Treatment of
melanoma cells by
sodium arsenite or
statins (
simvastatin and
lovastatin) dramatically modified activities of the main cell signaling pathways resulting in the induction of
heme oxygenase-1 (HO-1) and in a downregulation of
cyclooxygenase-2 (COX-2)
protein levels. Through
heme degradation and the production of
carbon monoxide and
biliverdin, HO-1 plays a protective role in different scenario of oxidative stress followed by mitochondrial apoptosis. Both
sodium arsenite and
statins could be efficient inducers of apoptosis in some
melanoma cell lines, but often exhibited only modest proapoptotic activity in others, due to numerous protective mechanisms. We demonstrated in the present study that treatment by
sodium arsenite or
statins with an additional inhibition of HO-1 expression (or activation) caused a substantial upregulation of apoptosis in
melanoma cells.
Sodium arsenite- or
statin-induced apoptosis was independent of BRAF status (wild type versus V600E) in
melanoma lines. Monotreatment required high doses of
statins (20-40 μM) for effective induction of apoptosis. As an alternative approach, pretreatment of
melanoma cells with
statin at decreased doses (5-20 μM) dramatically enhanced TRAIL-induced apoptosis, due to suppression of the NF-κB and STAT3-transcriptional targets (including COX-2) and downregulation of cFLIP-L (a
caspase-8 inhibitor)
protein levels. Furthermore, combined treatment with
sodium arsenite and TRAIL or
simvastatin and TRAIL efficiently induced apoptotic commitment in human
neuroblastoma cells. In summary, our findings on enhancing effects of combined treatment of
cancer cells using
statin and TRAIL provide the rationale for further preclinical evaluation.