Key result
Combination treatment with doxorubicin and gamitrinib synergistically increased apoptosis in various human cancer cells and dramatically reduced in vivo tumor growth in xenograft models without increasing cardiotoxicity.
Why the study?
Does combination treatment with doxorubicin and gamitrinib synergistically increase anticancer activity without aggravating cardiotoxicity in preclinical models?
Does combination treatment with doxorubicin and gamitrinib synergistically increase anticancer activity without aggravating cardiotoxicity in preclinical models?
The combination of doxorubicin and gamitrinib synergistically enhances anticancer efficacy through Bim activation without aggravating doxorubicin-induced cardiotoxicity in preclinical models.
Supports testing gamitrinib-doxorubicin combinations to limit cardiotoxicity; leaves open translation from xenografts to clinical trials.
BACKGROUND: A common approach to cancer therapy in clinical practice is the combination of several drugs to boost the anticancer activity of available drugs while suppressing their unwanted side effects. In this regard, we examined the efficacy of combination treatment with the widely-used genotoxic drug doxorubicin and the mitochondriotoxic Hsp90 inhibitor gamitrinib to exploit disparate stress signaling pathways for cancer therapy. METHODS: The cytotoxicity of the drugs as single agents or in combination against several cancer cell types was analyzed by MTT assay and the synergism of the drug combination was evaluated by calculating the combination index. To understand the molecular mechanism of the drug synergism, stress signaling pathways were analyzed after drug combination. Two xenograft models with breast and prostate cancer cells were used to evaluate anticancer activity of the drug combination in vivo. Cardiotoxicity was assessed by tissue histology and serum creatine phosphokinase concentration. RESULTS: Gamitrinib sensitized various human cancer cells to doxorubicin treatment, and combination treatment with the two drugs synergistically increased apoptosis. The cytotoxicity of the drug combination involved activation and mitochondrial accumulation of the proapoptotic Bcl-2 family member Bim. Activation of Bim was associated with increased expression of the proapoptotic transcription factor C/EBP-homologous protein and enhanced activation of the stress kinase c-Jun N-terminal kinase. Combined drug treatment with doxorubicin and gamitrinib dramatically reduced in vivo tumor growth in prostate and breast xenograft models without increasing cardiotoxicity. CONCLUSIONS: The drug combination showed synergistic anticancer activities toward various cancer cells without aggravating the cardiotoxic side effects of doxorubicin, suggesting that the full therapeutic potential of doxorubicin can be unleashed through combination with gamitrinib.
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Park et al. (2014) studied Cancer. Doxorubicin and gamitrinib combination vs. Single agents or vehicle was evaluated on Cytotoxicity and tumor growth inhibition. Combination treatment with doxorubicin and gamitrinib synergistically increased apoptosis in various human cancer cells and dramatically reduced in vivo tumor growth in xenograft models without increasing cardiotoxicity.
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