Abstract
Doxorubicin is a conventional and effective chemotherapy drug against hepatocellular carcinoma (HCC). However, during long-term doxorubicin monotherapy, HCC cells may eventually develop acquired-resistance to doxorubicin which results in recurrence and a poor prognosis. Salinomycin, an ionophore antibiotic, was recently reported to selectively kill human cancer stem cells (CSCs) which were response for chemoresistance. In this study, salinomycin was found to exert synergistic cytotoxicity with doxorubicin in HCC cells and be capable of inhibiting doxorubicin-induced epithelial-mesenchymal transition (EMT), an important cellular process involved in the acquired chemoresistance of tumors. Further experiments revealed that FOXO3a, a multifunctional transcription factor that can be activated by salinomycin, was vital in mediating doxorubicin-induced EMT. In addition, activated FOXO3a disturbed the interaction between β-catenin and TCF and inhibited the expression of β-catenin/TCF target genes (ZEB1, c-Myc and CyclinD1), which played important roles in doxorubicin-induced EMT in HCC cells. Finally, the enhanced curative efficacy of combination treatment of doxorubicin and salinomycin for HCC was confirmed in established xenograft models. In summary, the present study identifies a new doxorubicin-based chemotherapy for advanced HCC and provides a potential anti-cancer strategy targeting FOXO3a and related cell pathway molecules.
Highlights
Hepatocellular carcinoma (HCC) is one of the most intractable cancers worldwide, and has persistently increasing rates of both incidence and mortality [1]
This study demonstrated the synergism of salinomycin with doxorubicin for hepatocellular carcinoma (HCC) cells and the underlying mechanism focused on epithelial-mesenchymal transition (EMT) and FOXO3a
As an important signaling molecule in crucial cellular processes, FOXO3a is involved in metabolism, protein homeostasis, damage repair, stress resistance and cell fate decisions [22]
Summary
Hepatocellular carcinoma (HCC) is one of the most intractable cancers worldwide, and has persistently increasing rates of both incidence and mortality [1] Treatments such as surgical resection, liver transplantation or local ablation are available for early HCC, whereas for intermediate and advanced HCC, chemotherapy may be the only approach to control tumor progression [2, 3]. In the treatment of multiple tumors, combining doxorubicin with other agents such as selenocystine [6], 20(S)-ginsenoside Rg3 [7], JI-34 [8] and ganetespib [9], was found to exert synergetic anticancer effects and improved doxorubicinbased chemotherapy These reports indicated us that drug combinations may potentially be a viable strategy to improve the present situation of doxorubicin-resistance in HCC cells
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