Abstract
The toxicity of in vitro tested compounds is usually evaluated based on AC50 values calculated from dose-response curves. However, there is a large group of compounds for which a standard four-parametric sigmoid curve fitting may be inappropriate for estimating AC50. In the present study, 22 polyphenol-rich compounds were prioritized from the least to the most toxic based on the total area under and over the dose-response curves (AUOC) in relation to baselines. The studied compounds were ranked across three key cell indicators (mitochondrial membrane potential, cell membrane integrity and nuclear size) in a panel of five cell lines (HepG2, Caco-2, A549, HMEC-1, and 3T3), using a high-content screening (HCS) assay. Regarding AUOC score values, naringin (negative control) was the least toxic phenolic compound. Aronox, spent hop extract and kale leaf extract had very low cytotoxicity with regard to mitochondrial membrane potential and cell membrane integrity, as well as nuclear morphology (nuclear area). Kaempferol (positive control) exerted strong cytotoxic effects on the mitochondrial and nuclear compartments. Extracts from buckthorn bark, walnut husk and hollyhock flower were highly cytotoxic with regard to the mitochondrion and cell membrane, but not the nucleus. We propose an alternative algorithm for the screening of a large number of agents and for identifying those with adverse cellular effects at an early stage of drug discovery, using high content screening analysis. This approach should be recommended for series of compounds producing a non-sigmoidal cell response, and for agents with unknown toxicity or mechanisms of action.
Highlights
Plant polyphenols constitute a highly heterogeneous group of compounds which play a plethora of physiological and ecological roles in plants
The representative dose-response curves obtained from the measurements of mitochondrial membrane potential, with the estimated total area and IC50, are shown in S1 Fig
The present study uses the high-content screening (HCS) assay to prioritize twenty-two polyphenol-rich compounds through five established cell lines, according to their in vitro toxicity profile determined by total area under and over the dose-response curves obtained in the measurements of mitochondrial membrane potential, cell membrane permeability and nuclear area
Summary
Plant polyphenols constitute a highly heterogeneous group of compounds which play a plethora of physiological and ecological roles in plants. A new approach to the study of toxicity of polyphenol-rich compounds. European Regional Development Fund within the framework of the Innovative Economy Operational Programme. The part of the grant was used to pay for the contract with private company Proteon Pharmaceuticals. Proteon Pharmaceuticals and one of the co-authors (Magdalena Lukasiak) were responsible mainly for cell culture and for performing of HCS analysis.
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