Auranofin and Cold Atmospheric Plasma Synergize to Trigger Distinct Cell Death Mechanisms and Immunogenic Responses in Glioblastoma
Targeting the redox balance of malignant cells via the delivery of high oxidative stress unlocks a potential therapeutic strategy against glioblastoma (GBM). We investigated a novel reactive oxygen species (ROS)-inducing combination treatment strategy, by increasing exogenous ROS via cold atmospheri...
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2021
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oai:doaj.org-article:fb742ef891dc479883b58c28c9e1e5612021-11-25T17:09:18ZAuranofin and Cold Atmospheric Plasma Synergize to Trigger Distinct Cell Death Mechanisms and Immunogenic Responses in Glioblastoma10.3390/cells101129362073-4409https://doaj.org/article/fb742ef891dc479883b58c28c9e1e5612021-10-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/2936https://doaj.org/toc/2073-4409Targeting the redox balance of malignant cells via the delivery of high oxidative stress unlocks a potential therapeutic strategy against glioblastoma (GBM). We investigated a novel reactive oxygen species (ROS)-inducing combination treatment strategy, by increasing exogenous ROS via cold atmospheric plasma and inhibiting the endogenous protective antioxidant system via auranofin (AF), a thioredoxin reductase 1 (TrxR) inhibitor. The sequential combination treatment of AF and cold atmospheric plasma-treated PBS (pPBS), or AF and direct plasma application, resulted in a synergistic response in 2D and 3D GBM cell cultures, respectively. Differences in the baseline protein levels related to the antioxidant systems explained the cell-line-dependent sensitivity towards the combination treatment. The highest decrease of TrxR activity and GSH levels was observed after combination treatment of AF and pPBS when compared to AF and pPBS monotherapies. This combination also led to the highest accumulation of intracellular ROS. We confirmed a ROS-mediated response to the combination of AF and pPBS, which was able to induce distinct cell death mechanisms. On the one hand, an increase in caspase-3/7 activity, with an increase in the proportion of annexin V positive cells, indicates the induction of apoptosis in the GBM cells. On the other hand, lipid peroxidation and inhibition of cell death through an iron chelator suggest the involvement of ferroptosis in the GBM cell lines. Both cell death mechanisms induced by the combination of AF and pPBS resulted in a significant increase in danger signals (ecto-calreticulin, ATP and HMGB1) and dendritic cell maturation, indicating a potential increase in immunogenicity, although the phagocytotic capacity of dendritic cells was inhibited by AF. In vivo, sequential combination treatment of AF and cold atmospheric plasma both reduced tumor growth kinetics and prolonged survival in GBM-bearing mice. Thus, our study provides a novel therapeutic strategy for GBM to enhance the efficacy of oxidative stress-inducing therapy through a combination of AF and cold atmospheric plasma.Jinthe Van LoenhoutLaurie Freire BoullosaDelphine QuatannensJorrit De WaeleCéline MerlinHilde LambrechtsHo Wa LauChristophe HermansAbraham LinFilip LardonMarc PeetersAnnemie BogaertsEvelien SmitsChristophe DebenMDPI AGarticleoxidative stressauranofincold atmospheric plasmaglioblastomacancer cell deathBiology (General)QH301-705.5ENCells, Vol 10, Iss 2936, p 2936 (2021) |
| institution |
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| collection |
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| language |
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| topic |
oxidative stress auranofin cold atmospheric plasma glioblastoma cancer cell death Biology (General) QH301-705.5 |
| spellingShingle |
oxidative stress auranofin cold atmospheric plasma glioblastoma cancer cell death Biology (General) QH301-705.5 Jinthe Van Loenhout Laurie Freire Boullosa Delphine Quatannens Jorrit De Waele Céline Merlin Hilde Lambrechts Ho Wa Lau Christophe Hermans Abraham Lin Filip Lardon Marc Peeters Annemie Bogaerts Evelien Smits Christophe Deben Auranofin and Cold Atmospheric Plasma Synergize to Trigger Distinct Cell Death Mechanisms and Immunogenic Responses in Glioblastoma |
| description |
Targeting the redox balance of malignant cells via the delivery of high oxidative stress unlocks a potential therapeutic strategy against glioblastoma (GBM). We investigated a novel reactive oxygen species (ROS)-inducing combination treatment strategy, by increasing exogenous ROS via cold atmospheric plasma and inhibiting the endogenous protective antioxidant system via auranofin (AF), a thioredoxin reductase 1 (TrxR) inhibitor. The sequential combination treatment of AF and cold atmospheric plasma-treated PBS (pPBS), or AF and direct plasma application, resulted in a synergistic response in 2D and 3D GBM cell cultures, respectively. Differences in the baseline protein levels related to the antioxidant systems explained the cell-line-dependent sensitivity towards the combination treatment. The highest decrease of TrxR activity and GSH levels was observed after combination treatment of AF and pPBS when compared to AF and pPBS monotherapies. This combination also led to the highest accumulation of intracellular ROS. We confirmed a ROS-mediated response to the combination of AF and pPBS, which was able to induce distinct cell death mechanisms. On the one hand, an increase in caspase-3/7 activity, with an increase in the proportion of annexin V positive cells, indicates the induction of apoptosis in the GBM cells. On the other hand, lipid peroxidation and inhibition of cell death through an iron chelator suggest the involvement of ferroptosis in the GBM cell lines. Both cell death mechanisms induced by the combination of AF and pPBS resulted in a significant increase in danger signals (ecto-calreticulin, ATP and HMGB1) and dendritic cell maturation, indicating a potential increase in immunogenicity, although the phagocytotic capacity of dendritic cells was inhibited by AF. In vivo, sequential combination treatment of AF and cold atmospheric plasma both reduced tumor growth kinetics and prolonged survival in GBM-bearing mice. Thus, our study provides a novel therapeutic strategy for GBM to enhance the efficacy of oxidative stress-inducing therapy through a combination of AF and cold atmospheric plasma. |
| format |
article |
| author |
Jinthe Van Loenhout Laurie Freire Boullosa Delphine Quatannens Jorrit De Waele Céline Merlin Hilde Lambrechts Ho Wa Lau Christophe Hermans Abraham Lin Filip Lardon Marc Peeters Annemie Bogaerts Evelien Smits Christophe Deben |
| author_facet |
Jinthe Van Loenhout Laurie Freire Boullosa Delphine Quatannens Jorrit De Waele Céline Merlin Hilde Lambrechts Ho Wa Lau Christophe Hermans Abraham Lin Filip Lardon Marc Peeters Annemie Bogaerts Evelien Smits Christophe Deben |
| author_sort |
Jinthe Van Loenhout |
| title |
Auranofin and Cold Atmospheric Plasma Synergize to Trigger Distinct Cell Death Mechanisms and Immunogenic Responses in Glioblastoma |
| title_short |
Auranofin and Cold Atmospheric Plasma Synergize to Trigger Distinct Cell Death Mechanisms and Immunogenic Responses in Glioblastoma |
| title_full |
Auranofin and Cold Atmospheric Plasma Synergize to Trigger Distinct Cell Death Mechanisms and Immunogenic Responses in Glioblastoma |
| title_fullStr |
Auranofin and Cold Atmospheric Plasma Synergize to Trigger Distinct Cell Death Mechanisms and Immunogenic Responses in Glioblastoma |
| title_full_unstemmed |
Auranofin and Cold Atmospheric Plasma Synergize to Trigger Distinct Cell Death Mechanisms and Immunogenic Responses in Glioblastoma |
| title_sort |
auranofin and cold atmospheric plasma synergize to trigger distinct cell death mechanisms and immunogenic responses in glioblastoma |
| publisher |
MDPI AG |
| publishDate |
2021 |
| url |
https://doaj.org/article/fb742ef891dc479883b58c28c9e1e561 |
| work_keys_str_mv |
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