Department of Oncology, Hebei Medical University, Shijiazhuang 050017, China.
Department of Hematology, Affiliated Hospital of Hebei University, Baoding 071000, China.
Acta Biochim Biophys Sin (Shanghai). 2023 Aug 10;55(8):1247-1256. doi: 10.3724/abbs.2023160.
Circularly permuted TRAIL (CPT), a novel recombinant TRAIL mutant, is a potent antitumor agent. However, its efficacy in triple-negative breast cancer (TNBC) remains unclear. Treatment with CPT alone and in combination with doxorubicin (Dox) is explored for its effects on the proliferation and apoptosis of MDA-MB-231 (MB231) and MDA-MB-436 (MB436) breast cancer cells and . Here, we show that CPT combined with Dox exhibits time- and dose-dependent synergy to inhibit cell viability and enhance apoptosis of MB231 and MB436 cells. Combined treatment substantially increases caspase-8, caspase-3, and PARP cleavage in both cell lines and significantly suppresses tumor growth in nude mice bearing MB231 xenografts. Collectively, our findings demonstrate that treatment with CPT in combination with Dox exerts synergistic antitumor effects through activation of the caspase cascade pathway, a mechanism that is partly dependent on the Dox-induced upregulation of death receptor 4 and death receptor 5. Therefore, CPT combined with Dox may be a feasible therapeutic strategy for the management of TNBC.
环形排列 TRAIL（CPT），一种新型重组 TRAIL 突变体，是一种有效的抗肿瘤药物。然而，其在三阴性乳腺癌（TNBC）中的疗效尚不清楚。单独使用 CPT 以及与多柔比星（Dox）联合治疗，探索其对 MDA-MB-231（MB231）和 MDA-MB-436（MB436）乳腺癌细胞增殖和凋亡的影响。在这里，我们表明 CPT 与 Dox 联合使用具有时间和剂量依赖性协同作用，可抑制细胞活力并增强 MB231 和 MB436 细胞的凋亡。联合治疗可显著增加两种细胞系中 caspase-8、caspase-3 和 PARP 的切割，并显著抑制携带 MB231 异种移植物的裸鼠的肿瘤生长。总之，我们的研究结果表明，CPT 联合 Dox 通过激活半胱天冬酶级联途径发挥协同抗肿瘤作用，这种机制部分依赖于 Dox 诱导的死亡受体 4 和死亡受体 5 的上调。因此，CPT 联合 Dox 可能是治疗 TNBC 的一种可行的治疗策略。
