Alpha-tocopheryl succinate sensitizes human colon cancer cells to exisulind-induced apoptosis
Soo-Jeong Lim1, Young-Ju Lee, Dae-Hun Park
1Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea. sjlim@sejong.ac.kr
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.
Insights
Alpha-tocopheryl succinate (TOS) enhances exisulind's cancer-fighting effects. This combination therapy boosts apoptosis in colon cancer cells by activating caspases and JNK pathways.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Exisulind (Sulindac sulfone) is a promising anticancer agent inducing apoptosis in various cancer cells.
- Alpha-tocopheryl succinate (TOS) is another agent with anticancer potential.
- Investigating synergistic effects of TOS and exisulind on colon cancer is crucial.
Purpose of the Study:
- To evaluate the efficacy of alpha-tocopheryl succinate (TOS) in sensitizing colon cancer cells to exisulind-induced apoptosis.
- To elucidate the underlying molecular mechanisms of the observed synergistic effect.
Main Methods:
- Utilized human colon cancer cell lines (HCT116, LoVo, SNU-C4).
- Administered sub-apoptotic doses of TOS in combination with exisulind.
- Assessed apoptosis, poly(ADP-ribose) polymerase (PARP) cleavage, caspase activation (caspase-8, -9, -3), and JNK phosphorylation.
- Employed specific caspase and JNK inhibitors (z-VAD-FMK, z-IETD-FMK, z-LEHD-FMK, SP600151).
Main Results:
- Sub-apoptotic TOS doses significantly enhanced exisulind-induced growth suppression and apoptosis in colon cancer cells.
- Cotreatment led to augmented PARP cleavage and activation of caspase-8, -9, and -3.
- Inhibitor studies confirmed the critical roles of caspases and JNK in mediating the synergistic apoptosis.
- TOS/exisulind cotreatment induced JNK phosphorylation, which was partially blocked by a JNK inhibitor.
Conclusions:
- TOS effectively sensitizes human colon cancer cells to exisulind, leading to enhanced apoptosis.
- The synergistic effect is mediated through a mechanism involving the activation of caspases and JNK signaling pathways.
- This combination therapy holds potential for improved colon cancer treatment strategies.
