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Progression of early-stage breast cancer to advanced-stage metastatic disease represents a major cause of death in women. Long-term conventional and targeted therapy for breast cancer includes multi-drug combinations of cytotoxic chemotherapeutics and pathway-selective small molecule inhibitors. These treatment options are frequently associated with systemic toxicity, intrinsic/acquired therapy resistance and emergence of a drug-resistant cancer stem cell population. This stem cell population has a chemo-resistant, cancer-initiating, premalignant phenotype that is accompanied by cellular plasticity and metastatic potential. These limitations emphasize an unmet need to identify testable alternatives against therapy-resistant metastatic breast cancer. Natural products such as dietary phytochemicals, nutritional herbs and their constitutive bioactive agents have documented human consumption, and lack detectable systemic toxicity and resultant off-target unfavorable side effects. Because of these advantages, natural products may represent testable alternatives for therapy-resistant breast cancer. The present review discusses published evidence for growth inhibitory efficacy of natural products on cellular models for molecular subtypes of clinical breast cancer and development of drug-resistant stem cell models. Collectively, this evidence validates mechanism-based experimental approaches to screen and prioritize efficacious bioactive agents from natural products as novel drug candidates that may function as therapeutic alternatives for breast cancer. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The mechanism for the regulation of telomerase activity during DNA replication in immortalized cells is discussed. Phenotypic differentiation was induced in human promyelocytic leukemia cells by diverse agents and examined by electrophoretic mobility shift assay. The cells displayed a significant reduction in telomerase activity. Since the agents had no direct effect on telomerase activity, it is suggested that the downregulation was caused by the induction of terminal differentiation.

Triple-negative breast cancer (TNBC) lacks the expressions of estrogen receptor-α, progesterone receptor and human epidermal growth factor receptor-2. The treatment options for TNBC include anthracyclin/taxol based conventional chemotherapy and small molecular inhibitor based targeted therapy. However, the therapeutic efficacy is limited by systemic toxicity and acquired tumor resistance; identification of less toxic testable alternatives is urgently required. Non-toxic nutritional herbs are commonly used in traditional Chinese herbal medicine for general health management and may additionally represent a testable therapeutic alternative for TNBC. The present study examined the growth inhibitory efficacy of the nutritional herb Cornus officinalis (CO) in MDA-MB-231 cells, which represent a cell culture model for TNBC, and identified potential mechanistic leads. In MDA-MB-231 cells, CO induced dose-dependent cytostatic growth arrest [inhibitory concentration (IC)50, 0.1% and IC90, 0.5%], and inhibited anchorage independent colony formation. Mechanistically, CO inhibited G1 to S phase transition leading to G1 arrest and decreased the expression of cyclin D1 and phosphorylated-retinoblastoma proteins. CO additionally altered apoptosis specific BCL-2 associated X protein/B-cell lymphoma-2 expression and upregulated pro-apoptotic caspase-3/7 activity. Collectively, these data provided mechanistic evidence for the efficacy of CO, and validated a mechanism-based approach to prioritize efficacious nutritional herbs as testable alternatives for secondary prevention/treatment of TNBC. [ABSTRACT FROM AUTHOR]