Investigating the Selectivity of Novel Chalcones for Human Cancer Cells Compared to Non‐Cancerous Human Cell Lines
Authors: Stang Christopher R.T. , Inbody Laura R. , Hickey Mikaela C. , Mohamed Ahmed H. , Hollenbacher Courtney A. , Orahood Cassandra B. , Dick Matt J. , Eichel Amanda M. , Khupse Rahul S. , Schneider Ryan A. 
Published: June 2021

We previously presented data on the anticancer activity of a small library of synthetic flavonoid derivatives against glioblastoma and breast cancer lines in addition to several other human cancer cell lines. This data suggested that the chalcone structural backbone afforded more potent anticancer activity compared to its flavanone counterpart. Using this data, we selected three lead compounds: RK6, RK7, and RK15, to screen for activity against non‐cancerous cells to test for selectivity. Here we present updated IC50 values of these three analogs against MCF7 breast adenocarcinoma cells in addition to the previously reported data on the A‐172 glioblastoma cell line. To determine the selectivity of these lead compounds, RK6, RK7, and RK15 were screened against two non‐cancerous human cell lines: normal human astrocytes (NHA) and normal human mammary epithelial cells (NHME).

The activity of our lead compounds against A‐172 and MCF7 cells were assessed using the XTT cell viability assay to determine respective IC50 values. As reported previously, the IC50 values of our lead compounds in the A‐172 cell line were 20 μM, 22 μM, and 3 μM for RK6, RK7, and RK15 respectively. Updated IC50 values of the compounds in the MCF7 cell line were 19 μM, 99 μM, and 12 μM for RK6, RK7, and RK15.

In order to evaluate the selectivity of the lead compounds for cancerous vs. non‐cancerous cells, we utilized the Vialight cell viability assay to screen the chalcones in NHA and NHME cells. In the NHA cells, the determined IC50 values of RK6, RK7, and RK15 were 47 μM, 52 μM, and >200 μM respectively. IC50 values were 60 μM, >200 μM, and >200 μM for the NHME cells treated with RK6, RK7, and RK15 respectively. This data was used to calculate selectivity indices for our lead compounds against A‐172 cells compared to NHA cells and MCF7 cells compared to NHME cells. For RK6, there was a 2.3 fold selectivity for A‐172 cells and a 3.1 fold selectivity for MCF7 cells compared to their non‐cancerous comparator cells. The selectivity index for RK7 showed a 2.3 fold selectivity for A‐172 compared to the NHA. In these instances, RK6 and RK7 appear to be somewhat selective for cancerous vs. non‐cancerous cell lines. Given the IC50 values >200 μM for RK7 in NHA cells and RK15 in NHA and NHME cells, exact selectivity indices could not be determined. However, in these occurrences, it would appear that the compounds demonstrated a high degree of selectivity for cancerous vs. non‐cancerous cells.

Collectively, these results suggest that our lead chalcone compounds are at least somewhat selective for cancerous vs. non‐cancerous cells. Interestingly, the most potent compound in the A‐172 and MCF7 cells, RK15, demonstrated the highest degree of selectivity. This is intriguing given that recent trends in anticancer drug discovery favor compounds that are selective for cancer cells. These findings may provide some insights into the yet to be elucidated mechanisms of cell death by these novel chalcone derivatives, and will form the basis of future studies.

Support or Funding Information

This work was supported in part by an AFPE Gateway Scholarship for the first author.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.