Advertisement

A novel, semi-synthetic diterpenoid 16(R and S)-phenylamino-cleroda-3,13(14), Z-dien-15,16 olide (PGEA-AN) inhibits the growth and cell survival of human neuroblastoma cell line SH-SY5Y by modulating P53 pathway

  • Syed Saad Hussain
  • Kinza Rafi
  • Shaheen Faizi
  • Zaid Abdul Razzak
  • Shabana U. Simjee
Article

Abstract

Neuroblastoma being the most common extracranial pediatric solid tumor accounts for 15% of overall cancer-related childhood mortalities. Resistance to chemotherapeutic drugs is one of the limiting factors for positive prognosis for neuroblastoma. Therefore, there is always a need for developing new therapeutic moieties which can become a future prospect of neuroblastoma therapy. Terpenoids being the largest natural compounds have demonstrated many biological activities including anticancer activity. Keeping in mind the role of terpenoids in biological system, we aimed to identify novel semi-synthetic terpenoid derived from cleroda diterpene, 16-oxo-cleroda-3,13(14)E-diene-15-oic acid (1) as a potential anticancer moiety against neuroblastoma. We choose γ-amino γ-lactone (PGEA-AN, 2) of 1 to study further because it exhibited the most potent cytotoxic activity in preliminary screening. In comparison to cisplatin, PGEA-AN significantly decreased the nuclear area factor which suggest the potential apoptosis as cause of cell death. PGEA-AN demonstrated a significant increase in the percent of late apoptosis and necrotic cell death at 48-h treatment with IC50 dose. PGEA-AN significantly increased expression of P53 and BAX with no or little effect on BCL2 shifting BAX/BCL2 towards BAX promoting apoptosis. Increment in mitochondrial permeability supports P53 pathway involvement. Despite similarity in actions with cisplatin, PGEA-AN has found to have no effect on renal system. Based on these observations, we suggest that PGEA-AN modulates P53 system which further leads to the death of the neuroblastoma cells with no effect on renal system in vivo owing it to be a future prospect for development of anticancer moiety against neuroblastoma.

Keywords

Neuroblastoma Diterpenoids Synthetic γ-lactone Polyalthia longifolia var. pendula P53 

Notes

Compliance with ethical standards

Conflict of interest

There is no conflict of interest to disclose.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

Supplementary material

11010_2018_3347_MOESM1_ESM.docx (4.2 mb)
Supplementary material 1 (DOCX 4271 KB)

References

  1. 1.
    Andrew MD (2012) Neuroblastoma. Semin Pediatr Surg 21(1):2–14CrossRefGoogle Scholar
  2. 2.
    Schwab M, Westermann F, Hero B, Berthold F (2003) Neuroblastoma: biology and molecular and chromosomal pathology. Lancet Oncol 4:472–480CrossRefPubMedGoogle Scholar
  3. 3.
    Lanzkowsky P (2011) Manual of pediatric hematology and oncology. Elsevier, Amsterdam, pp 671–694CrossRefGoogle Scholar
  4. 4.
    Maris JM, Hogarty MD, Bagatell R, Cohn SL (2007) Neuroblastoma. Lancet 369:2106–2120CrossRefPubMedGoogle Scholar
  5. 5.
    Castleberry RP (1997) Neuroblastoma. Eur J Cancer 33(9):1430–1437CrossRefPubMedGoogle Scholar
  6. 6.
    Miller RW, Young JL, Novakovic B (1995) Childhood cancer. Cancer 75:395–405CrossRefPubMedGoogle Scholar
  7. 7.
    Matthay KK, Reynolds CP, Seeger RC, Shimada H, Adkins ES, Haas-Kogan D, Gerbing RB, London WB, Villablanca JG (2009) Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children’s oncology group study. J Clin Oncol 27:1007–1013CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Vermeulen J, De Preter K, Mestdagh P, Laureys G, Speleman F, Vandesompele J (2010) Predicting outcomes for children with neuroblastoma. Discov Med 10:29–36PubMedGoogle Scholar
  9. 9.
    American Cancer Society (2017) Chemotherapy for neuroblastoma. https://www.cancer.org/cancer/neuroblastoma/treating/chemotherapy.html. Accessed 14 Oct 2017
  10. 10.
    Annan K, Ekuadzi E, Asare C, Sarpong K, Pistorius D, Oberer L, Gyan BA, Ofori M (2015) Antiplasmodial constituents from the stem bark of Polyalthia longifolia var. pendula. Phytochem Lett 11:28–31CrossRefGoogle Scholar
  11. 11.
    Kathkar KV, Suthar AC, Chauhan VS (2010) The chemistry, pharmacologic and therapeutic applications of Polyalthia longifolia. Pharmacogn Rev 4(7):62–68CrossRefGoogle Scholar
  12. 12.
    Rubeena S, Ahmed M, Ahmed SI, Azeem M, Khan RA, Rasool M, Saleem H, Noor F, Faizi S (2005) Hypotensive activity and toxicology of constituents from root bark of Polyalthia longifolia var. pendula. Phytother Res 10:881–884Google Scholar
  13. 13.
    Lee TH, Wang MJ, Chen PY, Wu TY, Wen WC, Tsai FY, Lee CK (2009) Constituents of Polyalthia longifolia var. pendula. Nat Prod 72:1960–1963CrossRefGoogle Scholar
  14. 14.
    Chanda S, Dave R, Kaneria M, Shukla V (2012) Acute oral toxicity of Polyalthia longifolia var. pendula leaf extract in Wistar albino rats. Pharm Biol 50:1408–1415CrossRefPubMedGoogle Scholar
  15. 15.
    Sashidhara KV, Singh SP, Srivastava A, Puri A (2011) Identification of the antioxidant principles of Polyalthia longifolia var. pendula using TEAC assays. Nat Prod Res 25:918–926CrossRefPubMedGoogle Scholar
  16. 16.
    Tanna A, Nair R, Chanda S (2009) Assessment of anti-inflammatory and hepatoprotective potency of Polyalthia longifolia var. pendula leaf in Wistar albino rats. J Nat Med 63:80–85CrossRefPubMedGoogle Scholar
  17. 17.
    Faizi S, Khan RA, Azher S, Khan SA, Tauseef S, Ahmad A (2003) New antimicrobial alkaloids from the roots of Polyalthia longifolia var. pendula. Planta Med 69:350–355CrossRefPubMedGoogle Scholar
  18. 18.
    Faizi S, Khan RA, Mughal NR, Malik MS, Sajjadi KE, Ahmad A (2008) Antimicrobial activity of various parts of Polyalthia longifolia var. pendula: isolation of active principles from the leaves and the berries. Phytother Res 22:907–912CrossRefPubMedGoogle Scholar
  19. 19.
    Zhao G, Jung JH, Smith DL, Wood KV, McLaughlin JL (1991) Cytotoxic clerodane diterpenes from Polyalthia longifolia. Planta Med 57(04):380–383CrossRefPubMedGoogle Scholar
  20. 20.
    Gershenzon J, Dudareva N (2007) The function of terpene natural products in the natural world. Nat Chem Biol 3:408–414CrossRefPubMedGoogle Scholar
  21. 21.
    Li R, Morris-Natschke SL, Lee KH (2016) Clerodane diterpenes: sources, structures, and biological activities. Nat Prod Rep 33:1166–1226CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Strachan T, Read AP (1999) Chapter 18, cancer genetics. Human Molecular Genetics 2Google Scholar
  23. 23.
    Brooks CL, Gu W (2010) New insights into P53 activation. Cell Res 20:614–621CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Lewis JM, Truong TN, Schwartz MA (2002) Integrins regulate the apoptotic response to DNA damage through modulation of P53. Proc Natl Acad Sci USA 99:3627–3632CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Bouchet BP, Caron de Fromentel C, Puisieux A, Galmarini CM (2006) P53 as a target for anti-cancer drug development. Crit Rev Oncol/Hematol 58:190–207CrossRefGoogle Scholar
  26. 26.
    Hansen MB, Nielsen SE, Berg K (1989) Re-examination and further development of a precise and rapid dye method for measuring cell growth/cell kill. J Immunol Methods 119:203–210CrossRefPubMedGoogle Scholar
  27. 27.
    Hanif F, Perveen K, Jawed H, Ahmed A, Malhi SM, Jamall S, Simjee SU (2014) N-(2-hydroxyphenyl) acetamide (NA-2) and temozolomide synergistically induce apoptosis in human glioblastoma cell line U87. Cancer Cell Int 14(1):133CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    DeCoster MA (2007) The nuclear area factor: a measure for cell apoptosis using microscopy and image analysis. Modern research and educational topics in microscopy 378–384Google Scholar
  29. 29.
    Bron D, Mark A (2007) Quantification of sPLA2-induced early and late apoptosis changes in neuronal cell cultures using combined TUNEL and DAPI staining. Brain Res Protoc 13:144–150Google Scholar
  30. 30.
    Li PF, Dietz R, Von Harsdorf R (1999) P53 regulates mitochondrial membrane potential through reactive oxygen species and induces cytochrome c-independent apoptosis blocked by Bcl-2. EMBO J 18(21):6027–6036CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Chen CY, Chang FR, Shih YC, Hsieh TJ, Chia YC, Tseng HY, Wu YC (2000) Cytotoxic Constituents of Polyalthia longifolia var. pendula. J Nat Prod 63(11):1475–1478CrossRefPubMedGoogle Scholar
  32. 32.
    Liu Y, Whelan RJ, Pattnaik BR, Ludwig K, Subudhi E, Rowland H, Claussen N, Zucker N, Uppal S, Kushner DM, Felder M (2012) Terpenoids from Zingiber officinale (Ginger) induce apoptosis in endometrial cancer cells through the activation of p53. PLoS ONE 7(12):e53178CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Liontas A, Yeger H (2004) Curcumin and resveratrol induce apoptosis and nuclear translocation and activation of P53 in human neuroblastoma. Anticancer Res 24:987–998PubMedGoogle Scholar
  34. 34.
    Nikolaev AY, Li M, Puskas N, Qin J, Gu W (2003) Parc: a cytoplasmic anchor for P53. Cell 112:29–40CrossRefPubMedGoogle Scholar
  35. 35.
    Vaseva AV, Marchenko ND, Ji K, Tsirka SE, Holzmann S, Moll UM (2012) P53 opens the mitochondrial permeability transition pore to trigger necrosis. Cell 149(7):1536–1548CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Cui H, Schroering A, Ding HF (2002) P53 mediates DNA damaging drug-induced apoptosis through a caspase-9-dependent pathway in SH-SY5Y neuroblastoma cells. Mol Cancer Ther 1(9):679–686PubMedGoogle Scholar
  37. 37.
    Toshiyuki M, Reed JC (1995) Tumor suppressor P53 is a direct transcriptional activator of the human BAX gene. Cell 80(2):293–299CrossRefGoogle Scholar
  38. 38.
    Kobayashi T, Sawa H, Morikawa J, Zhang W, Shiku H (2000) BAX induction activates apoptotic cascade via mitochondrial cytochrome c release and BAX overexpression enhances apoptosis induced by chemotherapeutic agents in DLD-1 colon cancer cells. Cancer Sci 91(12):1264–1268Google Scholar
  39. 39.
    Youle RJ, Strasser A (2008) The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol 9(1):47–59CrossRefPubMedGoogle Scholar
  40. 40.
    Tsujimoto Y, Shimizu S (2007) Role of the mitochondrial membrane permeability transition in cell death. Apoptosis 12(5):835–840CrossRefPubMedGoogle Scholar
  41. 41.
    Kroemer G, Reed JC (2000) Mitochondrial control of cell death. Nat Med 6(5):513CrossRefPubMedGoogle Scholar
  42. 42.
    Manjula SN, Kenganora M, Parihar VK, Kumar S, Nayak PG, Kumar N, Ranganath Pai KS, Rao CM (2010) Antitumor and antioxidant activity of Polyalthia longifolia stem bark ethanol extract. Pharm Biol 48(6):690–696CrossRefPubMedGoogle Scholar
  43. 43.
    Jamie T, Mactier R, Geddes CC, Jonathan GF (2006) How to measure renal function in clinical practice. Br Med J 333:733–737CrossRefGoogle Scholar
  44. 44.
    Townsend DM, Deng M, Zhang L, Lapus MG, Hanigan MH (2003) Metabolism of cisplatin to a nephrotoxin in proximal tubule cells. J Am Soc Nephrol 14(1):1–10CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Syed Saad Hussain
    • 1
  • Kinza Rafi
    • 2
  • Shaheen Faizi
    • 1
  • Zaid Abdul Razzak
    • 2
  • Shabana U. Simjee
    • 1
    • 2
  1. 1.H.E.J. Research Institute of Chemistry, International Center for Chemical and Biological SciencesUniversity of KarachiKarachiPakistan
  2. 2.Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological SciencesUniversity of KarachiKarachiPakistan

Personalised recommendations