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

// Jianhong Yang 1, * , Heying Pei 1, * , Hong Luo 2, * , Afu Fu 1, * , Hansuo Yang 1 , Jia Hu 1 , Chengjian Zhao 1 , LuLu Chai 1 , Xiang Chen 1 , Ximing Shao 1 , Chunyu Wang 1 , Wenshuang Wu 1 , Li Wan 3 , Haoyu Ye 1 , Qiang Qiu 1 , Aihua Peng 1 , Yuquan Wei 1 , Li Yang 1 , Lijuan Chen 1 1 State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, P.R. China 2 Department of Ultrasonic Medicine, West China Second Hospital, Sichuan University, Chengdu, China 3 School of Pharmacy, Chengdu University of TCM, The Ministry of Education Key Laboratory of Standardization of Chinese Herbal Medicine, State Key Laboratory Breeding Base of Systematic Research, Development and Utilization of Chinese Medicine Resources, Chengdu, China * These authors contributed equally to this work Correspondence to: Lijuan Chen, email: ljchen@scu.edu.cn Keywords: liposomal honokiol, EGFR, metastasis, motility, hepatocellular carcinoma Received: September 22, 2015      Accepted: November 05, 2016      Published: November 29, 2016 ABSTRACT 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.