TY - JOUR T1 - Activation of Nuclear Factor-κB Pathway by Simvastatin and RhoA Silencing Increases Doxorubicin Cytotoxicity in Human Colon Cancer HT29 Cells JF - Molecular Pharmacology JO - Mol Pharmacol SP - 476 LP - 484 DO - 10.1124/mol.108.045286 VL - 74 IS - 2 AU - Chiara Riganti AU - Sophie Doublier AU - Costanzo Costamagna AU - Elisabetta Aldieri AU - Gianpiero Pescarmona AU - Dario Ghigo AU - Amalia Bosia Y1 - 2008/08/01 UR - http://molpharm.aspetjournals.org/content/74/2/476.abstract N2 - Doxorubicin efficacy in cancer therapy is hampered by the dose-dependent side effects, which may be overcome by reducing the drug's dose and increasing its efficacy. In the present work, we suggest that the activation of the nuclear factor-κB (NF-κB) pathway and of nitric-oxide (NO) synthase increases the doxorubicin efficacy in human colon cancer HT29 cells. To induce NF-κB, we took into account the effect of doxorubicin itself and of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin; as NF-κB inhibitors, we chose the sesquiterpene lactones parthenolide and artemisinin. Simvastatin increased the NF-κB activity and NO synthesis, elicited the tyrosine nitration of the multidrug resistance-related protein 3, and enhanced the doxorubicin intracellular accumulation and cytotoxicity. Simvastatin potentiated the effect of doxorubicin on the NF-κB pathway and the inducible NO synthase expression. The effects of simvastatin were due to the inhibition of the small G-protein RhoA and of its effector Rho kinase. Parthenolide and artemisinin prevented all of the statin effects by inducing RhoA/Rho kinase activation. On the other hand, they did not reduce the NF-κB translocation and doxorubicin intracellular content when RhoA was silenced by small interfering RNA (siRNA). It is interesting that RhoA siRNA was sufficient to increase NF-κB translocation, NO synthase activity, doxorubicin accumulation, and cytotoxicity also in non-stimulated cells. Our results suggest that artemisinin, a widely used antimalarial drug, may impair the response to doxorubicin in colon cancer cells; on the contrary, simvastatin and RhoA siRNA may represent future therapeutic approaches to improve doxorubicin efficacy, reducing the risk of doxorubicin-dependent adverse effects. The American Society for Pharmacology and Experimental Therapeutics ER -