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Abstract：
BACKGROUND: Irinotecan (CPT-11) is a first-line treatment for advanced colorectal cancer (CRC). Four components (baicalin, baicalein, wogonin, and glycyrrhizic acid) derived from Huangqin Decoction (HQD) have been proven to enhance the anticancer activity of CPT-11 in our previous study.
OBJECTIVE: This study aimed to determine the optimal combination of the four components for sensitizing CPT-11 as well as to explore the underlying mechanism.
METHODS: The orthogonal design method was applied to obtain candidate combinations (Cmb1-9) of the four components. The influence of different combinations on the anticancer effect of CPT-11 was first evaluated in vitro by cell viability, wound healing ability, cloning formation, apoptosis, and cell cycle arrest. Then, a CRC xenograft mice model was constructed to evaluate the anticancer effect of the optimal combination in vivo. Potential mechanisms of the optimal combination exerting a sensitization effect combined with CPT-11 against CRC were analyzed by targeted metabolomics.
RESULTS: In vitro experiments determined that Cmb8 comprised of baicalin, baicalein, wogonin, and glycyrrhizic acid at the concentrations of 17 μM, 47 μM, 46.5 μM and 9.8 μM respectively was the most effective combination. Importantly, the cell viability assay showed that Cmb8 exhibited synergistic anticancer activity in combination with CPT-11. In in vivo experiments, this combination (15 mg/kg of baicalin, 24 mg/kg of baicalein, 24 mg/kg of wogonin, and 15 mg/kg of glycyrrhizic acid) also showed a synergistic anticancer effect. Meanwhile, inflammatory factors and pathological examination of the colon showed that Cmb8 could alleviate the gastrointestinal damage induced by CPT-11. Metabolic profiling of the tumors suggested that the synergistic anticancer effect of Cmb8 might be related to the regulation of fatty acid metabolism.
CONCLUSIONS: The optimal combination of four components derived from HQD for the synergistic sensitization of CPT-11 against CRC was identified.
OBJECTIVE: This study aimed to determine the optimal combination of the four components for sensitizing CPT-11 as well as to explore the underlying mechanism.
METHODS: The orthogonal design method was applied to obtain candidate combinations (Cmb1-9) of the four components. The influence of different combinations on the anticancer effect of CPT-11 was first evaluated in vitro by cell viability, wound healing ability, cloning formation, apoptosis, and cell cycle arrest. Then, a CRC xenograft mice model was constructed to evaluate the anticancer effect of the optimal combination in vivo. Potential mechanisms of the optimal combination exerting a sensitization effect combined with CPT-11 against CRC were analyzed by targeted metabolomics.
RESULTS: In vitro experiments determined that Cmb8 comprised of baicalin, baicalein, wogonin, and glycyrrhizic acid at the concentrations of 17 μM, 47 μM, 46.5 μM and 9.8 μM respectively was the most effective combination. Importantly, the cell viability assay showed that Cmb8 exhibited synergistic anticancer activity in combination with CPT-11. In in vivo experiments, this combination (15 mg/kg of baicalin, 24 mg/kg of baicalein, 24 mg/kg of wogonin, and 15 mg/kg of glycyrrhizic acid) also showed a synergistic anticancer effect. Meanwhile, inflammatory factors and pathological examination of the colon showed that Cmb8 could alleviate the gastrointestinal damage induced by CPT-11. Metabolic profiling of the tumors suggested that the synergistic anticancer effect of Cmb8 might be related to the regulation of fatty acid metabolism.
CONCLUSIONS: The optimal combination of four components derived from HQD for the synergistic sensitization of CPT-11 against CRC was identified.
摘要：
背景：伊立替康（CPT-11）是晚期结直肠癌（CRC）的一线治疗方法。四种成分（黄芩苷，黄芩素,Wogonin,和来自黄芩汤（HQD）的甘草酸）在我们先前的研究中已被证明可以增强CPT-11的抗癌活性。
目的：本研究旨在确定4种成分对CPT-11致敏的最佳组合，并探讨其作用机制。
方法：应用正交设计方法获得了四种成分的候选组合（Cmb1-9）。首先通过细胞活力在体外评估不同组合对CPT-11抗癌作用的影响，伤口愈合能力，克隆形成，凋亡，和细胞周期停滞。然后，构建CRC异种移植小鼠模型以评估最佳组合在体内的抗癌作用。通过靶向代谢组学分析了与CPT-11组合对CRC发挥致敏作用的最佳组合的潜在机制。
结果：体外实验确定Cmb8由黄芩苷组成，黄芩素,Wogonin,和浓度为17μM的甘草酸，47μM,46.5μM和9.8μM分别是最有效的组合。重要的是,细胞活力分析表明，Cmb8与CPT-11联合具有协同抗癌活性。在体内实验中,这种组合(15毫克/千克黄芩苷，24mg/kg的黄芩苷，24mg/kg的汉黄芩素，和15mg/kg的甘草酸）也显示出协同抗癌作用。同时,炎症因子和结肠病理检查表明Cmb8可以减轻CPT-11引起的胃肠道损伤。肿瘤的代谢谱表明Cmb8的协同抗癌作用可能与脂肪酸代谢的调节有关。
结论：确定了来自HQD的四种成分对CPT-11对CRC的协同增敏的最佳组合。
目的：本研究旨在确定4种成分对CPT-11致敏的最佳组合，并探讨其作用机制。
方法：应用正交设计方法获得了四种成分的候选组合（Cmb1-9）。首先通过细胞活力在体外评估不同组合对CPT-11抗癌作用的影响，伤口愈合能力，克隆形成，凋亡，和细胞周期停滞。然后，构建CRC异种移植小鼠模型以评估最佳组合在体内的抗癌作用。通过靶向代谢组学分析了与CPT-11组合对CRC发挥致敏作用的最佳组合的潜在机制。
结果：体外实验确定Cmb8由黄芩苷组成，黄芩素,Wogonin,和浓度为17μM的甘草酸，47μM,46.5μM和9.8μM分别是最有效的组合。重要的是,细胞活力分析表明，Cmb8与CPT-11联合具有协同抗癌活性。在体内实验中,这种组合(15毫克/千克黄芩苷，24mg/kg的黄芩苷，24mg/kg的汉黄芩素，和15mg/kg的甘草酸）也显示出协同抗癌作用。同时,炎症因子和结肠病理检查表明Cmb8可以减轻CPT-11引起的胃肠道损伤。肿瘤的代谢谱表明Cmb8的协同抗癌作用可能与脂肪酸代谢的调节有关。
结论：确定了来自HQD的四种成分对CPT-11对CRC的协同增敏的最佳组合。
