Department of Biochemistry, Graduate School of Medicine, Toho University, Ota-ku, Tokyo 143-8540, Japan.
Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science, Katsushika-ku, Tokyo 125-8585, Japan.
Int J Mol Sci. 2022 Jun 23;23(13):6973. doi: 10.3390/ijms23136973.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytotoxic cytokine that induces cancer cell death by binding to TRAIL receptors. Because of its selective cytotoxicity toward cancer cells, TRAIL therapeutics, such as recombinant TRAIL and agonistic antibodies targeting TRAIL receptors, have garnered attention as promising cancer treatment agents. However, many cancer cells acquire resistance to TRAIL-induced cell death. To overcome this issue, we searched for agents to sensitize cancer cells to TRAIL-induced cell death by screening a small-molecule chemical library consisting of diverse compounds. We identified a cardiac glycoside, proscillaridin A, as the most effective TRAIL sensitizer in colon cancer cells. Proscillaridin A synergistically enhanced TRAIL-induced cell death in TRAIL-sensitive and -resistant colon cancer cells. Additionally, proscillaridin A enhanced cell death in cells treated with TRAIL and TRAIL sensitizer, the second mitochondria-derived activator of caspase mimetic. Proscillaridin A upregulated TRAIL receptor expression, while downregulating the levels of the anti-cell death molecules, cellular FADD-like IL-1β converting enzyme-like inhibitor protein and Mcl1, in a cell type-dependent manner. Furthermore, proscillaridin A enhanced TRAIL-induced cell death partly via -glycosylation. Taken together, our findings suggest that proscillaridin A is a promising agent that enhances the anti-cancer efficacy of TRAIL therapeutics.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）是一种细胞毒性细胞因子，通过与 TRAIL 受体结合诱导癌细胞死亡。由于其对癌细胞的选择性细胞毒性，TRAIL 治疗剂，如重组 TRAIL 和针对 TRAIL 受体的激动性抗体，已被视为有前途的癌症治疗药物。然而，许多癌细胞获得了对 TRAIL 诱导的细胞死亡的抗性。为了克服这个问题，我们通过筛选由多种化合物组成的小分子化学文库，寻找使癌细胞对 TRAIL 诱导的细胞死亡敏感的药物。我们确定了一种强心苷，即普罗沙林 A，是结肠癌细胞中最有效的 TRAIL 敏化剂。普罗沙林 A 与 TRAIL 协同增强了 TRAIL 敏感和耐药结肠癌细胞的细胞死亡。此外，普罗沙林 A 增强了用 TRAIL 和 TRAIL 敏化剂处理的细胞的细胞死亡，TRAIL 敏化剂是第二线粒体衍生的半胱天冬酶激活剂模拟物。普罗沙林 A 以细胞类型依赖的方式上调 TRAIL 受体表达，同时下调抗细胞死亡分子、细胞 FADD 样 IL-1β 转化酶样抑制剂蛋白和 Mcl1 的水平。此外，普罗沙林 A 通过 β-糖苷化增强了 TRAIL 诱导的细胞死亡。总之，我们的研究结果表明，普罗沙林 A 是一种有前途的增强 TRAIL 治疗剂抗癌疗效的药物。
