PO.MCB03.01 · 分子与细胞生物学
紫檀芪通过协同抑制 MAPK 和诱导凋亡增强达拉非尼在 BRAF 突变型黑色素瘤中的活性
Pterostilbene enhances dabrafenib activity in BRAF mutant melanoma through synergistic MAPK suppression and apoptotic induction
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
对 BRAF 抑制剂的耐药限制了黑色素瘤的持久应答。紫檀芪（PTB）是一种膳食多酚，具有抗增殖和促凋亡特性，可能增强靶向治疗。我们评估了 PTB 是否能增强 BRAF 抑制剂达拉非尼（DAB）在 BRAF 突变型黑色素瘤细胞中的活性。在 A375 和 HT144 黑色素瘤细胞中经 48 小时处理后测定了 PTB 和 DAB 的 IC50 值。协同作用研究在 HT144 细胞中进行，基于实验测定的 IC50 值使用 5×5 固定比例矩阵，并使用 Loewe 加和性、Bliss 独立性、ZIP 协同性和联合指数模型对协同作用进行量化。通过 Western blot 分析 MAPK 信号和凋亡的关键标志物评估机制效应。在 A375 细胞中，DAB 的 IC50 值约为 12 nM，PTB 约为 60 μM。在 HT144 细胞中，DAB 的 IC50 值约为 3 nM，PTB 约为 45 μM。HT144 中多种 PTB+DAB 组合产生了强协同作用，其中协同性最强的剂量（例如 PTB 约 12 μM + DAB 约 0.8-3 nM）显示 Loewe CI < 0.7 以及相应的 Bliss/ZIP 协同性。与单一药物相比，协同处理降低了 MAPK 通路激活并增加了凋亡标志物，与信号抑制和凋亡诱导增强一致。PTB 增强了 DAB 在 BRAF 突变型 HT144 黑色素瘤细胞中的疗效，产生强劲的协同作用以及 MAPK 通路抑制和凋亡的机制证据。这些发现支持进一步评估 PTB 作为一种低毒性佐剂，以改善黑色素瘤中对 BRAF 靶向治疗的应答。
查看英文原文 English abstract
Resistance to BRAF inhibitors limits durable responses in melanoma. Pterostilbene (PTB), a dietary polyphenol, has anti-proliferative and pro-apoptotic properties and may augment targeted therapy. We evaluated whether PTB enhances the activity of the BRAF inhibitor dabrafenib (DAB) in BRAF-mutant melanoma cells. IC₅₀ values for PTB and DAB were determined in A375 and HT144 melanoma cells following 48 h treatment. Synergy studies were conducted in HT144 cells using 5×5 fixed-ratio matrices based on experimentally determined IC₅₀ values, and synergy was quantified using Loewe additivity, Bliss independence, ZIP synergy, and Combination Index models. Mechanistic effects were assessed by Western blot analysis of key markers of MAPK signaling and apoptosis. In A375 cells, IC₅₀ values were ~12 nM for DAB and ~60 μM for PTB. In HT144 cells, IC₅₀ values were ~3 nM for DAB and ~45 μM for PTB. Multiple PTB+DAB combinations in HT144 produced strong synergy, with the most synergistic doses (e.g., PTB ~12 μM + DAB ~0.8-3 nM) showing Loewe CI < 0.7 and corresponding Bliss/ZIP synergy. Synergistic treatment decreased MAPK pathway activation and increased apoptotic markers relative to single agents, consistent with enhanced signaling suppression and apoptosis induction. PTB enhances DAB efficacy in BRAF-mutant HT144 melanoma cells, producing robust synergy and mechanistic evidence of MAPK pathway inhibition and apoptosis. These findings support further evaluation of PTB as a low-toxicity adjuvant to improve responses to BRAF-targeted therapy in melanoma.
利益披露 Disclosure
J. S. Fraser, None..
J. Bury, None..
C. Summers, None.