Sorafenib with ASC-J9^® synergistically suppresses the HCC progression via altering the pSTAT3-CCL2/Bcl2 signals

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• 作者：Junjie Xu ; Hui Lin ; Gonghui Li ; Yin Sun ; Liang Shi ; Wen-Lung Ma ; Jiang Chen ; Xiujun Cai and Chawnshang Chang
• 刊名：International Journal of Cancer
• 出版年：2017
• 出版时间：1 February 2017
• 年：2017
• 卷：140
• 期：3
• 页码：705-717
• 全文大小：955K
• ISSN：1097-0215

文摘

Sorafenib is currently used as a standard treatment to suppress the progression of hepatocellular carcinoma (HCC), especially in advanced stages. However, patients who receive Sorafenib treatment eventually develop resistance without clear mechanisms. There is a great need for better efficacy of Sorafenib treatment in combination with other therapies. Here, we demonstrated that the treatment combining Sorafenib with ASC-J9^® could synergistically suppress HCC progression via altering cell-cycle regulation, apoptosis and invasion. Mechanism dissection suggests that while Sorafenib impacts little or even slightly increases the activated/phosphorylated STAT3 (p-STAT3), a key stimulator to promote the HCC progression, adding ASC-J9^® significantly suppresses the p-STAT3 expression and its downstream genes including CCL2 and Bcl2. Interrupting these signals via constitutively active STAT3 partially reverses the synergistic suppression of Sorafenib-ASC-J9^® combination on HCC progression. In vivo studies further confirmed the synergistic effect of Sorafenib-ASC-J9^® combination. Together, these results suggest the newly developed Sorafenib-ASC-J9^® combination is a novel therapy to better suppress HCC progression.