The Synergistic In Vitro and In Vivo Antitumor Effect of Combination Therapy with Salinomycin and 5-Fluorouracil against Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is one of the few cancers in which a continuous increase in incidence has been observed over several years. Drug resistance is a major problem in the treatment of HCC. In the present study, we used salinomycin (Sal) and 5-fluorouracil (5-FU) combination therapy on HCC cell lines Huh7, LM3 and SMMC-7721 and nude mice subcutaneously tumor model to study whether Sal could increase the sensitivity of hepatoma cells to the traditional chemotherapeutic agent such as 5-FU. The combination of Sal and 5-FU resulted in a synergistic antitumor effect against liver tumors both in vitro and in vivo. Sal reversed the 5-FU-induced increase in CD133(+) EPCAM(+) cells, epithelial–mesenchymal transition and activation of the Wnt/β-catenin signaling pathway. The combination of Sal and 5-FU may provide us with a new approach to reverse drug resistant for the treatment of patients with HCC.

Salinomycin inhibits metastatic colorectal cancer growth and interferes with Wnt/β-catenin signaling in CD133+ human colorectal cancer cells

“…This is accompanied by inhibition of tumor cell migration and invasion. Interestingly, in contrast to other observations before, an additive synergistic effect of Sal and 5-FU in vitro was not observed [26–28]. …”

“…Given that CRC liver metastasis are the leading cause for CRC-related death [4] this observation promises an important clinical impact. The effectiveness of Sal in vivo has been described before predominantly in subcutaneous tumor models [1, 7, 17, 26, 29–31]. Our data demonstrate the effectiveness of Sal in clinical relevant CRC models for the first time in a convincing extent.…”

“…We focused on Wnt signaling in human CD133 + and CD133 - CRC cell lines given that aberrations in Wnt signaling cascade and its impact on CRC development are well known [9, 10, 32–34]. Additionally, the inhibitory effect of Sal on Wnt signaling has been described in other tumor entities before, including leukemia, breast, pancreatic, prostate, and lung cancer cells [11, 26, 35–38]. Hence, the hypothesis that Salinomycin acts as an inhibitor of Wnt signaling is not new.…”

Salvianolic acid A reverses the paclitaxel resistance and inhibits the migration and invasion abilities of human breast cancer cells by inactivating transgelin 2

“…Xiaowei Recently, emerging studies of breast cancer 5 , ovarian cancer 6 , hepatocellular carcinoma 7 and lung adenocarcinoma 8 have demonstrated that drug-resistant cancer cells display features of epithelial-mesenchymal transition (EMT). It is well-known that EMT is an essential physiological process in which epithelial cells change into mesenchymal cells through a specific signaling pathway.…”

Oncogenic role of the Notch pathway in primary liver cancer

“…Persistent activation of Notch signaling may lead to oncogenesis depending on modifier factors, including the inflammatory environment or the presence of other carcinogenic conditions that may cause HCC or CCA (88). A Notch signature has been reported in a subset of HCC patients and an overexpression of Notch receptors has been reported in human CCAs, which is fundamentally required for the development of targeted therapies (89).…”