Cardioprotection thread, page-377

Cardioprotection MoA - Calcium homeostasis

I think that the MoA for cardioprotection is going to be around the regulation of caclium (Ca2+) in cardiomyocytes - potentially the RyR2, SERCA2, CaMKII, NF-kB, and p53 gene networks. Calcium homeostasis is dysregulated in both Anthracycline and Proteasome Inhibitor dosing.



High FTO activity in cardiomyocytes improves calcium handling, while FTO knockdown models demonstrated irregular heartbeats. This may indicate why the FTO inhibitors (brequinar, FB23-2, and Dac51) show a steady decrease in cell viability (increase in cardiomyocyte death) as dose concentration increases (below) - observe the red line on each chart. It could also just be because of increased toxicity generally. A cell model does not provide enough detail to truly understand the relationship between pharmacology and biology of a dynamic organ.



Bisantrene clearly demonstrates improved cardioprotection, while also inhibiting FTO at significantly lower concentrations than the other molecules. I notice a dip in cell viability at the start, which starts to change around 250nM. If my wild speculation is correct, then this could be a sign of Bisantrene being counterproductive at lower concentrations (or just not working as a cardioprotective agent) where it is only inhibiting FTO, and when the cardioprotective concentrations are reached for the MoA, it begins positively influencing calcium homeostasis and providing cardioprotection.



If calcium handling is the MoA for cardioprotection, there are a couple of takeaways:

1. The cardioprotective MoA is enough to buffer the effects of FTO inhibition dysregulation of calcium handling (as well as anthracene) - indicating a significant strength of that pathway
2. If it is not a single pathway, then Bisantrene may be targeting multiple pathways that provide cardioprotection - indicating a truly unique drug
3. If either 1 or 2 are correct, Bisantrene will become very challenging to replace clinically and, of course, commercially

This is highly speculative, but I thought I would put my thoughts up.

@Boffin99 what were your thoughts?