Concentration-Dependent Pro- and Antitumor Activities of Quercetin in Human Melanoma Spheroids: Comparative Analysis of 2D and 3D Cell Culture Models.

Harald Hundsberger,Nico Jacobi,Christian T Klein,Dominik Schild,Jasmin Schimon,Josef Atzler,Victoria Sarne,Andreas Eger,Anna Stierschneider,Doris Ripper,Hans Peter Weitzenböck,Christoph Wiesner

doi:10.3390/molecules26030717

Harald Hundsberger, Nico Jacobi + Show 10 more

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https://doi.org/10.3390/molecules26030717

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Abstract

Quercetin, a dietary flavonoid found in fruits and vegetables, has been described as a substance with many anti-cancer properties in a variety of preclinical investigations. In the present study, we demonstrate that 2D and 3D melanoma models exhibit not only different sensitivities to quercetin, but also opposite, cancer-promoting effects when metastatic melanoma spheroids are treated with quercetin. Higher concentrations of quercetin reduce melanoma growth in three tested cell lines, whereas low concentrations induce the opposite effect in metastatic melanoma spheroids but not in the non-metastatic cell line. High (>12.5 µM) or low (<6.3 µM) quercetin concentrations decrease or enhance cell viability, spheroid size, and cell proliferation, respectively. Additionally, melanoma cells cultivated in 2D already show significant caspase 3 activity at very low concentrations (>0.4 µM), whereas in 3D spheroids apoptotic cells, caspase 3 activity can only be detected in concentrations ≥12.5 µM. Further, we show that the tumor promoting or repressing effect in the 3D metastatic melanoma spheroids are likely to be elicited by a precisely controlled regulation of Nrf2/ARE-mediated cytoprotective genes, as well as ERK and NF-κB phosphorylation. According to the results obtained here, further studies are needed to better characterize the mechanisms of action underlying the pro- and anti-carcinogenic effects of quercetin on human melanomas.

Highlights

Two-dimensional (2D) cell models grown on plastic surfaces have served the drug screening process well for decades, but it is becoming apparent that 2D cell cultures are unable to accurately aid in the selection of clinically relevant drugs [20]
Three dimensional culture models bridge the gap between 2D cultures and animal models and are ideally suited for phenotypic high-content screening (HCS)
This can be, at least partly, attributed to the fact that 2D cultures do not accurately represent how cells grow or how they are affected by disease and injury in vivo, which often leads to misinterpretations in drug screening [24,25]

Summary

Introduction

Malignant melanomas are severe forms of cancer and are responsible for more than. In the last 50 years, their incidence has risen faster than almost any other cancer worldwide [1]. This increase in incidence is alarming, but what is alarming is the very high propensity of melanomas to metastasize and the inefficiency of the current systemic treatments [2]. Once a melanoma becomes metastatic, the 5-year survival with treatment is approximately 15%–20%, and the median survival ranges from 8 to 12 months [3,4]

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