The Polyphenols α-Mangostin and Nordihydroguaiaretic Acid Induce Oxidative Stress, Cell Cycle Arrest, and Apoptosis in a Cellular Model of Medulloblastoma.

Alberto Rojas-Ochoa,Norma Osnaya,Adela Carrillo-García,José Pedraza-Chaverri,Emilio J Córdova,Marcela Lizano,Nelly Patiño,Alfredo Cruz-Gregorio

doi:10.3390/molecules26237230

Abstract

Medulloblastoma is a common malignant brain tumor in the pediatric age. The current therapeutics present serious collateral effects. Polyphenols α-mangostin and nordihydroguaiaretic acid (NDGA) exert potent antitumoral activity in different cancer models, although their antitumoral effects have not been described in medulloblastoma cells yet. This study aimed to examine the proapoptotic effects of these polyphenols on human medulloblastoma cells. Medulloblastoma cell line Daoy was incubated with increasing concentrations of α-mangostin or NDGA for 24 h. The cell viability was analyzed using crystal violet and trypan blue dyes. Determination of the glutathione (GSH)/glutathione disulfide (GSSG) ratio and levels of carbonylated proteins was performed to evaluate the oxidative stress. Cell cycle progression and induction of cell death by fluorochrome-couple and TUNEL assays were evaluated using flow cytometry assays. Individual treatments with α-mangostin or NDGA decreased the viability of Daoy cells in a dose-dependent manner, inducing G2/M and S-G2/M cell cycle arrest, respectively. Both polyphenols induced cell death and increased oxidative stress. Very interestingly, α-mangostin showed more potent effects than NDGA. Our results indicate that α-mangostin and NDGA exert important cytostatic and cytotoxic effects in the Daoy cell line. These data highlight the potential usefulness of these compounds as an alternative strategy in medulloblastoma treatment.

Highlights

Medulloblastoma, a malignant tumor that develops in the cerebellum, is considered the most frequent cerebral cancer in the pediatric age, accounting for approximately 20% of all primary neoplasia of the central nervous system [1]
We found a dose-dependent reduction in the number of attached cells in α-mangostin and nordihydroguaiaretic acid (NDGA)-treated cell cultures (Figure 1A,B)
Taken togethe4ro,f 15 these results suggest that α-mangostin and NDGA treatments induce oxidative damage to proteins, which might be a possible mechanism of cell death induction by α-mangostin and NDGA in theteDinas,owyhcicehllmliinghe.t be a possible mechanism of cell death induction by α-mangostin and NDGA in the Daoy cell line

Summary

Introduction

Medulloblastoma, a malignant tumor that develops in the cerebellum, is considered the most frequent cerebral cancer in the pediatric age, accounting for approximately 20% of all primary neoplasia of the central nervous system [1]. Recent therapeutic advances have increased the survival rate of patients, a significant number of collateral adverse effects related to these procedures are detrimental to the quality of life of the survivors [2,3]. These side effects include important affectation and deterioration of intellectual function and memory, motor ability deficits, and growth problems [1,2,3]. The discovery of nontoxic therapeutic alternatives against medulloblastoma is still an area of active research

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