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Salinomycin decreases doxorubicin resistance in hepatocellular carcinoma cells by inhibiting the ?-catenin/TCF complex association via FOXO3a activation.

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 ?-catenin and TCF and inhibited the expression of ?-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.

SUBMITTER: Zhou Y

PROVIDER: S-EPMC4496360 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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Salinomycin decreases doxorubicin resistance in hepatocellular carcinoma cells by inhibiting the β-catenin/TCF complex association via FOXO3a activation.

Zhou Yue Y Liang Chao C Xue Fei F Chen Wei W Zhi Xiao X Feng Xinhua X Bai Xueli X Liang Tingbo T

Oncotarget 20150401 12

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 d ...[more]

PMID: 25871400

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Project description:BACKGROUND:Cancer is a significant health threat in cats. Chemoresistance is prevalent in solid tumors. The ionophore salinomycin has anti-cancer properties and may work synergistically with chemotherapeutics. The purpose of our study was to determine if salinomycin could decrease cancer cell viability when combined with doxorubicin in feline sarcoma and carcinoma cells. RESULTS:We established two new feline injection-site sarcoma cell lines, B4 and C10, and confirmed their tumorigenic potential in athymic nude mice. B4 was more resistant to doxorubicin than C10. Dose-dependent effects were not observed until 92??M in B4 cells (p =?0.0006) vs. 9.2??M (p =?0.0004) in C10 cells. Dose-dependent effects of salinomycin were observed at 15??M in B4 cells (p =?0.025) and at 10??M in C10 cells (p =?0.020). Doxorubicin plus 5??M salinomycin decreased viability of B4 cells compared to either agent alone, but only at supra-pharmacological doxorubicin concentrations. However, doxorubicin plus 5??M salinomycin decreased viability of C10 cells compared to either agent alone at doxorubicin concentrations that can be achieved in vivo (1.84 and 4.6??M, p <?0.004). In SCCF1 cells, dose-dependent effects of doxorubicin and salinomycin were observed at 9.2 (p =?0.036) and 2.5 (p =?0.0049) ?M, respectively. When doxorubicin was combined with either 1, 2.5, or 5??M of salinomycin in SCCF1 cells, dose-dependent effects of doxorubicin were observed at 9.2 (p =?0.0021), 4.6 (p =?0.0042), and 1.84 (p?=?0.0021) ?M, respectively. Combination index calculations for doxorubicin plus 2.5 and 5??M salinomycin in SCCF1 cells were 0.4 and 0.6, respectively. CONCLUSIONS:We have developed two new feline sarcoma cell lines that can be used to study chemoresistance. We observed that salinomycin may potentiate (C10 cells) or work synergistically (SCCF1 cells) with doxorubicin in certain feline cancer cells. Further research is indicated to understand the mechanism of action of salinomycin in feline cancer cells as well as potential tolerability and toxicity in normal feline tissues.

Dataset Information

Salinomycin decreases doxorubicin resistance in hepatocellular carcinoma cells by inhibiting the ?-catenin/TCF complex association via FOXO3a activation.

Publications

Salinomycin decreases doxorubicin resistance in hepatocellular carcinoma cells by inhibiting the β-catenin/TCF complex association via FOXO3a activation.

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