Suo Fengzhi, Zhou Xinyu, Soto-Gamez Abel, Nijdam Fleur B, Setroikromo Rita, Quax Wim J
Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Department of Radiation Oncology and Department of Biomedical Sciences, University Medical Center Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
Int J Mol Sci. 2025 May 13;26(10):4635. doi: 10.3390/ijms26104635.
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a potential therapeutic for cancer patients due to its tumor specificity. However, TRAIL resistance in cancer cells limits its development in clinical trials. Given that ionizing radiation (IR) is an established method of inducing DNA damage for cancer during radiotherapy, we applied a combined treatment of IR and TRAIL. Our study shows that the combination treatment of IR and TRAIL promoted cell death due to IR upregulating both DR4/DR5 receptors on the surface of human lung carcinoma cell line H460 and human colon cancer cell line DLD-1 2D cells. However, when cultured as 3D spheroids, we observed that IR enhanced DR5-specific TRAIL-induced cell death but attenuated DR4-specific TRAIL-induced cell death. The immunohistochemical analysis of 3D cell spheroid sections indicates that it is due to a lack of DR4 overexpression by IR. Our findings elucidate a potential explanation for the failure of the combination treatment of radiotherapy with TRAIL in clinical trials. Additionally, our findings advocate the potential efficacy of employing DR5-specific TRAIL in combination with radiation as a promising therapeutic strategy.
肿瘤坏死因子（TNF）相关凋亡诱导配体（TRAIL）因其肿瘤特异性而成为癌症患者潜在的治疗手段。然而，癌细胞对TRAIL的抗性限制了其在临床试验中的发展。鉴于电离辐射（IR）是放疗期间诱导癌症DNA损伤的既定方法，我们采用了IR与TRAIL的联合治疗。我们的研究表明，IR与TRAIL的联合治疗促进了细胞死亡，因为IR上调了人肺癌细胞系H460和人结肠癌细胞系DLD-1 2D细胞表面的DR4/DR5受体。然而，当培养为3D球体时，我们观察到IR增强了DR5特异性TRAIL诱导的细胞死亡，但减弱了DR4特异性TRAIL诱导的细胞死亡。3D细胞球体切片的免疫组织化学分析表明，这是由于IR缺乏DR4过表达所致。我们的研究结果阐明了放疗与TRAIL联合治疗在临床试验中失败的潜在原因。此外，我们的研究结果支持将DR5特异性TRAIL与放疗联合使用作为一种有前景的治疗策略的潜在疗效。
