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

Abstract

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.

• Authors: Soo-Jeong Lim, Young-Ju Lee, Dae-Hun Park, Eunmyong Lee, Moon-Kyung Choi, Wanseo Park, Kyung-Hee Chun, Han-Gon Choi, Jung Sik Cho
• Journal: Apoptosis : an international journal on programmed cell death (Apoptosis) Vol. 12 Issue 2 Pg. 423-31 (Feb 2007) ISSN: 1360-8185 [Print] Netherlands
• PMID: 17191116 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Caspase Inhibitors
• Enzyme Inhibitors
• Vitamin E
• Sulindac
• JNK Mitogen-Activated Protein Kinases
• sulindac sulfone
• Tocopherols

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Caspase Inhibitors
• Cell Growth Processes (drug effects)
• Colonic Neoplasms (pathology)
• Drug Synergism
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• HCT116 Cells
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Sulindac (analogs & derivatives, pharmacology)
• Tocopherols
• Vitamin E (analogs & derivatives, pharmacology)