Ultra-Low Dose Amiodarone Reduces Tumor Growth and Angiogenesis

Steinberg, Eliana; Fluksman, Arnon; Zemmour, Chalom; Karsch-Bluman, Adi; Brill-Karniely, Yifat; Tischenko, Katerina; Birsner, Amy E.; D’Amato, Robert J.; Benny, Ofra

doi:10.21203/rs.3.rs-37463/v1

Cited by 3 publications

(2 citation statements)

References 39 publications

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“…This resulted in 11 FDA‐approved candidates from the three disease‐associated gene signature reversion results (two from DESeq2 and four from transfer learning, including three shared between DESeq2 and limma and two shared between all three). From those, simvastatin, floxuridine, vardenafil, amiodarone, and thioridazine had already been investigated for the treatment of GBM with in vitro and/or in vivo studies [ 65 , 66 , 67 , 68 , 69 , 70 , 71 ]. We did not further consider bivalirudin because there was evidence in DrugBank that this drug was unlikely to pass the blood–brain barrier.…”

Section: Resultsmentioning

confidence: 99%

Signature reversion of three disease‐associated gene signatures prioritizes cancer drug repurposing candidates

Fisher,

Wilk,

Oza

et al. 2024

FEBS Open Bio

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Drug repurposing is promising because approving a drug for a new indication requires fewer resources than approving a new drug. Signature reversion detects drug perturbations most inversely related to the disease‐associated gene signature to identify drugs that may reverse that signature. We assessed the performance and biological relevance of three approaches for constructing disease‐associated gene signatures (i.e., limma, DESeq2, and MultiPLIER) and prioritized the resulting drug repurposing candidates for four low‐survival human cancers. Our results were enriched for candidates that had been used in clinical trials or performed well in the PRISM drug screen. Additionally, we found that pamidronate and nimodipine, drugs predicted to be efficacious against the brain tumor glioblastoma (GBM), inhibited the growth of a GBM cell line and cells isolated from a patient‐derived xenograft (PDX). Our results demonstrate that by applying multiple disease‐associated gene signature methods, we prioritized several drug repurposing candidates for low‐survival cancers.

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Section: Resultsmentioning

confidence: 99%

Signature reversion of three disease‐associated gene signatures prioritizes cancer drug repurposing candidates

Fisher,

Wilk,

Oza

et al. 2024

FEBS Open Bio

View full text Add to dashboard Cite

show abstract

“…From those, simvastatin, floxuridine, vardenafil, amiodarone, and thioridazine had already been investigated for the treatment of GBM with in vitro and/or in vivo studies. [64][65][66][67][68][69][70] We did not further consider bivalirudin because there was evidence in DrugBank that this drug was unlikely to pass the blood-brain barrier. Vemurafenib was also excluded from further testing because of a basket clinical trial for gliomas with BRAFV600 mutation.…”

Section: Additional Validation Of Prioritized Gbm Drug Repurposing Ca...mentioning

confidence: 99%

Signature reversion of three disease-associated gene signatures prioritizes cancer drug repurposing candidates

Fisher

Wilk

Oza

et al. 2023

Preprint

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Drug repurposing is promising because approving a drug for a new indication requires fewer resources than approving a new drug. Signature reversion detects drug perturbations most inversely related to the disease-associated gene signature to identify drugs that may reverse that signature. We assessed the performance and biological relevance of three approaches for constructing disease-associated gene signatures (i.e, limma, DESeq2, and MultiPLIER) and prioritized the resulting drug repurposing candidates for four low-survival human cancers. Our results were enriched for candidates that had been used in clinical trials or performed well in the PRISM drug screen. Additionally, we found that pamidronate and nimodipine, drugs predicted to be efficacious against the brain tumor glioblastoma (GBM), inhibited the growth of a GBM cell line and cells isolated from a patient derived xenograft (PDX). Our results demonstrate that by applying multiple disease-associated gene signature methods, we prioritized several drug repurposing candidates for low-survival cancers.

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Assessing hepatoprotective effects of antioxidants on amiodarone-induced cytotoxicity in human hepatoma HepaRG cell line

Filimonova

Rogovskaya

Beltyukov

et al. 2021

MES

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Effective therapy of amiodarone-induced hepatotoxicity requires studying the mechanisms of the toxic effects of amiodarone on hepatocytes and assessing the potential impact of hepotoprotective agents. The study was aimed to assess hepatoprotective effects of antioxidants on the amiodarone-induced hepatotoxicity with the use of immortalized human hepatoma cells of the HepaRG cell line. Cell viability was evaluated upon exposure to amiodarone and in the mixture with vitamin Е, N-acetylcysteine and S-adenosylmethionine by impedance measurement; the levels of some hepatotoxicity biomarkers were defined using the Luminex xMAP technology. As a result of the research, the dose-dependent toxic effects of amiodarone were established. The IC50 value of amiodarone in the HepaRG cell line was 3.5 μМ. It is shown that cytotoxic effects decrease and the IC50 value increases in the presence of vitamin Е, N-acetylcysteine and S-adenosylmethionine. Amiodarone reduces the activity of cell cycle regulators: AKT, JNK kinases, and p53 protein. Exposure to amiodarone results in reduced intracellular ATP levels and the release of intracellular enzymes (malate dehydrogenase 1, glutathione S-transferase, sorbitol dehydrogenase, 5'-nucleotidase) into conditioned medium, indicating the necrotic cell death. Thus, vitamin Е, S-adenosylmethionine and N-acetylcysteine reduce amiodarone cytotoxicity in the model of amiodarone-induced damage to hepatocytes and can be considered as hepatoprotective agents in case of the need to protect liver against the hepatotoxic effects of amiodarone.

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Ultra-Low Dose Amiodarone Reduces Tumor Growth and Angiogenesis

Cited by 3 publications

References 39 publications

Signature reversion of three disease‐associated gene signatures prioritizes cancer drug repurposing candidates

Signature reversion of three disease‐associated gene signatures prioritizes cancer drug repurposing candidates

Signature reversion of three disease-associated gene signatures prioritizes cancer drug repurposing candidates

Assessing hepatoprotective effects of antioxidants on amiodarone-induced cytotoxicity in human hepatoma HepaRG cell line

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