The Flavonol Isoquercitrin Promotes Mitochondrial-Dependent Apoptosis in SK-Mel-2 Melanoma Cell via the PI3K/AKT/mTOR Pathway.

Yeong-Seon Won,Jeong-Ho Kim,Hye-Ji Min,Kwon-Il Seo,Hyun-Dong Cho,Seong-Min Hong,Rona Camille M. Lizardo

doi:10.3390/nu12123683

Abstract

Isoquercitrin (IQ), a major flavonol present in Prunus mume fruit, has gained much attention in recent studies because of its superior bioavailability and physiological effects. In this study, the anti-cancer mechanism of IQ against human melanoma, particularly its effect on the mitochondria-mediated apoptosis, was investigated. Treatment with IQ at 25 μM concentration effectively inhibited the proliferation of SK-MEL-2 skin cancer cells while the same concentration did not exhibit cytotoxicity against human keratinocytes HaCaT. Morphological analysis and clonogenic assay also showed that IQ can alter the growth and long-term survival of SK-MEL-2 cells. IQ also induced apoptosis in the melanoma cells as manifested in the nuclear morphology changes, DNA fragmentation, increase in the apoptosis rate (17.69% at 25 μM) and accumulation of sub-G1 cell cycle phase population (19.55% at 25 μM). Western blot analysis revealed the involvement of the mitochondrial apoptosis signaling pathway in the anti-cancer property of IQ. Treatment with IQ resulted in the decrease in the levels of procaspase-8 and -9, and Bcl-2 protein, and an increase in the expression of cleaved PARP and Bax. Moreover, AIF and Endo G protein expression increased, indicating a caspase-independent mitochondrial-mediated apoptosis. The anti-proliferative activity of IQ against SK-MEL-2 can also be attributed to the downregulation of the PI3K/AktmTOR signaling pathway. These findings showed that IQ can be developed into a chemopreventive therapeutic agent against the melanoma cells.

Highlights

Flavonoids are a diverse group of compounds which are ubiquitously distributed among plants, especially in fruits and vegetables
We demonstrated that IQ promotes mitochondrial apoptotic cell death of melanoma cells, the SK-MEL-2, through the the mitochondrial apoptotic cell death of melanoma cells, the SK-MEL-2, through the modulation of the PI3K/AKT/mTOR signaling pathway, without exhibiting cytotoxicity against modulation of the PI3K/AKT/mTOR signaling pathway, without exhibiting cytotoxicity against normal normal skin cells
The results showed that IQ brought about mitochondrial dysfunction and prompted apoptotic cell death in SK-MEL-2 melanoma cells by regulating signaling proteins associated with the mitochondrial apoptosis

Summary

Introduction

Flavonoids are a diverse group of compounds which are ubiquitously distributed among plants, especially in fruits and vegetables. Being a regular and essential part of the human diet, their toxicity is considered as negligible. Their biological activities, benefits to health, as well as pharmacological properties have been an important focus of several studies. Nutrients 2020, 12, 3683 flavonoids, some of the most well-known compounds are the polyphenols under the subgroup flavonol, which include quercetin and its derivatives [1]. A considerable amount of IQ has been found and isolated from Prunus mume [3], known as Japanese apricot, a traditional food and medicinal plant which originated from Southern part of China and was further cultivated in East Asian countries including Taiwan, Japan, and Korea [4]. Different extracts of Prunus mume fruit, including ethyl acetate extract [5] and methanol extract [6], contain IQ, to which the biological activities of these extracts can be largely attributed

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