Abstract
Paclitaxel is one of the chemotherapeutic 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.
Highlights
Introduction αTocopheryl succinate (TOS), which is obtained by the esterification of α-tocopherol is a more stable powder form of α-tocopherol, since the succinate group protects the hydroxyl group of the chromanol ring from oxidation
In the absence of tocopheryl succinate (TOS), 10 and 100 nM paclitaxel inhibited the growth of H460 cells by 45.1 and 63.3%, whereas same doses of paclitaxel inhibited the growth of cells by 60.5 and 89.6%. (Figure 1A)
We show for the first time that TOS, synergistically enhanced paclitaxel response in human nonsmall cell lung cancer (NSCLC) cell lines
Summary
Tocopheryl succinate (TOS), which is obtained by the esterification of α-tocopherol is a more stable powder form of α-tocopherol, since the succinate group protects the hydroxyl group of the chromanol ring from oxidation. Despite their similar chemical structures, TOS differs in activity from α-tocopherol. TOS was observed to induce apoptosis in cancer cells by transcriptional activation of activator protein-1 (AP-1)-controlled genes. TOS-induced apoptosis appears to be mediated by caspase activation in majority of cancer cell lines, the contribution of caspase 9 or caspase 8 differs depending on the cellular context (Swettenham et al, 2005)
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