Understanding the Underlying Biological Pathways Affected by Treatment of Triple Negative Breast Cancer Cell Lines with Novel Natural Product Derivatives

Breast cancer is a common disease and the second leading cause of cancer-related death in women. Therapeutic challenges arise due to the heterogeneity of breast cancer with multiple molecular phenotypes with no single therapy able to effectively treat all disease subtypes. Triple negative breast cancer (TNBC) is the most aggressive subtype with a high recurrence and metastasis rates, adding to the significant need to develop new therapies. Basal-like and claudin-low are two molecular subtypes of TNBC and the diversity of these subtypes further highlight the therapeutic challenges in treating TNBC.

Naturally-derived compounds are attractive drug candidates for cancer therapeutics due to their anti-cancer activity with minimal toxic side effects. Here we investigated two classes of novel small molecules, inspired by natural products: chalcones and azapodophyllotoxins (AzPs). These molecules were previously screened using a panel of 60 cancer cell lines and shown to have anti-cancer activity in TNBC cell lines. Chalcones have been previously shown to inhibit HSP90 while AzPs have been shown to inhibit tubulin assembly. Both of these mechanisms lead to an apoptotic response in TNBC cell lines.

In this study, we used three derivatives of chalcones and AzPs to treat basal-like and claudin-low TNBC cell lines. A viability assay was performed to determine the IC50 values of each drug candidate. Proteomic analysis by mass spectrometry was performed to identify the proteins and biological pathways affected by drug treatment. AzP derivatives were found to be more potent than chalcone derivatives and there was no significant differences in cell viability between basal-like and claudin-low cell lines. The proteomic results support previous findings of chalcone and AzP mechanisms in TNBC and also suggest new methods of action for these drug candidates.