| 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
(Affiliation: Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea. sjlim at sejong.ac.kr)
|
| Journal | Apoptosis : an international journal on programmed cell death
(Apoptosis)
Vol. 12
Issue 2
Pg. 423-31
(Feb 2007)
ISSN: 1360-8185 United States |
| PMID | 17191116
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
| Chemical References |
- Antineoplastic Agents
- Enzyme Inhibitors
- Vitamin E
- tocopherol succinate
- Sulindac
- sulindac sulfone
- JNK Mitogen-Activated Protein Kinases
- Caspases
|
| Topics |
- Antineoplastic Agents
(pharmacology)
- Apoptosis
(drug effects)
- Caspases
(antagonists & 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)
- Vitamin E
(analogs & derivatives, pharmacology)
|
