Thalidomide–A Notorious Sedative to a Wonder Anticancer Drug

Zhou, Shuang; Wang, Fengfei; Hsieh, Tze Chen; Wu, Joseph M.; Wu, Erxi

doi:10.2174/09298673113209990198

Cited by 69 publications

(44 citation statements)

References 83 publications

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“…In addition, several lines of evidence indicate that TNF-α signaling exacerbates amyloidogenesis, including up-regulation of BACE1 expression (see the TNF-α review paper in this Special Edition). Thalidomide is a very potent TNF-α inhibitor and immunomodulator used in the treatment of oncologic [13, 14], cardiovascular [15], dermatologic [16], and neurodegenerative [17] conditions. This prompted us to test the potential of thalidomide on APP23 mice, a transgenic model of AD, which resulted in a significant reduction of Aβ production (unpublished data).…”

Section: Introductionmentioning

confidence: 99%

Poor Safety and Tolerability Hamper Reaching a Potentially Therapeutic Dose in the Use of Thalidomide for Alzheimer’s Disease: Results from a Double-Blind, Placebo-Controlled Trial

Decourt

Drumm-Gurnee

Wilson

et al. 2017

CAR

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Introduction To date there is no cure for Alzheimer's disease (AD). After amyloid beta immunotherapies have failed to meet primary endpoints of slowing cognitive decline in AD subjects, the inhibition of the beta-secretase BACE1 appears as a promising therapeutic approach. Pre-clinical data obtained in APP23 mice suggested that the anti-cancer drug thalidomide decreases brainBACE1 and Aβ levels. This prompted us to develop an NIH-supported Phase IIa clinical trial to test the potential of thalidomide for AD. We hypothesized that thalidomide can decrease or stabilize brain amyloid deposits, which would result in slower cognitive decline in drug- versus placebo-treated subjects. Methods This was a 24-week, randomized, double-blind, placebo-controlled, parallel group study with escalating dose regimen of thalidomide with a target dose of 400mg daily in patients with mild to moderate AD. The primary outcome measures were tolerability and cognitive performance assessed by a battery of tests. Results A total of 185 subjects have been pre-screened, out of which25 were randomized. Mean age of the sample at baseline was 73.64 (±7.20) years; mean education was 14.24 (±2.3) years; mean MMSE score was 21.00 (±5.32); and mean GDS score was 2.76 (±2.28).Among the 25 participants, 14 (56%) terminated early due to adverse events, dramatically decreasing the power of the study. In addition, those who completed the study (44%) never reached the estimated therapeutic dose of 400 mg/day thalidomide because of reported adverse events. The cognitive data showed no difference between the treated and placebo groups at the end of the trial. Conclusion This study demonstrates AD patients have poor tolerability for thalidomide, and are unable to reach a therapeutic dose felt to be sufficient to have effects on BACE1. Because of poor tolerability, this study failed to demonstrate a beneficial effect on cognition.

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Section: Introductionmentioning

confidence: 99%

Poor Safety and Tolerability Hamper Reaching a Potentially Therapeutic Dose in the Use of Thalidomide for Alzheimer’s Disease: Results from a Double-Blind, Placebo-Controlled Trial

Decourt

Drumm-Gurnee

Wilson

et al. 2017

CAR

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“…It interacts with FGF-2 and heparin sulfate simultaneously to form a ternary complex and inhibits angiogenesis by binding with FGF-2/HS at the cell surface. It also obstructs the dimerization of bFGF [209,210].…”

Section: Therapeutic Inhibition Of Fgfs-fgfrsmentioning

confidence: 99%

Fibroblast Growth Factors and their Emerging Cancer-Related Aspects

Khalid¹,

Javaid²

2016

J Cancer Sci Ther

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“…The malformations include mainly congenital heart disease, and limb deformities in addition to malformations of the inner and outer ear, and ocular abnormalities. The exact mechanism by which Thalidomide triggers these malformations is still elusive, despite numerous publications on its effect on cell proliferation, DNA replication, transcription, synthesis and/or function of growth factors, synthesis and/or function of integrins, angiogenesis, chondrogenesis, and cell death 16, 18–20 . The only documented molecular target for Thalidomide is the cereblon protein (CRBN), a substrate receptor of the E3 ubiquitin ligase complex that plays a major role in targeted proteasomal degradation of proteins.…”

Section: Introductionmentioning

confidence: 99%

A HAND to TBX5 Explains the Link Between Thalidomide and Cardiac Diseases

Khalil

Tanos

El-Hachem

et al. 2017

Sci Rep

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Congenital heart disease is the leading cause of death in the first year of life. Mutations only in few genes have been linked to some cases of CHD. Thalidomide was used by pregnant women for morning sickness but was removed from the market because it caused severe malformations including CHDs. We used both in silico docking software, and in vitro molecular and biochemical methods to document a novel interaction involving Thalidomide, TBX5, and HAND2. Thalidomide binds readily to TBX5 through amino acids R81, R82, and K226 all implicated in DNA binding. It reduces TBX5 binding to DNA by 40%, and suppresses TBX5 mediated activation of the NPPA and VEGF promoters by 70%. We documented a novel interaction between TBX5 and HAND2, and showed that a p.G202V HAND2 variant associated with CHD and coronary artery diseases found in a large Lebanese family with high consanguinity, drastically inhibited this interaction by 90%. Similarly, thalidomide inhibited the TBX5/HAND2 physical interaction, and the in silico docking revealed that the same amino acids involved in the interaction of TBX5 with DNA are also involved in its binding to HAND2. Our results establish a HAND2/TBX5 pathway implicated in heart development and diseases.

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Thalidomide–A Notorious Sedative to a Wonder Anticancer Drug

Cited by 69 publications

References 83 publications

Poor Safety and Tolerability Hamper Reaching a Potentially Therapeutic Dose in the Use of Thalidomide for Alzheimer’s Disease: Results from a Double-Blind, Placebo-Controlled Trial

Poor Safety and Tolerability Hamper Reaching a Potentially Therapeutic Dose in the Use of Thalidomide for Alzheimer’s Disease: Results from a Double-Blind, Placebo-Controlled Trial

Fibroblast Growth Factors and their Emerging Cancer-Related Aspects

A HAND to TBX5 Explains the Link Between Thalidomide and Cardiac Diseases

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