Abstract
Combinatorial therapeutic strategies using siRNA and small molecules to eradicate tumors are emerging. Targeting multiple signaling pathways decreases the chances of cancer cells switching and adapting new signaling processes that may occur when using a single therapeutic modality. Aberrant functioning of Notch-1, Wnt/β-catenin, and STAT3 proteins and their crosstalk signaling pathways have been found to be involved in tumor survival, drug resistance, and relapse. In the current study, we describe a therapeutic potential of single and combinations of siRNA designed for silencing Notch-1, Wnt/β-catenin, and STAT3 in MCF7_DoxS (wild type) and MCF7_DoxR (doxorubicin resistant) breast cancer cells. The MCF7_DoxR cells were developed through treatment with a gradual increase in doxorubicin concentration, the expression of targeted genes was investigated, and the expression profiling of CD44/CD24 of the MCF7_DoxS and MCF7_DoxR cells were detected by flow cytometry. Both MCF7_DoxS and MCF7_DoxR breast cancer cells were treated with single and combinations of siRNA to investigate synergism and were analyzed for their effect on cell proliferation with and without doxorubicin treatment. The finding of this study showed the overexpression of targeted genes and the enrichment of the CD44−/CD24+ phenotype in MCF7_DoxR cells when compared to MCF7_DoxS cells. In both cell lines, the gene silencing efficacy showed a synergistic effect when combining STAT3/Notch-1 and STAT3/Notch-1/β-catenin siRNA. Interestingly, the chemosensitivity of MCF7_DoxS and MCF7_DoxR cells to doxorubicin was increased when combined with siRNA treatment. Our study shows the possibility of using single and combinations of siRNA to enhance the chemosensitivity of cancer cells to conventional antitumor chemotherapy.
Highlights
Cancer remains one of the most frequent causes of morbidity and mortality worldwide [1]
The MCF7 breast cancer cell line was gradually treated with increased concentrations of doxorubicin starting at 10 nM and reaching a maximum of 100 nM
We developed a doxorubicin resistant MCF7 breast cancer cell line, followed by study of the expression status of important oncogenes including STAT3, β-catenin, and Notch-1
Summary
Cancer remains one of the most frequent causes of morbidity and mortality worldwide [1]. Abnormal functioning of different signaling pathways such as HER2, PI3K/AKT, TP53, MAPK, mTOR, Notch-1, Hedgehog, Wnt/β-catenin, and STAT3 have been found to be involved in tumorigenesis, tumor maintenance, drug resistance, and relapse [12,13]. Since these signaling pathways are unable to function separately, the crosstalk among them is very important for their functionality, which enhances the complexity of the disease. Several studies have shown therapeutic efficacy by targeting Notch-1, β-catenin, and STAT3 using single siRNA modality, combinatorial siRNA therapy against these targets in wild type and drug resistant cancer cells have not been previously described. The current work provides new insights toward developing more potent combinatorial therapeutic strategies using siRNA and small molecules to eradicate tumors
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