TRAIL sensitisation by arsenic trioxide is caspase-8 dependent and involves modulation of death receptor components and Akt.
The majority of leukaemic cells are resistant to apoptosis induced by tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, we show that sublethal concentrations of arsenic trioxide (ATO) specifically enhanced TRAIL-induced apoptosis in leukaemic but not in other tumour cell lines. The combination of ATO and TRAIL synergistically enhanced cleavage of caspase-8, which was blocked by the caspase inhibitor IETD.fmk as well as in cells deficient for caspase-8, suggesting a requirement for the death-inducing signalling complex. Arsenic trioxide led to increased cell surface expression of DR5 (death receptor 5), inhibition of the serine/threonine kinase Akt and downregulation of the short isoform of FLIP (FLICE-inhibitory protein, FLIPS). Inhibition of the phosphatidylinositol 3 kinase (PI3K) was equally efficient in sensitising leukaemic cells to TRAIL with similar effects on DR5 and FLIPS expression, suggesting that ATO may in part act through inhibition of the PI3K/Akt signalling pathway. These results indicate that the enhancement in TRAIL-mediated apoptosis induced by ATO is due to alteration in the levels of multiple components and regulators of the death receptor-mediated pathway. These findings offer a promising and novel strategy involving a combination of TRAIL and ATO, or more specific Akt inhibitors in the treatment of various haematopoietic malignancies.
Szegezdi
E
E
Department of Biochemistry, National University of Ireland,University Road, Galway, Ireland.
Cahill
S
S
Meyer
M
M
O'Dwyer
M
M
Samali
A
A
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology / Q000627:therapeutic use*; D053181:Caspase 8; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D007938:Leukemia / Q000188:drug therapy* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000627:therapeutic use*; D009842:Oligopeptides / Q000494:pharmacology; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D001152:Arsenicals; D061945:Caspase Inhibitors; D008562:Membrane Glycoproteins; D009842:Oligopeptides; D010087:Oxides; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018124:Receptors, Tumor Necrosis Factor; D053221:TNF-Related Apoptosis-Inducing Ligand; C505639:TNFRSF10B protein, human; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C425644:isoleucyl-glutamyl-threonyl-aspartic acid fluoromethyl ketone; D051058:Oncogene Protein v-akt; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases; D000077237:Arsenic Trioxide