Investigation of the Role of Dietary Flavonoids on Cell Death: Evidence to Support a Non-Classical Apoptotic Mechanism

Flavonoids are polyphenolic compounds widely distributed in plants and have been shown to be cytotoxic to cancer cells. Our lab has previously shown that some flavonoids are able to induce cytotoxicity and inhibit caspase activity in human breast cancer cell lines. The goal of our study was to identify the specific molecular pathways required for flavonoid-induced cytotoxicity. MDA-MB-231 cells, mouse embryonic fibroblasts (MEFs) lacking caspase 3 and 7, and primary baby mouse kidney epithelial cells lacking Bax and Bak were cultured. Flavonoid-treated MDA-MB-231 cells showed cytochrome c release. We detected caspase 3 activation and PARP cleavage in MDA-MB-231 cells after treatment with some flavonoids. Quercetin did not activate caspase 3 but induced PARP cleavage at early time points. These results suggested that cytotoxicity in breast cancer cells involved caspase-independent mechanisms. To further test this, we treated wild-type and caspase-deficient MEFs with various flavonoids and performed cell death assays. Flavonoid-induced cell death in caspase-deficient MEFs and Bax/Bak deficient cell lines was similar to wild-type cells. Taken together, our results suggested that flavonoids induce cell death through caspase-independent mechanisms