Sophonnithiprasert Thanet, Nilwarangkoon Sirinun, Nakamura Yukio, Watanapokasin Ramida
Department of Biochemistry, Faculty of Medicine, Srinkharinwirot University, Bangkok 10110, Thailand.
Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto 390-8621, Japan.
Int J Oncol. 2015 Dec;47(6):2188-96. doi: 10.3892/ijo.2015.3204. Epub 2015 Oct 13.
The combination of TNF-related apoptosis-inducing ligand (TRAIL) and bioactive compound to enhance apoptosis in TRAIL-resistant cancer is one of cancer treatment strategies. TRAIL possesses the unique capacity to selectively induce apoptosis in cancer cells both in vitro and in vivo with little effect on normal cells. Recent studies have reported that there are many TRAIL-resistant cancers. Thus, bioactive compounds that enhance cytotoxicity of TRAIL would be potential candidates for cancer therapeutic application. This study evaluated the cytotoxic and apoptosis induction upon combined treatment of TRAIL and goniothalamin, the natural styryl-lactone compound extracted from plant Goniothalamus spp., in LoVo cells. The results showed that a combination of goniothalamin and TRAIL enhanced caspase-dependent apoptosis induction in LoVo cells via both death receptor- and mitochondrial-mediated apoptosis pathways. In addition, goniothalamin enhanced TRAIL-induced apoptosis through increased death receptor DR5 expression and decreased anti-apoptotic regulator cFLIP. Interestingly, goniothalamin increased translocation of DR5 to cell surface and consequently contributed to the enhancement of TRAIL-induced apoptosis. In conclusion, this is the first report showing the combined treatment of goniothalamin and TRAIL was able to effectively enhance TRAIL-mediated apoptosis induction in TRAIL-refractory colorectal cancer, LoVo cells. Therefore, this study may offer a strategic cancer treatment against TRAIL-resistant cancers.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）与生物活性化合物联合使用以增强对TRAIL耐药癌症细胞的凋亡作用，是癌症治疗策略之一。TRAIL具有独特的能力，能够在体外和体内选择性地诱导癌细胞凋亡，而对正常细胞影响很小。最近的研究报道，存在许多对TRAIL耐药的癌症。因此，增强TRAIL细胞毒性的生物活性化合物可能是癌症治疗应用的潜在候选物。本研究评估了TRAIL与从植物哥纳香属植物中提取的天然苯乙烯基内酯化合物角鲨胺联合处理对LoVo细胞的细胞毒性和凋亡诱导作用。结果表明，角鲨胺与TRAIL联合使用可通过死亡受体介导和线粒体介导的凋亡途径增强LoVo细胞中半胱天冬酶依赖性凋亡诱导。此外，角鲨胺通过增加死亡受体DR5表达和降低抗凋亡调节因子cFLIP来增强TRAIL诱导的凋亡。有趣的是，角鲨胺增加了DR5向细胞表面的转位，从而有助于增强TRAIL诱导的凋亡。总之，这是首次报道表明角鲨胺与TRAIL联合治疗能够有效增强TRAIL介导的对TRAIL难治性结直肠癌LoVo细胞的凋亡诱导作用。因此，本研究可能为针对TRAIL耐药癌症提供一种战略性癌症治疗方法。
