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Chrysin and silibinin sensitize human glioblastoma cells for arsenic trioxide
Michael Gülden1, Daniel Appel1, Malin Syska1
1Institute of Toxicology and Pharmacology for Natural Scientists, University Medical School Schleswig-Holstein, Campus Kiel, Brunswiker Str. 10, 24105 Kiel, Germany.
Abstract:
Arsenic trioxide (ATO) is highly efficient in treating acute promyelocytic leukemia. Other malignancies, however, are often less sensitive. Searching for compounds sensitizing arsenic resistant tumours for ATO the plant polyphenols, chrysin and silibinin, and the ATP binding cassette (ABC) transporter inhibitor MK-571, respectively, were investigated in human glioblastoma A-172 cells. The sensitivity of A-172 cells to ATO was characterized by a median cytotoxic concentration of 6 μM ATO. Subcytotoxic concentrations of chrysin, silibinin and MK-571, respectively, remarkably increased the sensitivity of the cells to ATO by factors of 4-6. Isobolographic analysis revealed synergistic interaction of the polyphenols and MK-571, respectively, with ATO. Sensitization by chrysin was associated with depletion of cellular glutathione and increased accumulation of arsenic. In contrast, silibinin and also MK-571 increased the accumulation of arsenic more strongly but without affecting the glutathione level. The increase of arsenic accumulation could be attributed to a decreased rate of arsenic export and, additionally, in the case of silibinin and MK-571, to an increasing amount of irreversibly accumulated arsenic. Direct interaction with ABC transporters stimulating export of glutathione and inhibiting export of arsenic, respectively, are discussed as likely mechanisms of the sensitizing activity of chrysin and silibinin.
Insights
Plant compounds chrysin and silibinin, and MK-571, enhance arsenic trioxide (ATO) cancer treatment. These agents sensitize glioblastoma cells to ATO, showing synergistic effects and increasing arsenic accumulation for improved efficacy.
Area of Science:
- Oncology
- Pharmacology
- Biochemistry
Background:
- Arsenic trioxide (ATO) is effective against acute promyelocytic leukemia but less so for other cancers.
- Glioblastoma exhibits resistance to ATO, necessitating strategies to enhance its efficacy.
- Plant-derived polyphenols and transporter inhibitors are explored for overcoming drug resistance.
Purpose of the Study:
- To investigate the sensitizing effects of chrysin, silibinin, and MK-571 on arsenic trioxide (ATO)-resistant human glioblastoma cells.
- To elucidate the mechanisms underlying the sensitization, including effects on arsenic accumulation and cellular glutathione levels.
- To assess the synergistic interactions between ATO and the tested compounds using isobolographic analysis.
Main Methods:
- Human glioblastoma A-172 cells were treated with ATO alone and in combination with subcytotoxic concentrations of chrysin, silibinin, or MK-571.
- Cytotoxicity was assessed, and median cytotoxic concentrations were determined.
- Isobolographic analysis was employed to evaluate drug interactions.
- Cellular arsenic accumulation and glutathione levels were measured.
Main Results:
- Chrysin, silibinin, and MK-571 significantly increased ATO sensitivity in glioblastoma cells by 4-6 fold.
- Isobolographic analysis indicated synergistic interactions between ATO and each sensitizing compound.
- Chrysin reduced cellular glutathione and increased arsenic accumulation.
- Silibinin and MK-571 strongly increased arsenic accumulation without affecting glutathione levels, potentially via reduced arsenic export.
Conclusions:
- Chrysin, silibinin, and MK-571 act synergistically with arsenic trioxide to enhance its efficacy against glioblastoma cells.
- The sensitizing mechanisms involve altered arsenic transport and, for chrysin, glutathione depletion.
- These findings suggest potential therapeutic strategies for overcoming ATO resistance in certain cancers.
