Non-toxic dose of liposomal honokiol suppresses metastasis of hepatocellular carcinoma through destabilizing EGFR and inhibiting the downstream pathways

• Published in: Oncotarget Vol. 8; no. 1; pp. 915 - 932
• Main Authors: Yang, Jianhong, Pei, Heying, Luo, Hong, Fu, Afu, Yang, Hansuo, Hu, Jia, Zhao, Chengjian, Chai, LuLu, Chen, Xiang, Shao, Ximing, Wang, Chunyu, Wu, Wenshuang, Wan, Li, Ye, Haoyu, Qiu, Qiang, Peng, Aihua, Wei, Yuquan, Yang, Li, Chen, Lijuan
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 03.01.2017
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Apoptosis - drug effects; Biphenyl Compounds - administration & dosage; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; cdc42 GTP-Binding Protein - antagonists & inhibitors; Cell Cycle - drug effects; Cell Line, Tumor; Cell Movement - drug effects; Cell Proliferation - drug effects; Disease Models, Animal; ErbB Receptors - metabolism; Female; Hep G2 Cells; Heterografts; Humans; Lignans - administration & dosage; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; MAP Kinase Signaling System - drug effects; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - metabolism; Melanoma, Experimental; Mice; Neoplasm Metastasis; Neoplasm Staging; Protein Stability - drug effects; rac1 GTP-Binding Protein - antagonists & inhibitors; Research Paper; Signal Transduction - drug effects; Zebrafish; liposomal honokiol; motility; metastasis; EGFR; hepatocellular carcinoma
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.13687

At present, there is no specific anti-metastasis drug in HCC treatment. Drugs used for primary HCC tumors and tumor metastasis are very similar, among which cytotoxic drugs are prevalent, such as cisplatin, doxorubicin and 5-FU. The EGFR pathway plays an important role in promoting hepatocellular carcinoma (HCC) metastasis. Hence, development of non-toxic anti-metastasis drugs, such as EGFR or downstream pathways inhibitors, is of great importance. In our present study, we found non-toxic dose of liposomal honokiol (LH) could inhibit the HCC metastasis by destabilizing EGFR and inhibiting the downstream pathways. Non-toxic dose of LH significantly inhibited the motility, migration and lamellipodia formation of HepG2 cells in vitro and decreased extravasation of HepG2 cells in a novel metastasis model of transgenic zebrafish. In two lung metastasis models (HepG2 and B16F10) and a spontaneous metastasis model of HepG2 cells, LH remarkably inhibited pulmonary metastasis and regional lymph nodes metastasis without obvious toxicity. Further study showed that destabilizing EGFR and inhibiting the downstream pathways were the main mechanisms of non-toxic dose of LH on metastasis inhibition. Our results provide the preclinical rationale and the underlying mechanisms of LH to suppress HCC metastasis, implicating LH as a potential therapeutic agent to block HCC metastasis without severe side effects.