An isocorydine derivative (d-ICD) inhibits drug resistance by downregulating IGF2BP3 expression in hepatocellular carcinoma.

Abstract

In our previous studies, we reported that CD133(+) cancer stem cells (CSCs) were chemoresistant in hepatocellular carcinoma (HCC) and that isocorydine treatment decreased the percentage of CD133(+) CSCs. Here, we found that a derivative of isocorydine (d-ICD) inhibited HCC cell growth, particularly among the CD133(+) subpopulation, and rendered HCC cells more sensitive to sorafenib treatment. d-ICD inhibited IGF2BP3 expression in a time-dependent manner, and IGF2BP3 expression negatively correlated with d-ICD-induced growth suppression. IGF2BP3 overexpression enriched the CD133(+) CSC subpopulation in HCC, enhanced tumor sphere formation and suppressed the cytotoxic effects of sorafenib and doxorubicin. The expression of drug resistance-related genes, including ABCB1 and ABCG2, and the CSC marker CD133 expression was increased after IGF2BP3 overexpression. The significance of these observations was underscored by our findings that high IGF2BP3 expression predicted poor survival in a cohort of 236 patients with HCC and positively correlated with ABCG2 and CD133 expression in vivo. These results suggested that the d-ICD may inhibit HCC cells growth by IGF2BP3 decrease and that IGF2BP3 may serve as a therapeutic target for HCC.

• Authors: Meng Li, Lixing Zhang, Chao Ge, Lijuan Chen, Tao Fang, Hong Li, Hua Tian, Junxi Liu, Taoyang Chen, Guoping Jiang, Haiyang Xie, Ying Cui, Ming Yao, Jinjun Li
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 28 Pg. 25149-60 (Sep 22 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26327240 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCB1 protein, human
• ABCG2 protein, human
• AC133 Antigen
• ATP Binding Cassette Transporter, Subfamily B
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters
• Antibiotics, Antineoplastic
• Antigens, CD
• Antineoplastic Agents
• Aporphines
• Biomarkers, Tumor
• Glycoproteins
• IGF2BP3 protein, human
• Neoplasm Proteins
• PROM1 protein, human
• Peptides
• Phenylurea Compounds
• Protein Kinase Inhibitors
• RNA-Binding Proteins
• Niacinamide
• isocorydine
• Doxorubicin
• Sorafenib

Topics

• AC133 Antigen
• ATP Binding Cassette Transporter, Subfamily B (metabolism)
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• ATP-Binding Cassette Transporters (metabolism)
• Antibiotics, Antineoplastic (pharmacology)
• Antigens, CD (metabolism)
• Antineoplastic Agents (pharmacology)
• Aporphines (pharmacology)
• Biomarkers, Tumor (genetics, metabolism)
• Carcinoma, Hepatocellular (drug therapy, genetics, metabolism, mortality, pathology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Dose-Response Relationship, Drug
• Down-Regulation
• Doxorubicin (pharmacology)
• Drug Resistance, Neoplasm (drug effects)
• Female
• Glycoproteins (metabolism)
• Humans
• Liver Neoplasms (drug therapy, genetics, metabolism, mortality, pathology)
• Male
• Middle Aged
• Neoplasm Proteins (metabolism)
• Neoplastic Stem Cells (drug effects, metabolism)
• Niacinamide (analogs & derivatives, pharmacology)
• Peptides (metabolism)
• Phenylurea Compounds (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• RNA Interference
• RNA-Binding Proteins (drug effects, genetics, metabolism)
• Sorafenib
• Survival Analysis
• Time Factors
• Transfection