Department of Urology, The First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
Department of Nephrology, First Hospital of Jilin University, Changchun, Jilin 130021, P.R. China.
Oncol Rep. 2020 Nov;44(5):1939-1948. doi: 10.3892/or.2020.7737. Epub 2020 Aug 18.
Tumor necrosis factor‑related apoptosis‑inducing ligand (TRAIL) selectively induces apoptosis in cancer cells, with minimal toxicity to normal tissues. However, accumulating evidence suggests that certain cancer types are insensitive to TRAIL signaling. The aim of this study was to identify an effective combination regimen, which can overcome TRAIL resistance in renal cancer cell. Herein, we found that human renal carcinoma cells (RCCs) are widely resistant to TRAIL‑mediated growth inhibition and subsequently identified that andrographolide (Andro), a major constituent of Andrographis paniculate, an annual herbaceous plant in the family Acanthaceae, counteracts TRAIL resistance in RCCs. Combined treatment with TRAIL and Andro suppressed cell viability as determined by MTS and proliferation as determined by EdU in a dose‑dependent manner and inactivated the clonogenic and migration ability of RCCs. Andro significantly enhances TRAIL‑mediated cell cycle arrest at the G2/M phase as determined by flow cytometry and senescence. Moreover, Andro restored TRAIL signaling, which in turns activated pro‑apoptosis caspases as determined by immunoblot assay. The TRAIL receptor, death receptor (DR)4, but not DR5, was found to be significantly upregulated in Andro‑treated RCC cells, which contributed to the role of Andro as a TRAIL sensitizer. The present study demonstrated that the combined treatment of Andro and TRAIL has potential therapeutic value against renal cancer.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）选择性地诱导癌细胞凋亡，对正常组织的毒性最小。然而，越来越多的证据表明，某些癌症类型对 TRAIL 信号不敏感。本研究旨在确定一种有效的联合治疗方案，以克服肾癌细胞对 TRAIL 的耐药性。在此，我们发现人肾癌细胞（RCC）对 TRAIL 介导的生长抑制广泛耐药，随后发现穿心莲内酯（Andro），穿心莲的主要成分，一种爵床科一年生草本植物，可抵抗 RCC 中的 TRAIL 耐药性。联合 TRAIL 和 Andro 处理以剂量依赖性方式显著抑制 MTS 测定的细胞活力和 EdU 测定的增殖，并失活 RCC 的集落形成和迁移能力。Andro 通过流式细胞术显著增强 TRAIL 介导的细胞周期阻滞在 G2/M 期和衰老期。此外，Andro 恢复了 TRAIL 信号，这反过来又通过免疫印迹分析激活了促凋亡半胱天冬酶。在 Andro 处理的 RCC 细胞中发现肿瘤坏死因子受体（DR）4，而不是 DR5，显著上调，这有助于 Andro 作为 TRAIL 敏化剂的作用。本研究表明，Andro 和 TRAIL 的联合治疗对肾癌具有潜在的治疗价值。
