Abstract
BackgroundBreast cancer remains a major health problem worldwide, and is becoming increasingly resistant to traditional drug treatments. For instance, Adriamycin (ADR) is beneficial for the treatment of breast cancer. However, its wide application often leads to drug resistance in clinic practice, which results in treatment failure. Gambogenic acid (GNA), a polyprenylated xanthone isolated from the traditional medicine gamboge, has been reported to effectively inhibit the survival and proliferation of cancer cells. Its effects on ADR resistance have not yet been reported in breast cancer. In this study, we examined the ability of GNA to modulate ADR resiatance and the molecular mechanisms underlying this process using a cell based in vitro system.MethodsAn MTT assay was used to evaluate the inhibitory effect of the drugs on the growth of MCF-7 and MCF-7/ADR cell lines. The effects of drugs on apoptosis were detected using Annexin-V APC/7-AAD double staining. The expression of apoptosis-related proteins and the proteins in the PTEN/PI3K/AKT pathway were evaluated by Western blot analysis.ResultsIn the MCF-7/ADR cell lines, the IC50 (half maximal inhibitory concentration) of the group that received combined treatment with GNA and ADR was significantly lower than that in the ADR group, and this value decreased with an increasing concentration of GNA. In parallel, GNA treatment increased the chemosensitivity of breast cancer cells to ADR. The cell apoptosis and cell cycle anaysis indicated that the anti-proliferative effect of GNA is in virtue of increased G0/G1 arrest and potentiated apoptosis. When combined with GNA in MCF-7/ADR cell lines, the expression levels of the tumor suppressor gene PTEN (phosphatase and tensin homolog deleted on chromosome ten) and the apoptosis-related proteins caspase-3 and capsese-9 were significantly increased, while the expression of phosphorylated AKT was decreased.ConclusionsOur study has indicated a potential role for GNA to increase the chemosensitivity of breast cancer cells to ADR. This modulatory role was mediated by suppression of the PTEN/PI3K/AKT pathway that led to apoptosis in MCF-7/ADR cells. This work suggests that GNA may be used as a regulatory agent for treating ADR resistance in breast cancer patients.
Highlights
Breast cancer remains a major health problem worldwide, and is becoming increasingly resistant to traditional drug treatments
Modulation of chemosensitivity to ADR in MCF-7/ADR Cells To study the biologic mechanisms of chemosensitivity to ADR and find an opportunity to control resistance, we used an MTT assay to determine the IC50 values of ADR and Gambogenic acid (GNA) alone or in combination in MCF-7 and MCF-7/ADR cell lines
The combination of ADR and GNA enhanced the growth-inhibitory effect in MCF-7/ADR cells, while the IC50 decreased from 4.31 μg/ml to 3.34 μg/ml (GNA1: 0.078125 μg/ml), 1.84 μg/ml (GNA2: 0.15625 μg/ml), and 1.45 μg/ml (GNA3: 0.3125 μg/ml) (Fig. 1d, e)
Summary
Breast cancer remains a major health problem worldwide, and is becoming increasingly resistant to traditional drug treatments. Gambogenic acid (GNA), a polyprenylated xanthone isolated from the traditional medicine gamboge, has been reported to effectively inhibit the survival and proliferation of cancer cells. It has been reported that GNA can inhibit cell proliferation by inducing apoptosis and cell cycle arrest by inactivation of the PTEN/PI3K/AKT signaling pathway in human tumors [12,13,14,15]. GNA causes cell cycle arrest during the G0/G1 phase by inhibiting AKT phosphorylation and inducing the apoptosis of cancer cells via caspase-3. The experiment by Sokolosky [19] GSK-3β activity could result in the altered chemosensitivity of MCF-7 breast cancer cells to ADR through regulation of the PI3K/Akt/mTORC1 pathway by phosphorylating signaling molecules such as PTEN and TSC2
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