Alpha-tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells.
Malignant mesothelioma (MM) is a fatal type of neoplasia with poor therapeutic prognosis, largely due to resistance to apoptosis. We investigated the apoptotic effect of alpha-tocopheryl succinate (alpha-TOS), a strong proapoptotic agent, in combination with the immunological apoptogen TNF-related apoptosis-inducing ligand (TRAIL) on both MM and nonmalignant mesothelial cells, since MM cells show low susceptibility to the clinically intriguing TRAIL. All MM cell lines tested were sensitive to alpha-TOS-induced apoptosis, and exerted high sensitivity to TRAIL in the presence of subapoptotic doses of the vitamin E analogue. Neither TRAIL or alpha-TOS alone or in combination caused apoptosis in nonmalignant mesothelial cells. Isobologram analysis of the cytotoxicity assays revealed a synergistic interaction between the two agents in MM cells and their antagonistic effect in nonmalignant mesothelial cells. TRAIL-induced apoptosis and its augmentation by alpha-TOS were inhibited by the caspase-8 inhibitor Z-IETD-FMK and the pan-caspase inhibitor Z-VAD-FMK. Activation of caspase-8 was required to induce apoptosis, which was amplified by alpha-TOS via cytochrome c release following Bid cleavage, with ensuing activation of caspase-9. Enhancement of TRAIL-induced apoptosis in MM cells by alpha-TOS was also associated with upregulation of the TRAIL cognate death receptors DR4 and DR5. Our results show that alpha-TOS and TRAIL act in synergism to kill MM cells via mitochondrial pathway, and are nontoxic to nonmalignant mesothelial cells. These findings are indicative of a novel strategy for treatment of thus far fatal MM.
Tomasetti
M
M
Department of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, 60131 Ancona, Italy. mtomasetti@virgilio.it
Rippo
M R
MR
Alleva
R
R
Moretti
S
S
Andera
L
L
Neuzil
J
J
Procopio
A
A
D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins; D004347:Drug Interactions; D006801:Humans; D008024:Ligands; D008562:Membrane Glycoproteins / Q000493:pharmacokinetics / Q000494:pharmacology*; D008654:Mesothelioma / Q000473:pathology*; D008928:Mitochondria / Q000502:physiology; D053221:TNF-Related Apoptosis-Inducing Ligand; D024505:Tocopherols; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000493:pharmacokinetics / Q000494:pharmacology*; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology*; D019014:fas Receptor
D051017:Apoptosis Regulatory Proteins; D008024:Ligands; D008562:Membrane Glycoproteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D014810:Vitamin E; D024505:Tocopherols