Anti‑proliferative effects of Drynaria fortunei in a model for triple negative breast cancer

Abstract

Triple negative breast cancer (TNBC) is characterized by the absence of hormones and growth factor receptors. It is typically responsive to anthracycline/taxol-based conventional chemotherapy. However, major therapeutic limitations include systemic toxicity and acquired resistance to chemotherapeutics. To combat this, nutritional herbs from traditional Chinese medicine (TCM) with limited reported toxicity may represent treatment alternatives for TNBC. Such herbs can effectively target multiple signaling pathways in numerous breast cancer models. The efficacy of various nutritional herbs in a cellular model of TNBC is associated with the downregulation of retinoblastoma (RB) signaling through the cyclin D-CDK4/6-RB axis. Therefore, the present study was designed to examine the effects of Drynaria fortunei (DF) in the same cellular model of TNBC to identify potential mechanistic leads for its efficacy. DF is a nutritional herb that represents a common component of herbal formulations used in TCM. The estrogen receptor-negative, progesterone receptor-negative and human epidermal growth factor receptor-2-negative MDA-MB-231 human breast carcinoma-derived cell line was used as the cellular model for TNBC in the present study. Non-fractionated aqueous extract from the bark of DF represented the test agent. Quantitative end-point biomarkers for the efficacy of DF assessed in the present study included cell cycle progression, RB signaling and caspase 3/7 activity. Treatment with DF at cytostatic concentration induced S phase cell cycle arrest and inhibited RB signaling as evidenced by the downregulated expression of cyclin E, CDK2, E2F1 and RB phosphorylation. DF treatment increased pro-apoptotic caspase 3/7 activity which was inhibited by the pan-caspase inhibitor Z-VAD-FMK. DF treatment also exhibited increased expression of cleaved ADP-ribose) polymerase-1. These data identify potential mechanistic leads for anti-proliferative and pro-apoptotic effects of DF in the present TNBC model. The present experiments validated a mechanism-driven experimental approach to identify efficacious nutritional herbs and/or their bioactive constituents as treatment alternatives for TNBC.