Methacycline, a tetracycline antibiotic, protects cells from statin toxicity
We previously showed that inhibition of the mevalonate pathway inC. eleganscauses inhibition of protein prenylation, developmental arrest and lethality. We also showed that constitutive activation of the mitochondrial unfolded protein response, UPRmt, is an effective way forC. elegansto become resistant to the negative effects of mevalonate pathway inhibition. This was an important finding since statins, a drug class prescribed to lower cholesterol levels in patients, act by inhibiting the mevalonate pathway, and it is therefore possible that some of their undesirable side effects could be alleviated by activating the UPRmt. Here, we screened a chemical library and identified 4 compounds that specifically activated the UPRmt. One of these compounds, methacycline hydrochloride (a tetracycline antibiotic) also protectedC. elegansand mammalian cells from statin toxicity. Methacycline hydrochloride and ethidium bromide, a known UPRmtactivator, were also tested in mice: only ethidium bromide significantly activate the UPRmtin skeletal muscles.
Drug cocktail could double the average survival time
- Oral Atorvastatin up to 80mg uid
- Oral Metformin up to 1000mg uid, increased to bid if tolerated after 2 weeks
- Oral Doxycycline 100mg uid
- Oral Mebendazole 100mg uid
Interestingly, doxycycline extended lifespan of worms via increasing mitochondrial unfolded protein response and attenuating mitochondrial ...
So Doxycycline may activate the mitochondrial unfolded protein response and reduce the toxicity of Atorvastatin.