α-tocopheryl succinate and TRAIL selectively synergise in induction of apoptosis in human malignant mesothelioma cells
2004 (English)In: British Journal of Cancer, ISSN 0007-0920, Vol. 90, no 8, 1644-1653 p.Article in journal (Refereed) Published
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 α-tocopheryl succinate (α-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 α-TOS-induced apoptosis, and exerted high sensitivity to TRAIL in the presence of subapoptotic doses of the vitamin E analogue. Neither TRAIL or α-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 α-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 α-TOS via cytochrome c release following Bid cleavage, with ensuing activation of caspase-9. Enhancement of TRAIL-induced apoptosis in MM cells by α-TOS was also associated with upregulation of the TRAIL cognate death receptors DR4 and DR5. Our results show that α-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.
Place, publisher, year, edition, pages
2004. Vol. 90, no 8, 1644-1653 p.
National CategoryMedical and Health Sciences
IdentifiersURN: urn:nbn:se:liu:diva-24639DOI: 10.1038/sj.bjc.6601707Local ID: 6825OAI: oai:DiVA.org:liu-24639DiVA: diva2:244961