Department of Internal Medicine, Research Institute of Clinical Medicine, Biomedical Research Institute, Jeonbuk National University Hospital, Jeonbuk National University Medical School, Jeonju, Korea.
Cell Mol Biol (Noisy-le-grand). 2023 May 31;69(5):12-18. doi: 10.14715/cmb/2023.69.5.3.
Colorectal cancer (CRC) displays noticeable resistance to chemotherapeutic drugs or innovative tumor cell apoptosis-inducing agents such as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Thus, sensitizers are needed to enhance the effects of TRAIL-based cancer therapies. Elevated tumor cell death has been reported when various HDAC inhibitors are administered with TRAIL in various human cancers; however, SB939-TRAIL combined treatment has not been reported. In this study, we determined the ability of SB939 and TRAIL, as single agents or in combination, to inhibit the growth and survival of colorectal cancer cells. Our results demonstrated the effects of SB939 and TRAIL on cell viability, apoptosis, and morphological changes in HT-29 cells. SB939 treatment induces hyper-acetylation of histones and death receptors (DR) by activating MAPK proteins in a dose- and time-dependent manner. The ability of SB939 to sensitize HT-29 cells suggests that SB939 can induce essential changes in cell signaling pathways. Thus, the pan-HDAC inhibitor SB939 sensitizes TRAIL-induced apoptosis via up-regulation of DR5, and SB939-TRAIL combined treatment may target the MAPK pathways and serve as an effective therapeutic strategy against CRC.
结直肠癌（CRC）对化疗药物或新型肿瘤细胞凋亡诱导剂（如肿瘤坏死因子相关凋亡诱导配体（TRAIL））具有明显的耐药性。因此，需要增敏剂来增强基于 TRAIL 的癌症治疗效果。在各种人类癌症中，当用 TRAIL 联合各种 HDAC 抑制剂给药时，已报道肿瘤细胞死亡增加；然而，尚未报道 SB939-TRAIL 联合治疗。在这项研究中，我们确定了 SB939 和 TRAIL 作为单一药物或联合用药抑制结直肠癌细胞生长和存活的能力。我们的结果表明 SB939 和 TRAIL 对 HT-29 细胞活力、细胞凋亡和形态变化的影响。SB939 通过激活 MAPK 蛋白，以剂量和时间依赖的方式诱导组蛋白和死亡受体（DR）的过度乙酰化。SB939 使 HT-29 细胞敏感的能力表明，SB939 可以诱导细胞信号通路的必要变化。因此，pan-HDAC 抑制剂 SB939 通过上调 DR5 使 TRAIL 诱导的凋亡敏感，并且 SB939-TRAIL 联合治疗可能靶向 MAPK 通路并作为针对 CRC 的有效治疗策略。
