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Regulation of apoptosis in human melanoma and neuroblastoma cells by statins, sodium arsenite and TRAIL: a role of combined treatment versus monotherapy.
- Source :
-
Apoptosis : an international journal on programmed cell death [Apoptosis] 2011 Dec; Vol. 16 (12), pp. 1268-84. - Publication Year :
- 2011
-
Abstract
- 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.
- Subjects :
- Cell Line, Tumor
Cyclooxygenase 2 genetics
Cyclooxygenase 2 metabolism
Drug Therapy, Combination
Gene Expression Regulation, Neoplastic drug effects
Heme Oxygenase-1 genetics
Heme Oxygenase-1 metabolism
Humans
Melanoma drug therapy
Melanoma genetics
Melanoma metabolism
Neuroblastoma drug therapy
Neuroblastoma genetics
Neuroblastoma metabolism
Receptors, TNF-Related Apoptosis-Inducing Ligand genetics
Receptors, TNF-Related Apoptosis-Inducing Ligand metabolism
TNF-Related Apoptosis-Inducing Ligand genetics
TNF-Related Apoptosis-Inducing Ligand pharmacology
Amino Acids pharmacology
Apoptosis drug effects
Arsenites pharmacology
Melanoma physiopathology
Neuroblastoma physiopathology
Sodium Compounds pharmacology
TNF-Related Apoptosis-Inducing Ligand metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1573-675X
- Volume :
- 16
- Issue :
- 12
- Database :
- MEDLINE
- Journal :
- Apoptosis : an international journal on programmed cell death
- Publication Type :
- Academic Journal
- Accession number :
- 21910007
- Full Text :
- https://doi.org/10.1007/s10495-011-0649-2