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Abstract
Radiation is a widely used therapeutic method for treating breast cancer. N-dihydrogalactochitosan (GC), a biocompatible immunostimulant, is known to enhance the effects of various treatment modalities in different tumor types. However, whether GC can enhance the radiosensitivity of cancer cells remains to be explored. In this study, triple-negative murine 4T1 breast cancer cells transduced with multi-reporter genes were implanted in immunocompetent Balb/C mice to track, dissect, and identify liver-metastatic 4T1 cells. These cells expressed cancer stem cell (CSC) -related characteristics, including the ability to form spheroids, the expression of the CD44 marker, and the increase of protein stability. We then ex vivo investigated the potential effect of GC on the radiosensitivity of the liver-metastatic 4T1 breast cancer cells and compared the results to those of parental 4T1 cells subjected to the same treatment. The cells were irradiated with increased doses of X-rays with or without GC treatment. Colony formation assays were then performed to determine the survival fractions and radiosensitivity of these cells. We found that GC preferably increased the radiosensitivity of liver-metastatic 4T1 breast cancer cells rather than that of the parental cells. Additionally, the single-cell DNA electrophoresis assay (SCDEA) and γ-H2AX foci assay were performed to assess the level of double-stranded DNA breaks (DSBs). Compared to the parental cells, DNA damage was significantly increased in liver-metastatic 4T1 cells after they were treated with GC plus radiation. Further studies on apoptosis showed that this combination treatment increased the sub-G1 population of cells, but not caspase-3 cleavage, in liver-metastatic breast cancer cells. Taken together, the current data suggest that the synergistic effects of GC and irradiation might be used to enhance the efficacy of radiotherapy in treating metastatic tumors.
Highlights
Cancer is a leading cause of mortality, decreased quality of life, and overwhelming stress for patients, their families, and our societies [1]
Triple-negative breast cancer that does not express the genes for estrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 (HER2) is the most lethal and malignant breast cancer subtype, is notorious for its extremely high metastatic ability [2]
A number of new therapeutic strategies have been developed in the past decades to combat metastatic cancers, including targeted therapy [4,5], hormonal therapy [6], and immunotherapy [7,8], the treatment of metastatic tumors remains the biggest challenge for researchers and clinicians
Summary
Cancer is a leading cause of mortality, decreased quality of life, and overwhelming stress for patients, their families, and our societies [1]. The intrinsic radiosensitivity of tumor cells is an important factor for determining the efficacy of radiotherapy. Ideal radiosensitizers should be biocompatible and have low cell toxicity [14]. This is important to obtain synergistic effects with radiotherapy. We investigated the potential effect of GC on radiation-induced cell death in murine parental and sibling liver-metastatic 4T1 breast cancer cells. Our results showed the synergistic effects of GC and radiotherapy in the treatment of 4T1 tumors. The findings may lead to effective radiotherapy for the treatment of metastatic cancers, with enhanced effects resulting from the administration of GC
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