Sorafenib and Carfilzomib Synergistically Inhibit the Proliferation, Survival, and Metastasis of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the most common and deadly human cancers. The 5-year survival rate is very low. Unfortunately, there are few efficacious therapeutic options. Until recently, Sorafenib has been the only available systemic drug for advanced HCC. However, it has very limited survival benefits, and new therapies are urgently needed. In this study, we investigated the anti-HCC activity of carfilzomib, a second-generation, irreversible proteasome inhibitor, as a single agent and in combination with sorafenib. , we found that carfilzomib has moderate anticancer activity toward liver cancer cells, but strongly enhances the ability of sorafenib to suppress HCC cell growth, proliferation, migration, invasion, and survival. Remarkably, the drug combination exhibits even more potent antitumor activity when tested in animal tumor models. Mechanistically, the combined treatment activates caspase-dependent and endoplasmic reticulum stress/CHOP-mediated apoptotic pathways, and suppresses epithelial-mesenchymal transition. In conclusion, our results demonstrate that the combination of carfilzomib and sorafenib has synergistic antitumor activities against HCC, providing a potential therapeutic strategy to improve the mortality and morbidity of HCC patients.

Antipsychotic agent pimozide promotes reversible proliferative suppression by inducing cellular quiescence in liver cancer

“…Given the mediocre clinical efficacy of sorafenib alone in patients with HCC, it is hoped that its efficacy may be enhanced by combining it with another intervention (34). Previously, carfilzomib has been shown to work synergistically with sorafenib in inhibiting the proliferation, survival and metastasis of HCC cells in vitro (35). Here, we showed that pimozide can enhance the proliferative inhibition of sorafenib in HCC cells, suggesting that it has the potential to improve HCC outcomes as an adjuvant therapy.…”

The Tumor Vessel Targeting Strategy: A Double-Edged Sword in Tumor Metastasis

“…Sorafenib is the priority drug used for advanced hepatocellular carcinoma (HCC) [65], as it inhibits the lung metastasis of HCC mediated by CD90 + cancer stem cells (CSCs) [66]. The combination of sorafenib and carfilzomib synergistically suppresses the metastasis of HCC via inducing tumor cell apoptosis [67]. Sorafenib may benefit patients with metastatically differentiated thyroid cancers that are resistant to radioactive iodine [68].…”

WNT7A Overexpression Inhibits Growth and Migration of Hepatocellular Carcinoma via the β-Catenin Independent Pathway

“…At this point, a previous study also revealed that Wnt7a obviously reduced the cell viability of cervical cancer [9], which shows no difference from our results. The migration ability of liver cancer cells is the primary factor that results in decreased survival rate of HCC patients [27]. Using transwell assay, we revealed that WNT7A overexpression inhibited tumor cell migration.…”