https://www.ncbi.nlm.nih.gov/pubmed/30602587
Repurposing of idebenone as a potential anti-cancer agent.
Abstract
Glioblastoma (GB) represents the most common and aggressive form of malignant primary brain tumour associated with high rates of morbidity and mortality. In the present study, we considered the potential use of idebenone (IDE), a Coenzyme Q10 analogue, as a novel chemotherapeutic agent for GB. On two GB cell lines, U373MG and U87MG, IDE decreased the viable cell number and enhanced the cytotoxic effects of two known anti-proliferative agents: temozolomide and oxaliplatin. IDE also affected the clonogenic and migratory capacity of both GB cell lines, at 25 and 50 µM, a concentration equivalent to that transiently reached in plasma after oral intake that is deemed safe for humans. p21 protein expression was decreased in both cell lines, indicating that IDE likely exerts its effects through cell cycle dysregulation, and this was confirmed in U373MG cells only by flow cytometric cell cycle analysis which showed S-phase arrest. Caspase-3 protein expression was also significantly decreased in U373MG cells indicating IDE-induced apoptosis that was confirmed by flow cytometric Annexin V/propidium iodide staining. No major decrease in caspase-3 expression was observed in U87MG cells nor apoptosis as observed by flow cytometry analysis. Overall, the present study demonstrates that IDE has potential as an anti-proliferative agent for GB by interfering with several features of glioma pathogenesis such as proliferation and migration, and hence might be a drug that could be repurposed for aiding cancer treatments. Furthermore, the synergistic combinations of IDE with other agents aimed at different pathways involved in this type of cancer are promising.
© 2019 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.
To be honest I rarely read cell culture studies like this anymore because I find them to be generally unreliable. If they could show anti-tumour effects in a living organism (rather than just isolated cells), that would be a little more notable, and if they could prove sufficient crossing of the blood-brain barrier in an orthotopic glioma model, that would be even more notable. Of course human, clinical data is even better.
ReplyDeleteI believe many drugs fail in GBM not because they're ineffective, but because they don't reach the target tissue in sufficient quantities. Cell culture studies completely bypass this problem and therefore show a false promise for molecules that have little chance to reach therapeutic quantities in the brain.
These are just general comments, I don't know if this is the case for this particular drug.
Full study link:
http://sci-hub.tw/http://www.biochemj.org/content/476/2/245.full-text.pdf
In the discussion it says "The human safety of IDE is well-established and a daily dose of 60 mg/kg/day has been shown to reach a transient concentration in plasma equivalent to 29.6 [micromolar]" and they provide a reference to this study:
https://jamanetwork.com/journals/jamaneurology/fullarticle/793937
The problem with this is that 99% of idebenone in the plasma is bound to plasma proteins (according to wikipedia), and so the large majority of the total drug will be pharmacodynamically unavailable. This is one reason in vitro (cell culture) studies are often unreliable.
Here is the source of the plasma protein binding data:
Deletehttps://www.ema.europa.eu/documents/assessment-report/sovrima-epar-public-assessment-report_en.pdf
"Distribution
More than 99% of idebenone is bound to plasma proteins in all species tested including humans. A smaller fraction <25% was bound to lipoproteins and the remainder to albumin and other protein(s)."