Abstract
Less optimized therapeutic effects constrain the use of doxorubicin as the main agent of chemotherapy for metastatic breast cancer, resistance and side effects. Therefore we need a combination of more than one chemopreventive agent which has different molecular targets to solve that problem. The aims of this study is to prove the inhibitory effect of ethanolic extract of rhizome of Curcuma xanthorrhiza (ECx), fruit of Brucea javanica (EBj), leave of Ficus septica (EFs) and doxorubicin (Dox) alone and its combination on migration and invasion of a highly metastatic 4T1 breast cancer cell line. Cytotoxic activity of single and combination treatment was evaluated by MTT assay, followed by an experiment of apoptosis induction by using flow cytometry. The inhibitory effect on migration was observed by the scratch wound-healing assay. Furthermore, the observation of the activity of matrix metalloproteinase-9 (MMP-9) was analyzed by gelatin zymography. The results showed that ECx, EBj, EFs, and Dox has cytotoxic activity on 4T1 cells with the value of IC 50 respectively 49.7±1.53mg/mL, 59.9±1.79mg/mL, 15.2±2.12mg/mL and 1.2±0.23mM. Furthermore, combination of ECx-EBj-Dox and ECx-EBj-EFs revealed synergistic effect on 4T1 cells and decrease cell viability through the induction of apoptosis and necrosis. Based on wound healing assay, 24 hours incubation of this combination inhibited 4T1 cells migration compared to single treatment. Gelatin zymography analysis showed that this combination also inhibited the activity of MMP-9 greater than a single use. Curcuma xanthorrhiza , Brucea javanica , and Ficus septica may have potential to be developed as a combination with or without doxorubicin for metastatic breast cancer treatment.
Highlights
Breast cancer is the first leading cause of cancer deaths in women
The reduction of cell viability of combination of extract of rhizome of Curcuma xanthorrhiza (ECx)-EBj-EFs and ECx-EBj-Dox is greater than the single treatment
The observation of apoptosis was done by using concentration 1⁄3IC50 of each agent
Summary
Doxorubicin is an important modality for the treatment of breast cancer metastasis in addition to surgery (Bapsy and Sahoo, 2006). The chemopreventive agent used in this research is a combination of Brucea javanica (EBj), Ficus septica (EFs) and Curcuma xanthorrhiza (ECx). Many clinical studies have suggested that Brucea javanica can be used alone as a conventional treatment for various cancers. The present study shows that Brucea javanica has synergistic effects when combined with certain anticancer drugs or radiotherapy (Nie et al, 2012). The ethanolic extract of Ficus septica showed a cytotoxic effect on breast cancer T47D cell lines with an IC50 value of 13μg/mL. The extract at 4.88μg/mL showed an optimum synergistic effect in combination with doxorubicin (3.75nM) (Pratama et al, 2010). Choi et al (2005) observed that injection of 0.2-1.0mg/kg BW xanthorrhizol had an antimetastatic effect in a mouse lung metastasis model
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