Abstract
Paclitaxel is a mitotic inhibitor used in cancer chemotherapy. Mulberry fruit is rich in phenolic compounds and flavonoids and exhibits chemopreventive activities. In this study, mulberry water extract (MWE) was used as a supplement to synergize with the effects of paclitaxel in the treatment of the TSGH 8301 human bladder cancer cell line. Treatment with paclitaxel combined with MWE (paclitaxel/MWE) enhanced the cytotoxicity of paclitaxel and induced severe G2/M arrest, mitotic catastrophe and subsequent apoptosis, as shown by MTT assay, HE staining and flow cytometry analyses. Differences in the expression and activation of Aurora A and Plk1between cells treated with paclitaxel/MWE and paclitaxel alone suggested that the combined treatment caused a defect in the early steps of cytokinesis. Paclitaxel/MWE decreased EEA1immunofluorescence staining and increased the expression of PTEN, indicating that the regimen inhibited the formation of the recycling endosome, which is required for cytokinesis. Paclitaxel/MWE also retarded tumor growth in a TSGH 8301 xenograft model via activation of PTEN and Caspase 3. These data demonstrated a synergistic effect on the anticancer efficacy of paclitaxel through MWE supplementation by promoting mitotic catastrophe through the activation of PTEN, providing a novel and effective therapeutic option for bladder cancer treatment strategies.
Highlights
Mitotic catastrophe is one of the strategies used by higher eukaryotes to eliminate mitosis-incompetent cells[10,11]
We demonstrated that the cytotoxicity of paclitaxel was enhanced by MWE via promoting mitotic catastrophe through a mechanism in which increased phosphatase and tensin homolog (PTEN) activity reduced the formation of early endosomes and influenced cytoplasmic membrane division in bladder cancer cells
These results suggested that the induction of mitotic catastrophe could be considered as an alternative strategy for cancer therapy and that MWE could be used as an auxiliary to enhance clinical cancer chemotherapy
Summary
Mitotic catastrophe is one of the strategies used by higher eukaryotes to eliminate mitosis-incompetent cells[10,11]. We demonstrated that the cytotoxicity of paclitaxel was enhanced by MWE via promoting mitotic catastrophe through a mechanism in which increased PTEN activity reduced the formation of early endosomes and influenced cytoplasmic membrane division in bladder cancer cells. These results suggested that the induction of mitotic catastrophe could be considered as an alternative strategy for cancer therapy and that MWE could be used as an auxiliary to enhance clinical cancer chemotherapy
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