Chrysin and silibinin sensitize human glioblastoma cells for arsenic trioxide

Gülden, Michael; Appel, Daniel; Syska, Malin; Uecker, Stephanie; Wages, Franziska; Seibert, Hasso

doi:10.1016/j.fct.2017.04.035

Cited by 19 publications

(7 citation statements)

References 54 publications

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“…Silibinin–etoposide, silibinin–ATO, and chrysin–ATO combinations reduce GBM cell viability in vitro; silibinin and ATO, in particular, induce apoptosis and inhibit cell migration and metabolism [ 47 ]. However, the mechanisms of action of silibinin–etoposide and chrystin–ATO combinations remain largely unclarified [ 35 , 46 ].…”

Section: Mechanisms Of Gbm and Synergistic Flavonoid-chemotherapeutic Effectsmentioning

confidence: 99%

Flavonoids Synergistically Enhance the Anti-Glioblastoma Effects of Chemotherapeutic Drugs

et al. 2021

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Flavonoids are polyphenolic plant secondary metabolites with pleiotropic biological properties, including anti-cancer activities. These natural compounds have potential utility in glioblastoma (GBM), a malignant central nervous system tumor derived from astrocytes. Conventional GBM treatment modalities such as chemotherapy, radiation therapy, and surgical tumor resection are beneficial but limited by extensive tumor invasion and drug/radiation resistance. Therefore, dietary flavonoids—with demonstrated anti-GBM properties in preclinical research—are potential alternative therapies. This review explores the synergistic enhancement of the anti-GBM effects of conventional chemotherapeutic drugs by flavonoids. Primary studies published between 2011 and 2021 on flavonoid–chemotherapeutic synergy in GBM were obtained from PubMed. These studies demonstrate that flavonoids such as chrysin, epigallocatechin-3-gallate (EGCG), formononetin, hispidulin, icariin, quercetin, rutin, and silibinin synergistically enhance the effects of canonical chemotherapeutics. These beneficial effects are mediated by the modulation of intracellular signaling mechanisms related to apoptosis, proliferation, autophagy, motility, and chemoresistance. In this light, flavonoids hold promise in improving current therapeutic strategies and ultimately overcoming GBM drug resistance. However, despite positive preclinical results, further investigations are necessary before the commencement of clinical trials. Key considerations include the bioavailability, blood–brain barrier (BBB) permeability, and safety of flavonoids; optimal dosages of flavonoids and chemotherapeutics; drug delivery platforms; and the potential for adverse interactions.

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Section: Mechanisms Of Gbm and Synergistic Flavonoid-chemotherapeutic Effectsmentioning

confidence: 99%

Flavonoids Synergistically Enhance the Anti-Glioblastoma Effects of Chemotherapeutic Drugs

et al. 2021

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“…Silibinin sensitization did not affect GSH levels but doubled the accumulation of arsenic. Accumulation of arsenic may be related to the inhibition of the ATP-binding cassette transporter and multidrug resistance-associated protein, which would slow down the excretion of arsenic and increase its accumulation [ 65 ]. It was also found that butylthionine sulfoxide, an inhibitor of GSH biosynthesis, could deplete intracellular GSH and had a synergistic effect with arsenic trioxide in the C6 cell line [ 66 ].…”

Section: Enhanced Anti-glioma Effect Of Arsenic Trioxide Combined Witmentioning

confidence: 99%

Arsenic trioxide as a novel anti-glioma drug: a review

Fang

Zhang

2020

Cell Mol Biol Lett

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Arsenic trioxide has shown a strong anti-tumor effect with little toxicity when used in the treatment of acute promyelocytic leukemia (APL). An effect on glioma has also been shown. Its mechanisms include regulation of apoptosis and autophagy; promotion of the intracellular production of reactive oxygen species, causing oxidative damage; and inhibition of tumor stem cells. However, glioma cells and tissues from other sources show different responses to arsenic trioxide. Researchers are working to enhance its efficacy in anti-glioma treatments and reducing any adverse reactions. Here, we review recent research on the efficacy and mechanisms of action of arsenic trioxide in the treatment of gliomas to provide guidance for future studies.

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“…It has been widely used to treat and prevent many types of hepatobiliary disorders including alcoholic liver disease, nonalcoholic fatty liver disease, and mushroom poisoning 12,13 . Moreover, silibinin not only exert potent inhibitory effect on various types of cancer cells, such as breast cancer cells, prostate cancer cells, and glioma cells 7,14,15 , but also sensitizes glioma cells to TMZ, TRAIL or arsenic trioxide treatment and prevents hepatocyte injury induced by chemotherapy agent cisplatin [16][17][18][19] . Although silibinin could induce autophagic death in cancer cells 7,8 , the biochemical events downstream silibinin-induced autophagy remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Autophagy activated by silibinin contributes to glioma cell death via induction of oxidative stress-mediated BNIP3-dependent nuclear translocation of AIF

Wang

et al. 2020

Cell Death Dis

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Induction of lethal autophagy has become a strategy to eliminate glioma cells, but it remains elusive whether autophagy contributes to cell death via causing mitochondria damage and nuclear translocation of apoptosis inducing factor (AIF). In this study, we find that silibinin induces AIF translocation from mitochondria to nuclei in glioma cells in vitro and in vivo, which is accompanied with autophagy activation. In vitro studies reveal that blocking autophagy with 3MA, bafilomycin A1 or by knocking down ATG5 with SiRNA inhibits silibinin-induced mitochondrial accumulation of superoxide, AIF translocation from mitochondria to nuclei and glioma cell death. Mechanistically, silibinin activates autophagy through depleting ATP by suppressing glycolysis. Then, autophagy improves intracellular H 2 O 2 via promoting p53-mediated depletion of GSH and cysteine and downregulation of xCT. The increased H 2 O 2 promotes silibinin-induced BNIP3 upregulation and translocation to mitochondria. Knockdown of BNIP3 with SiRNA inhibits silibinin-induced mitochondrial depolarization, accumulation of mitochondrial superoxide, and AIF translocation from mitochondria to nuclei, as well as prevents glioma cell death. Furthermore, we find that the improved H 2 O 2 reinforces silibinin-induced glycolysis dysfunction. Collectively, autophagy contributes to silibinininduced glioma cell death via promotion of oxidative stress-mediated BNIP3-dependent nuclear translocation of AIF.

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Chrysin and silibinin sensitize human glioblastoma cells for arsenic trioxide

Cited by 19 publications

References 54 publications

Flavonoids Synergistically Enhance the Anti-Glioblastoma Effects of Chemotherapeutic Drugs

Flavonoids Synergistically Enhance the Anti-Glioblastoma Effects of Chemotherapeutic Drugs

Arsenic trioxide as a novel anti-glioma drug: a review

Autophagy activated by silibinin contributes to glioma cell death via induction of oxidative stress-mediated BNIP3-dependent nuclear translocation of AIF

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