Alpha-tocopheryl succinate sensitizes human colon cancer cells to exisulind-induced apoptosis

作者：Lim Soo Jeong^*; Lee Young Ju; Park Dae Hun; Lee Eunmyong; Choi Moon Kyung; Park Wanseo; Chun Kyung Hee; Choi Han Gon; Cho Jung Sik

来源：Apoptosis, 2007, 12(2): 423-431.

DOI：10.1007/s10495-006-0620-9

• exisulind
• alpha-tocopheryl succinate
• apoptosis
• caspase
• JNK
• colon cancer

Sulindac sulfone (also known as exisulind) and its chemical derivatives are promising anticancer agents capable of inducing apoptosis in a variety of malignant cell types with minimal toxicity to normal cells. Here, we tested the ability of alpha-tocopheryl succinate (TOS), another promising anticancer agent, to sensitize colon cancer cells to exisulind-induced apoptosis. We found that sub-apoptotic doses of TOS greatly enhanced exisulind-induced growth suppression and apoptosis in the HCT116, LoVo and SNU-C4 human colon cancer cell lines. Our results revealed that this was accounted for primarily by an augmented cleavage of poly(ADP-ribose) polymerase (PARP) and enhanced activation of caspase-8, -9 and -3. Pretreatment with z-VAD-FMK (a pan-caspase inhibitor), z-IETD-FMK (a caspase-8 inhibitor) or z-LEHD-FMK (a caspase-9 inhibitor) blocked TOS and exisulind cotreatment-induced PARP cleavage and apoptosis. Furthermore, TOS/exisulind cotreatment induced JNK phosphorylation, while pretreatment with SP600151 (a JNK inhibitor) partially blocked cotreatment-induced caspase-dependent PARP cleavage and apoptosis. Taken together, these findings indicate that TOS sensitizes human colon cancer cells to exisulind-induced apoptosis. Apoptotic synergy induced by exisulind plus TOS seems likely to be mediated through a mechanism involving activation of caspases and JNK.

• 出版日期2007-2