Wang Keming  HeY  Ding J Lin Y  Li J  Shi Y Wang J  Zhu Y  Hu X

Nanjing, China Second Affiliated Hospital, NanjingMedical University Department of Oncology

Objective：Breastcancer remains a major health problem worldwide, and is becoming increasinglyresistant to traditional drug treatments. For instance, Adriamycin (ADR) isbeneficial for the treatment of breast cancer. However, its wide applicationoften leads to drug resistance in clinic practice, which results in treatmentfailure. Gambogenic acid (GNA), a polyprenylated xanthone isolated from thetraditional medicine gamboge, has been reported to effectively inhibit thesurvival and proliferation of cancer cells. Its effects on ADR resistance havenot yet been reported in breast cancer. In this study, we examined the abilityof GNA to modulate ADR resiatance and the molecular mechanisms underlying this processusing a cell based in vitro system. Method：AnMTT assay was used to evaluate the inhibitory effect of the drugs on the growthof MCF-7 and MCF-7/ADR cell lines. The effects of drugs on apoptosis weredetected using Annexin-V APC/7-AAD double staining. The expression of apoptosis-relatedproteins and the proteins in the PTEN/PI3K/AKT pathway were evaluated byWestern blot analysis. Result：Inthe MCF-7/ADR cell lines, the IC50 (half maximal inhibitory concentration) ofthe group that received combined treatment with GNA and ADR was significantlylower than that in the ADR group, and this value decreased with an increasingconcentration of GNA. In parallel, GNA treatment increased the chemosensitivityof breast cancer cells to ADR. The cell apoptosis and cell cycle anaysisindicated that the anti-proliferative effect of GNA is in virtue of increasedG0/G1 arrest and potentiated apoptosis. When combined with GNA in MCF-7/ADRcell lines, the expression levels of the tumor suppressor gene PTEN (phosphataseand tensin homolog deleted on chromosome ten) and the apoptosis-related proteinscaspase-3 and capsese-9 were significantly increased, while the expression of phosphorylatedAKT was decreased. Conclusion：Ourstudy has indicated a potential role for GNA to increase the chemosensitivityof breast cancer cells to ADR. This modulatory role was mediated by suppressionof the PTEN/PI3K/AKT pathway that led to apoptosis in MCF-7/ADR cells. Thiswork suggests that GNA may be used as a regulatory agent for treating ADRresistance in breast cancer patients.

Key words：breast cancer