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


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.


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


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

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Supplementary material 1 (DOCX 4271 KB)


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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

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