Experimental Therapeutics Alpha-Tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells M Tomasetti1, M R Rippo1, R Alleva2, S Moretti1, L Andera3, J Neuzil4,5 and A Procopio1 1Department of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, 60131 Ancona, Italy 2Department of Anesthesiology, IRCCS Istituti Ortopedici Rizzoli, 40100 Bologna, Italy 3Institute of Molecular Genetics, Czech Academy of Sciences, 14000 Prague, Czech Republic 4Department of Pathology II, Faculty of Health Sciences, University Hospital, 58183 Linköping, Sweden 5School of Health Sciences, Griffith University Gold Coast Campus, Southport, 9726 Queensland, Australia Correspondence to: Dr M Tomasetti, Dipartimento di Patologia Molecolare e Terapie Innovative, Università Politecnica delle Marche, via Ranieri 1, Ancona, Italy. E-mail: mtomasetti@virgilio.it 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 -tocopheryl succinate (-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 -TOS-induced apoptosis, and exerted high sensitivity to TRAIL in the presence of subapoptotic doses of the vitamin E analogue. Neither TRAIL or -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 -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 -TOS via cytochrome c release following Bid cleavage, with ensuing activation of caspase-9. Enhancement of TRAIL-induced apoptosis in MM cells by -TOS was also associated with upregulation of the TRAIL cognate death receptors DR4 and DR5. Our results show that -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. British Journal of Cancer (2004) 90, 1644-1653. doi:10.1038/sj.bjc.6601707 Published online 23 March 2004 Remember we are NOT Doctors and have NO medical training. This site is like an Encylopedia - there are many pages, many links on many topics. Support our work with any size DONATION - see left side of any page - for how to donate. You can help raise awareness of CAM.