# Protection against Shiga Toxins
## 2 Compounds that Protect Cells against Stx
### Statins  
Statins, also known as HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors, are a class of compounds that inhibit cholesterol biosynthesis and prenylation of proteins (reviewed in [171]). Statins are widely prescribed to lower serum cholesterol levels for the prevention of cardiac diseases [172; 173; 174]. Recently, statins were found to inhibit Stx1B transport to the Golgi apparatus and to protect cells against Stx1 and Stx2 [110]. ACHN (epithelial carcinoma from renal tubular adenocarcinoma pleural metastasis) cells were pretreated with rosuvastatin (5-20 uM) for 24 h prior to addition of Stx1 or Stx2, and the number of surviving cells was measured after 72 h. Treatment with rosuvastatin increased cell survival by approx. 25% in the group treated with 5 uM rosuvastatin and then challenged with 1 pg/mL of Stx1 or Stx2, but there was essentially no improvement in cell survival in the group challenged with 100 pg/mL of the toxins. On the other hand, cell treatment with 10 uM of rosuvastatin increased cell survival by approx 70% in the groups challenged with 1 pg/mL of Stx1 or Stx2, and by approx. 25% in the groups challenged with100 pg/mL of the toxins. Although increasing the concentrations of rosuvastatin to 20 uM showed even better protection, there seemed to appear a difference in protection against Stx1 and Stx2, with the protection against Stx2 being lower than that against Stx1, especially at high toxin doses. As previously mentioned, Stx2 is suggested to exploit an additional transport pathway [65] which might not be blocked by rosuvastatin. In addition, a protective effect by lovastatin has previously been shown for several other protein toxins, including ricin, modeccin, _Pseudomonas_ toxin, and diphthe toxin, suggesting that statins might have a potential to be used against several toxins [175].  
Cell treatment with statins was found to increase the protein level and activity of GlcCer synthase, which in turn led to increased cellular levels of GlcCer [110]. The fact that the cells were maintained in a medium containing cholesterol during the treatment with statins, and that the isoprenol precursor counteracted the upregulation of GlcCer synthesis induced by statins, indicated that the effects observed, at least for the upregulation of GlcCer synthesis, were mediated by the inhibition of isoprenylation rather than by depletion of cellular cholesterol. In addition, by the use of specific inhibitors of different prenylation enzymes, the authors were able to show that it was only the inhibition of geranylgeranyl transferase II, also known as Rab geranylgeranyl transferase, that led to similar upregulation of GlcCer as statin treatment. Rab prenylation facilitates their membrane association and activity [176; 177]. Rab GTPases regulate intracellular vesicular trafficking events, and several Rabs have also been implicated in Stx retrograde transport (reviewed in [1]), suggesting that rosuvastatin-induced protection against Stx is mediated via aberrant Rab prenylation.  
Importantly, although for the prevention of cholesterol-related cardiac diseases statins are prescribed in relatively low doses (recommended daily dose of lovastatin is 20-40 mg per day [174]) the achievable safe serum values might be as high as 0.2-12 uM (shown for lovastatin at doses of 133-412 mg/m\({}^{2}\), which corresponds to approx. 200-650 mg) [178], and are within the dose range found to protect cells against Stx1 and Stx2 [110].