TIC10/ONC201—a potential therapeutic in glioblastoma

Karpel‐Massler, Georg; Siegelin, Markus D.

doi:10.21037/tcr.2017.10.51

Cited by 11 publications

(8 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Considering the potent role of metabolism on the inflammatory and functional status of macrophages and the metabolic changes occurring in tumor cells, metabolic reprogramming represents an extremely attractive therapeutic strategy. Recently, the small molecule ONC201/TIC10 has emerged as a very valuable drug in cancer therapy and has been included in clinical trials for glioblastoma [15][16][17][18]. ONC201 works as an antagonist of the dopamine receptor D2 (DRD2) [19] and as a ligand for the mitochondrial ClpP protein [20,21].…”

Section: Introductionmentioning

confidence: 99%

Metabolic and inflammatory reprogramming of macrophages by ONC201 translates in a pro‐inflammatory environment even in presence of glioblastoma cells

et al. 2021

View full text Add to dashboard Cite

Tumor-associated macrophages facilitate tumor progression and resistance to therapy. Their capacity for metabolic and inflammatory reprogramming represents an attractive therapeutic target. ONC201/TIC10 is an anticancer molecule that antagonizes the dopamine receptor D2 and affects mitochondria integrity in tumor cells. We examined whether ONC201 induces a metabolic and pro-inflammatory switch in primary human monocyte-derived macrophages that reactivates their antitumor activities, thus enhancing the onco-toxicity of ONC201. Contrary to glioblastoma cells, macrophages exhibited a low ratio of dopamine receptors D2/D5 gene expression and were resistant to ONC201 cytotoxicity. Macrophages responded to ONC201 with a severe loss of mitochondria integrity, a switch to glycolytic ATP production, alterations in glutamate transport, and a shift towards a pro-inflammatory profile. Treatment of macrophages-glioblastoma cells co-cultures with ONC201 induced similar alterations in glutamatergic and inflammatory gene expression profiles of macrophages. It induced as well metabolic changes and a proinflammatory switch of the co-culture milieu. However, these changes did not translate into increased onco-toxicity. This study provides the first evidence that ONC201 affects macrophage immunometabolism and leads to a pro-inflammatory tumor environment. This speaks in favor of implementing ONC201 in combinatorial therapies and warrants further investigation of the mechanisms of action of ONC201 in macrophages and other immune cells.

show abstract

Section: Introductionmentioning

confidence: 99%

Metabolic and inflammatory reprogramming of macrophages by ONC201 translates in a pro‐inflammatory environment even in presence of glioblastoma cells

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Importantly, ONC201, a TRAIL-inducing compound, has proven well tolerated, capable of passing the blood–brain barrier, and has shown preliminary signs of efficacy in 17 patients with aggressive and recurrent GBM in a phase 2 clinical trial [ 41 ]. These results are very encouraging and tests in an expanded cohort of GBM patients are ongoing [ 42 , 43 ]. Given this promising therapeutic impact of the TRAIL receptor/ligand system for GBM treatment, more clinical trials are expected to launch in the future to test TRAIL-based combinatory modalities for treating GBM.…”

Section: Targeting the Trail Receptor/ligand System: An Emerging Opportunity For Gbm Treatmentmentioning

confidence: 99%

Overcoming TRAIL Resistance for Glioblastoma Treatment

et al. 2021

View full text Add to dashboard Cite

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) shows a promising therapeutic potential in cancer treatment as it exclusively causes apoptosis in a broad spectrum of cancer cells through triggering the extrinsic apoptosis pathway via binding to cognate death receptors, with negligible toxicity in normal cells. However, most cancers, including glioblastoma multiforme (GBM), display TRAIL resistance, hindering its application in clinical practice. Recent studies have unraveled novel mechanisms in regulating TRAIL-induced apoptosis in GBM and sought effective combinatorial modalities to sensitize GBM to TRAIL treatment, establishing pre-clinical foundations and the reasonable expectation that the TRAIL/TRAIL death receptor axis could be harnessed to treat GBM. In this review, we will revisit the status quo of the mechanisms of TRAIL resistance and emerging strategies for sensitizing GBM to TRAIL-induced apoptosis and also discuss opportunities of TRAIL-based combinatorial therapies in future clinical use for GBM treatment.

show abstract

“…Earlier, the antitumor effects of several small molecules had been investigated against A2058 cells, particularly the TRAIL (TNF-related apoptosis-inducing ligand)-inducing compound TIC10 [ 14 ]. Possible antitumor effects can be linked to TIC10: (i) it can selectively antagonize dopamine receptor D2, (ii) inactivate the intracellular Akt/ERK pathway, (iii) induce an ER stress response and (iv) upregulate the expression of TNF-related apoptosis-inducing ligand (TRAIL) [ 15 , 16 , 17 ]. TRAIL can initiate extrinsic apoptosis through binding its receptors (death receptor 4 (DR4) and death receptor 5 (DR5)) [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

The Synergistic Activity of Bortezomib and TIC10 against A2058 Melanoma Cells

et al. 2021

View full text Add to dashboard Cite

Combination antitumor treatments are essential parts of modern tumor therapy as—compared to monotherapies—(i) they are more effective; (ii) the dose of the compounds can be reduced; and (iii) therefore the side effects are improved. Our research group previously demonstrated the antitumor character of bortezomib (BOZ) in A2058 melanoma cells. Unfortunately, dose-related side effects are common during BOZ therapy, which could be prevented by reducing the dose of BOZ. This study aimed to characterize synergistic combinations of BOZ with a TRAIL (TNF-related apoptosis-inducing ligand) -inducing compound (TIC10), where the doses can be cut down but the efficacy is preserved. Endpoint cell viability assays were performed on A2058 cells, and synergism of BOZ and TIC10 was observed after 72 h. Synergism was further validated in a real-time impedimetric assay, and our results showed that BOZ-treated melanoma cells survived the treatment, an effect not registered in the co-treatments. Treatment with the combinations resulted in increased apoptosis, which was not accompanied by enhanced LDH release. Nevertheless, the expression of death receptor 5 (DR5) was increased on the cell surface without transcriptional regulation. In summary, our findings support the theory that the application of BOZ and TIC10 in combination could provide higher efficacy in vitro.

show abstract

TIC10/ONC201—a potential therapeutic in glioblastoma

Cited by 11 publications

References 7 publications

Metabolic and inflammatory reprogramming of macrophages by ONC201 translates in a pro‐inflammatory environment even in presence of glioblastoma cells

Metabolic and inflammatory reprogramming of macrophages by ONC201 translates in a pro‐inflammatory environment even in presence of glioblastoma cells

Overcoming TRAIL Resistance for Glioblastoma Treatment

The Synergistic Activity of Bortezomib and TIC10 against A2058 Melanoma Cells

Contact Info

Product

Resources

About