Anti-Proliferative and Pro-Apoptotic Effects Of Dipsacus Asperoides in a Cellular Model for Triple-Negative Breast Cancer

Abstract

Background: Triple negative breast cancer (TNBC) lacks expressions of estrogen receptor-α (ER-α), progesterone receptor (PR) and amplified human epidermal growth factor receptor-2 (HER-2). Current treatment for TNBC includes anthracyclin, taxol and cisplatin-based conventional chemotherapy and survival pathway PARP, PI3K, AKT and mTOR selective targeted therapy. These treatments exhibit dose-limiting systemic toxicity and presence of drug resistant cancer stem cells, which highlight the need for identification of efficacious testable alternatives that are not toxic to non-tumorigenic cells. Dipsacus asperoides (DA) is a Chinese nutritional herb and its root represents a common ingredient in Chinese herbal formulations used in women for estrogen related health issues, osteoporosis and breast diseases. This study aims to investigate the growth inhibitory effects of DA, and to detect mechanisms for its efficacy. Methods: Human mammary carcinoma derived triple negative MDA-MB-231 cell line represented the TNBC model. Non-fractionated aqueous extract from DA represented the test agent. Anchorage dependent growth, anchorage independent (AI) colony formation and cell cycle progression quantified growth inhibition. Western blot-based analysis for inhibition of RAS, PI3K and AKT and RB signaling identified mechanistic leads. Results: Treatment with DA induced a dose dependent cytostatic growth arrest (IC50:15 µg/ml; IC90: 30 µg/ml), reduced AI growth and inhibited cell cycle progression via G2/M arrest. DA affected the RAS, PI3K, AKT and RB signaling pathways, and functioned as a natural inhibitor of cyclin dependent kinase 4/6. Cellular apoptosis paralleled increase in pro-apoptotic Caspase 3/7 activity. Conclusion: These results demonstrate that DA inhibited growth, affected cell cycle progression, induced apoptosis and inhibited cancer cell survival pathways. This study validates a mechanism-based approach to identifying testable substitutes for secondary prevention/therapy of TNBC.

Keywords

• Breast cancer Melittin, combinational therapy, Honeybee venom