Exp Mol Med.  2009 Oct;41(10):737-745. 10.3858/emm.2009.41.10.080.

alpha-Tocopheryl succinate potentiates the paclitaxel-induced apoptosis through enforced caspase 8 activation in human H460 lung cancer cells

• Lim SJ
• Choi MK
• Kim MJ
• Kim JK

• KMID: 1009395
• DOI: http://doi.org/10.3858/emm.2009.41.10.080

Abstract

Paclitaxel is one of the chemotheraputic drugs widely used for the treatment of nonsmall cell lung cancer (NSCLC) patients. Here, we tested the ability of alpha-tocopheryl succinate (TOS), another promising anticancer agent, to enhance the paclitaxel response in NSCLC cells. We found that sub-apoptotic doses of TOS greatly enhanced paclitaxel-induced growth suppression and apoptosis in the human H460 NSCLC cell lines. Our data revealed that this was accounted for primarily by an augmented cleavage of poly(ADP-ribose) polymerase (PARP) and enhanced activation of caspase-8. Pretreatment with z-VAD-FMK (a pan-caspase inhibitor) or z-IETD-FMK (a caspase-8 inhibitor) blocked TOS/paclitaxel cotreatment-induced PARP cleavage and apoptosis, suggesting that TOS potentiates the paclitaxel-induced apoptosis through enforced caspase 8 activation in H460 cells. Furthermore, the growth suppression effect of TOS/paclitaxel combination on human H460, A549 and H358 NSCLC cell lines were synergistic. Our observations indicate that combination of paclitaxel and TOS may offer a novel therapeutic strategy for improving paclitaxel drug efficacy in NSCLC patient therapy as well as for potentially lowering the toxic side effects of paclitaxel through reduced drug dosage.

Keyword

apoptosis; carcinoma, non-small-cell lung; caspase 8; paclitaxel; alpha-tocopherol

MeSH Terms

Antineoplastic Agents/*pharmacology
Apoptosis/*drug effects
Carcinoma, Non-Small-Cell Lung/*drug therapy/metabolism/pathology
Caspase 8/metabolism
Cell Growth Processes/drug effects
Cell Line, Tumor
Drug Synergism
Drug Therapy, Combination
Humans
Neoplastic Stem Cells
Paclitaxel/pharmacology
alpha-Tocopherol/*pharmacology