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

• Published in: Molecular and cellular biochemistry 2018-12, Vol.449 (1-2), p.105-115
• Main Authors: Hussain, Syed Saad, Rafi, Kinza, Faizi, Shaheen, Razzak, Zaid Abdul, Simjee, Shabana U.
• Format: Article
• Language: English
• Subjects: Animals; Anticancer properties; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Apoptosis - drug effects; Biochemistry; Biological activity; Biomedical and Life Sciences; Cancer; Cardiology; Cell death; Cell Line, Tumor; Cell survival; Cell Survival - drug effects; Children; Cisplatin; Cytotoxicity; Diterpenes - chemical synthesis; Diterpenes - chemistry; Diterpenes - pharmacology; Drug resistance; Humans; Life Sciences; Limiting factors; Medical Biochemistry; Medical prognosis; Mice; Mitochondria; Mortality; Neuroblastoma; Neuroblastoma - drug therapy; Neuroblastoma - genetics; Neuroblastoma - metabolism; Neuroblastoma - pathology; Neuroblasts; Oncology; p53 Protein; Permeability; Signal Transduction - drug effects; Signal Transduction - genetics; Solid tumors; Terpenes; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Xenograft Model Antitumor Assays
• ISSN: 0300-8177; 1573-4919
• DOI: 10.1007/s11010-018-3347-3

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 IC 50 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.