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An oral 2-hydroxypropyl-β-cyclodextrin-loaded spirooxindole-pyrrolizidine derivative restores p53 activity via targeting MDM2 and JNK1/2 in hepatocellular carcinoma.
Pharmacol Res 2019; 148:104400PR

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.

Authors+Show Affiliations

Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, PR China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, PR China.Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, PR China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, PR China.Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, PR China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, PR China.Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, PR China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, PR China.Department of Chemistry, School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, PR China.Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, PR China; Center of Clinical Oncology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, PR China.Department of Chemistry, School of Pharmacy, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, PR China. Electronic address: songleizhu@xzhmu.edu.cn.Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu Province, 221002, PR China; Department of Cancer Biotherapy Center, Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan Province, 650118, PR China. Electronic address: yaohong20055@hotmail.com.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31425749

Citation

Gao, Xiaoge, et al. "An Oral 2-hydroxypropyl-β-cyclodextrin-loaded Spirooxindole-pyrrolizidine Derivative Restores P53 Activity Via Targeting MDM2 and JNK1/2 in Hepatocellular Carcinoma." Pharmacological Research, vol. 148, 2019, p. 104400.
Gao X, Wei M, Shan W, et al. An oral 2-hydroxypropyl-β-cyclodextrin-loaded spirooxindole-pyrrolizidine derivative restores p53 activity via targeting MDM2 and JNK1/2 in hepatocellular carcinoma. Pharmacol Res. 2019;148:104400.
Gao, X., Wei, M., Shan, W., Liu, Q., Gao, J., Liu, Y., ... Yao, H. (2019). An oral 2-hydroxypropyl-β-cyclodextrin-loaded spirooxindole-pyrrolizidine derivative restores p53 activity via targeting MDM2 and JNK1/2 in hepatocellular carcinoma. Pharmacological Research, 148, p. 104400. doi:10.1016/j.phrs.2019.104400.
Gao X, et al. An Oral 2-hydroxypropyl-β-cyclodextrin-loaded Spirooxindole-pyrrolizidine Derivative Restores P53 Activity Via Targeting MDM2 and JNK1/2 in Hepatocellular Carcinoma. Pharmacol Res. 2019 Aug 16;148:104400. PubMed PMID: 31425749.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - An oral 2-hydroxypropyl-β-cyclodextrin-loaded spirooxindole-pyrrolizidine derivative restores p53 activity via targeting MDM2 and JNK1/2 in hepatocellular carcinoma. AU - Gao,Xiaoge, AU - Wei,Mengxue, AU - Shan,Wenhua, AU - Liu,Qian, AU - Gao,Jian, AU - Liu,Yong, AU - Zhu,Songlei, AU - Yao,Hong, Y1 - 2019/08/16/ PY - 2019/03/26/received PY - 2019/08/12/revised PY - 2019/08/13/accepted PY - 2019/8/20/pubmed PY - 2019/8/20/medline PY - 2019/8/20/entrez KW - 2-Acetylpyrrolidine (PubChem CID: 550747) KW - 2-Chlorobenzaldehyde (PubChem CID: 6996) KW - Anti-tumor KW - Ethanol (PubChem CID: 702) KW - Hepatocellular carcinoma KW - Isatin (PubChem CID: 7054) KW - JNK1/2 KW - L-Proline (PubChem CID: 145742) KW - MDM2 KW - Spirooxindole-pyrrolizidine derivative KW - p53 SP - 104400 EP - 104400 JF - Pharmacological research JO - Pharmacol. Res. VL - 148 N2 - 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. SN - 1096-1186 UR - https://www.unboundmedicine.com/medline/citation/31425749/An_oral_2-hydroxypropyl-β-cyclodextrin-loaded_spirooxindole-pyrrolizidine_derivative_restores_p53_activity_via_targeting_MDM2_and_JNK1/2_in_hepatocellular_carcinoma L2 - https://linkinghub.elsevier.com/retrieve/pii/S1043-6618(19)30531-6 DB - PRIME DP - Unbound Medicine ER -