All-trans retinoic acid potentiates the chemotherapeutic effect of cisplatin by inducing differentiation of tumor initiating cells in liver cancer.

Abstract

BACKGROUND & AIMS:

Systemic chemotherapy serves as an adjuvant treatment for post-operation patients with hepatocellular carcinoma (HCC), and provides curative option for the patients with unresectable HCC. However, its efficiency is largely limited because of the high incidence of chemo-resistance. Increasing evidence has shown that tumor initiating cells (TICs) not only have the ability to self-renew and drive the initiation and progression of cancer, but also exhibit greater resistance to conventional chemo- and radio-therapies than non-TICs. It was the aim of this study to investigate the effects of ATRA with and without cisplatin on TIC differentiation and apoptosis in human HCC.

METHODS:

In the present study, we evaluated the TICs of HCC cell differentiation induced by all-trans retinoic acid (ATRA), and developed a novel chemotherapeutic approach to HCC, by characterizing the function of combinatorial treatment with cis-diammineplatinum(II) (cisplatin) and ATRA in vitro and in vivo.

RESULTS:

ATRA effectively induced differentiation of TICs, which potentiated the cytotoxic effects of cisplatin. The combinatorial treatment of ATRA acid and cisplatin reduced protein kinase B (AKT) (Thr308) phosphorylation, and promoted apoptosis of HCC cells more significantly than treatment with cisplatin alone. In addition, the combined treatment with the two drugs exerted stronger inhibition on either HCC cell migration in vitro or metastasis in vivo, when compared to the treatment with either drug alone.

CONCLUSIONS:

These results indicated that ATRA could significantly improve the effect of cisplatin, which is at least partially attributed to ATRA-induced differentiation of HCC TICs, and the subsequent decrease in this chemo-resistant subpopulation.

• Authors: Yang Zhang, Dong-xian Guan, Jie Shi, Hong Gao, Jing-jing Li, Jiang-sha Zhao, Lin Qiu, Jiang Liu, Nan Li, Wei-xing Guo, Jie Xue, Fei-guo Zhou, Meng-chao Wu, Hong-yang Wang, Dong Xie, Shu-qun Cheng
• Journal: Journal of hepatology (J Hepatol) Vol. 59 Issue 6 Pg. 1255-63 (Dec 2013) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 23867314 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antigens, Neoplasm
• Antineoplastic Agents
• Cell Adhesion Molecules
• Epithelial Cell Adhesion Molecule
• Tretinoin
• Proto-Oncogene Proteins c-akt
• Cisplatin

Topics

• Animals
• Antigens, Neoplasm (physiology)
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Hepatocellular (drug therapy, pathology)
• Cell Adhesion Molecules (physiology)
• Cell Differentiation (drug effects)
• Cisplatin (pharmacology)
• Drug Synergism
• Epithelial Cell Adhesion Molecule
• Humans
• Liver Neoplasms (drug therapy, pathology)
• Male
• Mice
• Neoplastic Stem Cells (cytology, drug effects)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Tretinoin (pharmacology)