Graduate Program in Clinical Biochemistry and Molecular Medicine, Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand.
Department of Clinical Chemistry, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok 10330, Thailand.
Nutrients. 2023 Jul 10;15(14):3090. doi: 10.3390/nu15143090.
Cholangiocarcinoma (CCA) is an aggressive cancer associated with a very poor prognosis and low survival rates, primarily due to late-stage diagnosis and low response rates to conventional chemotherapy. Therefore, there is an urgent need to identify effective therapeutic strategies that can improve patient outcomes. Flavonoids, such as quercetin and kaempferol, are naturally occurring compounds that have attracted significant attention for their potential in cancer therapy by targeting multiple genes. In this study, we employed network pharmacology and bioinformatic analysis to identify potential targets of quercetin and kaempferol. The results revealed that the target genes of these flavonoids were enriched in G2/M-related genes, and higher expression of G2/M signature genes was significantly associated with shorter survival in CCA patients. Furthermore, in vitro experiments using CCA cells demonstrated that quercetin or kaempferol induced cell-cycle arrest in the G2/M phase. Additionally, when combined with a Smac mimetic LCL-161, an IAP antagonist, quercetin or kaempferol synergistically induced RIPK1/RIPK3/MLKL-mediated necroptosis in CCA cells while sparing non-tumor cholangiocyte cells. These findings shed light on an innovative therapeutic combination of flavonoids, particularly quercetin and kaempferol, with Smac mimetics, suggesting great promise as a necroptosis-based approach for treating CCA and potentially other types of cancer.
胆管癌（CCA）是一种侵袭性癌症，预后极差，生存率低，主要原因是诊断较晚和对常规化疗的反应率低。因此，迫切需要确定有效的治疗策略，以改善患者的预后。类黄酮如槲皮素和山奈酚是天然存在的化合物，由于其在癌症治疗方面具有靶向多个基因的潜力，因此受到了极大的关注。在这项研究中，我们采用网络药理学和生物信息学分析来鉴定槲皮素和山奈酚的潜在靶点。结果表明，这些类黄酮的靶基因富集在 G2/M 相关基因中，并且 G2/M 特征基因的高表达与 CCA 患者的生存时间缩短显著相关。此外，在 CCA 细胞的体外实验中，槲皮素或山奈酚诱导细胞周期停滞在 G2/M 期。此外，当与 Smac 模拟物 LCL-161（一种 IAP 拮抗剂）联合使用时，槲皮素或山奈酚在 CCA 细胞中协同诱导 RIPK1/RIPK3/MLKL 介导的坏死，同时保留非肿瘤胆管细胞。这些发现为类黄酮（特别是槲皮素和山奈酚）与 Smac 模拟物的创新治疗组合提供了启示，表明其作为一种基于坏死的治疗 CCA 及潜在其他类型癌症的方法具有很大的潜力。
