells. Biochem Biophys Res Commun 473:490–496

    Article  CAS  PubMed  Google Scholar 

  39. Unahabhokha T, Chanvorachote P, Sritularak B, Kitsongsermthon J, Pongrakhananon V (2016) Gigantol inhibits epithelial to mesenchymal process in human lung cancer cells. Evid Based Complement Alternat Med 2016:4561674

    Article  PubMed  PubMed Central  Google Scholar 

  40. Charoenrungruang S, Chanvorachote P, Sritularak B, Pongrakhananon V (2014) Gigantol-induced apoptosis in lung cancer cells through mitochondrial-dependent pathway. Thai J Pharm Sci 38:67–73

    Google Scholar 

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Acknowledgements

This research was supported by the Ratchadaphiseksomphot Endowment Fund, Chulalongkorn University.

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Correspondence to Varisa Pongrakhananon.

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The authors have no conflicts of interest.

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The original version of this article was revised: One of the author names was published incorrectly as "Boonchu Sritularuk" and the name is corrected in this version.

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Wattanathamsan, O., Treesuwan, S., Sritularak, B. et al. Cypripedin, a phenanthrenequinone from Dendrobium densiflorum, sensitizes non-small cell lung cancer H460 cells to cisplatin-mediated apoptosis. J Nat Med 72, 503–513 (2018). https://doi.org/10.1007/s11418-018-1176-z

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  • DOI: https://doi.org/10.1007/s11418-018-1176-z

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