Abstract
Cancer nano-therapy has been progressing rapidly with the introduction of many novel drug delivery systems. The previous study has reported on the in vitro cytotoxicity of citral-loaded nanostructured lipid carrier (NLC-Citral) on MDA-MB-231 cells and some preliminary in vivo antitumor effects on 4T1 breast cancer cells challenged mice. However, the in vivo apoptosis induction and anti-metastatic effects of NLC-Citral have yet to be reported. In this study, the in vitro cytotoxic, anti-migration, and anti-invasion effects of NLC-Citral were tested on 4T1 breast cancer cells. In addition, the in vivo antitumor effects of oral delivery of NLC-Citral was also evaluated on BALB/c mice induced with 4T1 cells. In vitro cytotoxicity results showed that NLC-Citral and citral gave similar IC50 values on 4T1 cells. However, wound healing, migration, and invasion assays reflected better in vitro anti-metastasis potential for NLC-Citral than citral alone. Results from the in vivo study indicated that both NLC-Citral and citral have anti-tumor and anti-metastasis effects, whereby the NLC-Citral showed better efficacy than citral in all experiments. Also, the delay of tumor progression was through the suppression of the c-myc gene expression and induction of apoptosis in the tumor. In addition, the inhibition of metastasis of 4T1 cells to lung and bone marrow by the NLC-Citral and citral treatments was correlated with the downregulation of metastasis-related genes expression including MMP-9, ICAM, iNOS, and NF-kB and the angiogenesis-related proteins including G-CSF alpha, Eotaxin, bFGF, VEGF, IL-1alpha, and M-CSF in the tumor. Moreover, NLC-Citral showed greater downregulation of MMP-9, iNOS, ICAM, Eotaxin, bFGF, VEGF, and M-CSF than citral treatment in the 4T1-challenged mice, which may contribute to the better anti-metastatic effect of the encapsulated citral. This study suggests that NLC is a potential and effective delivery system for citral to target triple-negative breast cancer.
Highlights
Cancer has become one of the major public health problems in the world
Treated tumors as compared to the Nanostructured lipid carrier (NLC)-Blank (Figure 5). These results showed that NLC-Citral a higher numberinduced of apoptosis cells were observed thetumors
Significance indicated by different alphabet was set at p < 0.05 comparing between groups
Summary
Cancer has become one of the major public health problems in the world. A broad range of research initiatives are focused on finding a cure for cancer. [3] Triple-negative breast cancer (TNBC), which is clinically defined by the absence of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), contributes to an approximate 15–20% of all breast cancer cases. This is one of the most aggressive subtypes of breast cancer that is associated with poor prognosis [4]. Among the breast cancer cell line, triple-negative 4T1 murine breast cancer cells have been widely used as an in vitro and in vivo model for drug discovery against TNBC as it is highly tumorigenic, metastatic, and does not express ER, PR, and HER2 receptors [5]. Previous studies have shown that citral, which is an aldehyde compound found in the essential oil from citrus fruits and lemongrass, has in vitro cytotoxicity effects on TNBC
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