Reversal of chemoresistance and enhancement of apoptosis by statins through down-regulation of the NF-kappaB pathway.

We recently found that simvastatin can modulate the nuclear factor-kappaB (NF-kappaB) activation pathway, but whether other statins have similar effects to those of simvastatin is unknown. Therefore, we evaluated the effect six different statins on TNF-induced NF-kappaB activation in human myeloid leukemia cells. We then determined whether the combination of statins and standard chemotherapeutic agents could overcome chemoresistance and augment apoptosis. Of the six statins evaluated, only the natural statins (simvastatin, mevastatin, lovastatin, and pravastatin), not the synthetic statins (fluvastatin and atorvastatin), inhibited TNF-induced NF-kappaB activation. Simvastatin suppressed the NF-kappaB activation and potentiated the apoptosis induced by doxorubicin, paclitaxel, and 5-fluorouracil. These results suggest that different statins behave differently from one another and that they may be useful in overcoming chemoresistance.