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

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.