PO.CH01.07 · 化学
抗肿瘤药物与缝隙连接增强剂在异质性结直肠癌中的协同效应
Synergistic effects of antineoplastic drugs and gap junction enhancer in heterogenous colorectal cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
成纤维细胞与肿瘤细胞之间的相互作用，尤其是通过缝隙连接介导的信号传导，正日益被认为是结直肠癌药物反应的调节因素。为检验恢复缝隙连接功能能否增强化疗效果，我们在96孔板中以1:1的比例使用由CCD-112 CoN成纤维细胞与结直肠癌细胞（SW620、SW480、HT-29或Caco-2）组成的共培养球体。在多种浓度下单独测试doxorubicin、erlotinib、nilotinib和cediranib，并将其与缝隙连接增强剂PQ联用，药物相互作用采用ZIP模型这一分析工具进行量化，并通过gigamap方法进行可视化。对于doxorubicin与PQ的联合治疗，ZIP分析同时揭示了拮抗区域和协同区域。单独使用PQ以及低浓度doxorubicin主要表现为拮抗，ZIP评分范围约为0.2至−17.19。相反，两种化合物的高浓度组合产生了显著的协同作用，最大ZIP评分为44.05，整体全局ZIP协同评分为4.53。在二维热图上，这表现为低至中等剂量下大体呈相加至轻度拮抗的效应，并在右上角（高[PQ]/高[Doxorubicin]）出现一个明显的红色协同热点。与此一致，三维曲面图显示了一条随两种药物浓度升高而增大的正ZIP评分脊。综上所述，这些发现表明PQ以浓度依赖的方式增强doxorubicin的疗效，协同作用仅限于特定的高剂量窗口，而非所有剂量组合。类似地，靶向BCR-ABL的疗法nilotinib在与PQ联用时表现出双相反应，其特征为在低浓度和高浓度处出现两个协同峰，中间剂量处则被一个拮抗谷分隔。总之，这些结果既凸显了PQ与常用抗肿瘤药物之间的协同特性，也凸显了其拮抗特性，并支持结直肠癌联合治疗的策略。
查看英文原文 English abstract
Fibroblast tumor cell crosstalk, particularly through gap junction mediated signaling, is increasingly recognized as a modifier of colorectal cancer drug response. To test whether restoring gap junction function can enhance chemotherapy, we used co-culture spheroids composed of CCD-112 CoN fibroblasts and colorectal cancer cells (SW620, SW480, HT-29, or Caco-2) in a 1:1 ratio in 96-well plates. Doxorubicin, erlotinib, nilotinib, and cediranib were tested across multiple concentrations, alone and in combination with the gap junction enhancer, PQ, and drug interactions were quantified using the ZIP model, analytic tool and visualized using gigamap approach. For the combination treatment of doxorubicin and PQ, ZIP analysis revealed both antagonistic and synergistic regions. PQ alone and low concentrations of doxorubicin were predominantly antagonistic, with ZIP scores ranging from approximately 0.2 to −17.19. In contrast, high concentrations of both chemicals produced marked synergy, with a maximal ZIP score of 44.05 and an overall global ZIP synergy score of 4.53. On the 2D heatmap, this appears as largely additive to mild antagonistic effects at low to intermediate doses, with a distinct red hot spot of synergy in the upper-right corner (high [PQ]/high [Doxorubicin]). Consistently, the 3D surface plot shows a ridge of positive zip scores that increases with rising concentrations of both drugs. Together, these findings indicate that PQ enhances doxorubicin efficacy in a concentration dependent manner, with synergy restricted to a specific high-dose window rather than across all dose combinations. Similarly, the BCR-ABL targeted therapy nilotinib displayed a biphasic response in combination with PQ, characterized by two synergistic peaks at low and high concentrations separated by an antagonistic valley at intermediate doses. In conclusion, these results highlight both the synergistic and antagonistic properties of PQ with commonly used antineoplastic agents and support the approach of combinational treatment for colorectal cancer.
利益披露 Disclosure
T. Lugo, None.