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

Zhou Y, Liang C, Xue F, Chen W, Zhi X, Feng X, Bai X, Liang T - Oncotarget (2015)

Bottom Line: However, during long-term doxorubicin monotherapy, HCC cells may eventually develop acquired-resistance to doxorubicin which results in recurrence and a poor prognosis.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, PR China.

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.

No MeSH data available.


Related in: MedlinePlus

Salinomycin enhances the efficacy of doxorubicin in subcutaneous xenografts of HCC cells in nude mice(A) Representative pictures of mouse xenografts captured after 2 weeks of treatment. (B) Volume of tumor xenografts in the control group (black), groups treated with doxorubicin (blue), salinomycin (green) or doxorubicin plus salinomycin (red). Relative tumor volume ratios (% of original volume when therapy initiated) were presented as the mean ± SD, n = 6 (** p < 0.01, *** p < 0.001, for control vs. doxorubicin alone; ## p < 0.01, ### p < 0.001, for doxorubicin plus salinomycin vs. doxorubicin alone). (C) After 2 weeks of treatment, mice of different groups were euthanized and tumors were dissected. (D) Tumor regression rates were calculated and compared with the combination group. Results are presented as the mean ± SD, n=6 (*** p < 0.001, for doxorubicin plus salinomycin vs. salinomycin alone; ### p < 0.001, for doxorubicin plus salinomycin vs. doxorubicin alone).
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Figure 6: Salinomycin enhances the efficacy of doxorubicin in subcutaneous xenografts of HCC cells in nude mice(A) Representative pictures of mouse xenografts captured after 2 weeks of treatment. (B) Volume of tumor xenografts in the control group (black), groups treated with doxorubicin (blue), salinomycin (green) or doxorubicin plus salinomycin (red). Relative tumor volume ratios (% of original volume when therapy initiated) were presented as the mean ± SD, n = 6 (** p < 0.01, *** p < 0.001, for control vs. doxorubicin alone; ## p < 0.01, ### p < 0.001, for doxorubicin plus salinomycin vs. doxorubicin alone). (C) After 2 weeks of treatment, mice of different groups were euthanized and tumors were dissected. (D) Tumor regression rates were calculated and compared with the combination group. Results are presented as the mean ± SD, n=6 (*** p < 0.001, for doxorubicin plus salinomycin vs. salinomycin alone; ### p < 0.001, for doxorubicin plus salinomycin vs. doxorubicin alone).

Mentions: To investigate the in vivo effects of doxorubicin and salinomycin combined therapy for HCC, we established xenograft models via subcutaneous injection of HuH-7 cells into nude mice and monitored tumor growth under different treatments every other day. We found that intraperitoneal injection of doxorubicin or salinomycin alone for two weeks inhibited the growth of tumors, while combined treatment resulted in a significantly increased inhibition of tumor-growth (Fig. 6A and B). Following two weeks of chemotherapy, the mice were euthanized and the tumors were dissected and weighed. Tumor regression rates for different treatments were calculated, and salinomycin was found to significantly enhance the curative efficacy of doxorubicin for HCC in vivo as shown in Fig. 6C and D.


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

Zhou Y, Liang C, Xue F, Chen W, Zhi X, Feng X, Bai X, Liang T - Oncotarget (2015)

Salinomycin enhances the efficacy of doxorubicin in subcutaneous xenografts of HCC cells in nude mice(A) Representative pictures of mouse xenografts captured after 2 weeks of treatment. (B) Volume of tumor xenografts in the control group (black), groups treated with doxorubicin (blue), salinomycin (green) or doxorubicin plus salinomycin (red). Relative tumor volume ratios (% of original volume when therapy initiated) were presented as the mean ± SD, n = 6 (** p < 0.01, *** p < 0.001, for control vs. doxorubicin alone; ## p < 0.01, ### p < 0.001, for doxorubicin plus salinomycin vs. doxorubicin alone). (C) After 2 weeks of treatment, mice of different groups were euthanized and tumors were dissected. (D) Tumor regression rates were calculated and compared with the combination group. Results are presented as the mean ± SD, n=6 (*** p < 0.001, for doxorubicin plus salinomycin vs. salinomycin alone; ### p < 0.001, for doxorubicin plus salinomycin vs. doxorubicin alone).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496360&req=5

Figure 6: Salinomycin enhances the efficacy of doxorubicin in subcutaneous xenografts of HCC cells in nude mice(A) Representative pictures of mouse xenografts captured after 2 weeks of treatment. (B) Volume of tumor xenografts in the control group (black), groups treated with doxorubicin (blue), salinomycin (green) or doxorubicin plus salinomycin (red). Relative tumor volume ratios (% of original volume when therapy initiated) were presented as the mean ± SD, n = 6 (** p < 0.01, *** p < 0.001, for control vs. doxorubicin alone; ## p < 0.01, ### p < 0.001, for doxorubicin plus salinomycin vs. doxorubicin alone). (C) After 2 weeks of treatment, mice of different groups were euthanized and tumors were dissected. (D) Tumor regression rates were calculated and compared with the combination group. Results are presented as the mean ± SD, n=6 (*** p < 0.001, for doxorubicin plus salinomycin vs. salinomycin alone; ### p < 0.001, for doxorubicin plus salinomycin vs. doxorubicin alone).
Mentions: To investigate the in vivo effects of doxorubicin and salinomycin combined therapy for HCC, we established xenograft models via subcutaneous injection of HuH-7 cells into nude mice and monitored tumor growth under different treatments every other day. We found that intraperitoneal injection of doxorubicin or salinomycin alone for two weeks inhibited the growth of tumors, while combined treatment resulted in a significantly increased inhibition of tumor-growth (Fig. 6A and B). Following two weeks of chemotherapy, the mice were euthanized and the tumors were dissected and weighed. Tumor regression rates for different treatments were calculated, and salinomycin was found to significantly enhance the curative efficacy of doxorubicin for HCC in vivo as shown in Fig. 6C and D.

Bottom Line: However, during long-term doxorubicin monotherapy, HCC cells may eventually develop acquired-resistance to doxorubicin which results in recurrence and a poor prognosis.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, PR China.

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.

No MeSH data available.


Related in: MedlinePlus