An oral 2-hydroxypropyl-β-cyclodextrin-loaded spirooxindole-pyrrolizidine derivative restores p53 activity via targeting MDM2 and JNK1/2 in hepatocellular carcinoma

Abstract

Validation of a small molecular compound targeting the oncogenic pathways is the primary approach for the development of the anti-cancer drugs. In the present study, we employed the computational mimic drug targets prediction software to foresee the molecular targets of a series of spirooxindole-pyrrolizidine derivatives, which were synthesized by our laboratory viatargeted combinational chemistry. We found that CPHSP, a novel spirooxindole-pyrrolizidine derivative, can target the MDM2/p53 signaling that is essential for the tumorigenesis of hepatocellular carcinoma (HCC). To validate its anti-tumoral function, we firstly established the soluble receipt of CPHSP through 2-hydroxypropyl-β-cyclodextrin (HBC) loading and showed that oral administration of HBC-loaded CPHSP significantly inhibited the tumor growth and prolonged the survival time of tumor-bearing mice in the subcutaneously human hepatoma cells-xenografted nude mouse model of HCC. Immunohistochemistry staining showed that HBC-loaded CPHSP treatment suppressed the proliferation and induced apoptosis of tumor cells in this model. Our mechanistic studies showed that CPHSP treatment inhibited MDM2 protein expression and up-regulated p53 activity and activated MKK4/MKK7/JNK1/2/C-Jun signaling pathway, which resulted in cell cycle arrest and apoptosis of HepG2 cells in vitro. Moreover, we showed that JNK1/2 activation could also up-regulate p53 expression in CPHSP-treated HepG2 cells. Finally, we documented the antitumor activities of oral administration of the HBC-loaded CPHSP in the ML-1 bearing orthotopic mouse model. In summary, this study suggests that oral administration of HBC-loaded CPHSP is a safe and effective treatment for HCC, of which the clinical potency for patients with HCC warrants further studies.

Keywords: 2-Acetylpyrrolidine (PubChem CID: 550747); 2-Chlorobenzaldehyde (PubChem CID: 6996); Anti-tumor; Ethanol (PubChem CID: 702); Hepatocellular carcinoma; Isatin (PubChem CID: 7054); JNK1/2; L-Proline (PubChem CID: 145742); MDM2; Spirooxindole-pyrrolizidine derivative; p53.