Pharmacological and genetic targeting of Rac1‐signaling: protection from anticancer drug‐induced normal tissue damage and prevention of chemical hepatocarcinogenesis

Background/Aim Rho GTPases influence multiple processes associated with malignancy. Yet, the impact of Rho‐regulated mechanisms on (i) normal tissue damage induced by anticancer drugs and (ii) chemical carcinogenesis is unclear. Here, we aim to elucidate the effect of Rac1 signalling on anthracycline‐induced normal tissue damage and chemical hepatocarcinogenesis. Method: Employing cardiomyoblasts (H9c2) and liver (HepG2) cells we examined the impact of the HMG‐CoA reductase inhibitor lovastatin (Lova) or Rac1‐specific small‐molecule inhibitors (e.g. EHT1864) on doxorubicin (Doxo) stimulated DNA damage response (DDR) and cytotoxicity in vitro as well as cardio‐ and hepatotoxicity in vivo . Furthermore, Doxo‐induced stress responses and diethylnitrosamine (DEN)‐induced liver tumor formation were investigated using liver‐specific rac1 ko mice. Result: Lova and EHT1864 blocked the DDR and promoted cell survival following Doxo treatment in vitro . Pharmacological and/or genetic targeting of Rac1 was also hepato‐ and cardioprotective in vivo . Besides, DEN‐stimulated hepatocarcinogenesis was attenuated in rac1 ko mice. The data show that inhibition of Rac1‐signaling protects from normal tissue damage triggered by Doxo and counteracts the formation of liver tumors. Conclusion Pharmacological targeting of Rac1‐signaling by lipid lowering drugs (i.e. statins) is suggested (i) to widen the therapeutic window of anthracyclines by mitigating cardiac damage and (ii) to protect from nitrosamine‐induced hepatocarcinogenesis.