Novel Mannich base 3FB3FA8H induces apoptosis by upregulating P53 pathway in neuroblastoma cells.

P53 plays an important role in maintaining genetic stability and development of resistance against tumors. Dysregulation of P53 gene is one of the key factors contributing to the etiology of neuroblastoma which causes cells to evade apoptosis. Activating P53 pathway can be a therapeutic alternative to the currently available medicinal strategies. Mannich bases have been known to possess various biological activities including the anticancer activity. In this study, we have targeted the P53 pathway by novel Mannich base (3FB3FA8H) which can be a future prospect to cure neuroblastoma. 3FB3FA8H has shown modulation of P53 pathway leading to apoptosis of neuroblastoma cells. Mitochondrial membrane permeability is also increased by 3FB3FA8H which may be a consequence of P53 pathway modulation. 3FB3FA8H increases the mRNA levels of P53 leading to activation of BAX. Inclining BAX/BCL2 ratio towards apoptotic BAX leads to cleavage of caspase 3, ultimately, causing apoptosis. Series of experiments provide the evidence that Mannich base 3FB3FA8H leads to P53-mediated apoptosis. Inducing apoptosis by this mechanism could be of central importance in reducing tumor burden which can be a good prospect for neuroblastoma patients.

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.

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.