Sorafenib sensitizes hepatocellular carcinoma cell to cisplatin via suppression of Wnt/β-catenin signaling

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Systemic chemotherapy plays an important role in the treatment of patients with advanced liver cancer. However, chemoresistance to cisplatin is a major limitation of cisplatin-based chemotherapy in the clinic, and the underlying mechanism of such resistance is not fully understood. In this study, we found that nuclear accumulation of β-catenin was higher in cisplatin-resistant Huh7 cells than in Huh7 cells, indicating that Wnt signaling was activated in cisplatin-resistant cells. Wnt signaling inhibition increased cisplatin-induced growth inhibition in hepatoma cell. We further demonstrated that sorafenib could inhibit Wnt signaling in Huh7 cells and cisplatin-resistant Huh7 cells. Co-treatment with cisplatin and sorafenib was more effective in inhibiting cancer cell proliferation than cisplatin alone in vitro and in vivo, whereas Wnt3a (Wnt activator) treatment abrogated sorafenib-induced growth inhibition. These data demonstrated that sorafenib sensitizes human HCC cell to cisplatin via suppression of Wnt/β-catenin signaling, thus offering a new target for chemotherapy of HCC.

Anti-tumor activity of sorafenib in a model of a pediatric hepatocellular carcinoma

“…Using the β-catenin inhibitor ICG001 combined with sorafenib we observed a relevantly decreased lC 50 in pHCC cells. This is in line with the interaction between activation of ERK and activity of β-catenin [24], and the inhibition of the wnt/β-catenin pathway by sorafenib [21]. Additional inhibition of β-catenin activity at the formation of transcription complex might also block the activation through tyrosine kinase signaling and enhance the effect of sorafenib in pediatric HCC, a tumor, in which β-catenin is often mutated and constitutively active.…”

“…In contrast to adult HCC [21], sorafenib did not reduce β-catenin expression in HC-AFW1 cells ( Supplemental Fig. 3).…”

“…In aHCC sorafenib suppressed β-catenin signaling and the signal transduction through wnt/b-catenin pathway [21]. Thus, the impact of additional inhibition of β-catenin on viability of HC-AFW1 cells was investigated.…”

Synergistic growth inhibition by sorafenib and cisplatin in human osteosarcoma cells

“…accumulating evidence has shown that CDDP in combination with other drugs, such as methotrexate and pemetrexed, significantly inhibited OS cells growth in vitro and in vivo (29,30). Of note, the synergistic anti-proliferative and pro-apoptotic effects of SOR in combination with CDDP were confirmed in human liver and gastric cancer cells (18,31). although SOR and CDDP alone or in combination have been found to inhibit other types of tumor growth, the effect on OS of SOR in combination CDDP has, to the best of our knowledge, yet to be reported.…”

SL1122-37, a novel derivative of sorafenib, has greater effects than sorafenib on the inhibition of human hepatocellular carcinoma (HCC) growth and prevention of angiogenesis

“…Survivin is an anti-apoptotic molecule widely expressed in HCC. Overexpression of survivin leads to antiapoptosis (20). In this study, SL1122-37 was observed to have a greater activity than sorafenib in modulation of this pathway, suggesting its roles in the inhibition of HCC.…”