Fruit Peel Polyphenolic Extract-Induced Apoptosis in Human Breast Cancer Cells Is Associated with ROS Production and Modulation of p38MAPK/Erk1/2 and the Akt Signaling Pathway

ABSTRACT

Polyphenols represent a large group of natural substances with different biological properties. Currently, polyphenols are well studied due to their free radicals' scavenging and antioxidant activities. However, some studies indicate that polyphenols also exhibit pro-oxidant properties. In this study, the possible involvement of the pro-oxidant activities of fruit polyphenols was investigated in relation to apoptosis induction. To determine the type of cell death induced by fruit polyphenols (Flavine; F7), we assessed a series of assays, including measurements of caspase-7 activation, membrane mitochondrial potential changes, reactive oxygen (ROS) and nitrogen species production, lipid peroxidation, antioxidant enzymes activities, and PARP cleavage. Moreover, the effect of F7 on selected pro- and antisurvival signaling pathways was determined. We demonstrated that fruit polyphenols induced caspase-dependent cell death associated with increased oxidative stress. We also showed fruit polyphenol-mediated release of mitochondrial pro- and antiapoptotic proteins of the Bcl-2 family and modulation activity of the Akt, p38 MAPK, and Erk 1/2 pathways as well as the signaling of ROS-mediated DNA damage. Our data demonstrated that fruit peel polyphenols suppressed breast cancer cell growth through increased intracellular oxidative stress and the activation of p38 MAPK and de-activation of the Erk 1/2 and Akt signaling pathways.

Funding

This study was supported by the Slovak Grant Agency for Science (Grant Nos. 1/0782/15, 1/0018/16, and 1/0753/17) and by SEPO-II (ITMS code: 26220120039).