“肺复康”调控PI3K/Akt/mTOR通路和端粒酶治疗非小细胞肺癌的临床和基础研究
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摘要
目的：探讨“肺复康”联合化疗对晚期非小细胞肺癌的治疗作用；探讨“肺复康”对小鼠Lewis肺癌PI3K/Akt/mTOR信号通路以及端粒酶表达和活性的影响,观察其对小鼠化疗增效减毒的效果。为益气养阴清热解毒法联合化疗治疗晚期非小细胞肺癌提供有力的理论依据。
方法：针对临床上证型为气阴两虚和阴虚内热的晚期非小细胞肺癌患者,分别给予“肺复康”联合化疗或单纯化疗,观察中医证候及生活质量的改善状况,观察客观有效率和毒性反应的不同及人淋巴细胞亚群变化。复制荷Lewis肺癌小鼠模型,将其分为中药大中小3个剂量组、联合组、化疗组和荷瘤对照组共6组,采用流式细胞分析、免疫组织化学分析、Western blot、逆转录PCR (RT-PCR)、活性光密度酶联免疫测定(TRAP-ELISA)等方法,对Lewis肺癌小鼠的外周血象、淋巴细胞亚群,小鼠Lewis肺癌组织中PI3K、Akt、mTOR三个信号分子的表达分布特征和表达量,小鼠Lewis肺癌组织中端粒酶表达及其活性进行了检测。
结果：“肺复康”联合化疗能够改善晚期非小细胞肺癌患者的中医证候及生活质量评分,提高客观有效率,减轻骨髓和胃肠道毒性反应,提高细胞免疫功能状态。“肺复康”治疗Lewis肺癌小鼠,具有显著的抑制肿瘤生长的作用,同时改善了荷瘤小鼠的生存状态,保护了化疗药物对骨髓和免疫功能的破坏,有效地下调了Lewis肺癌组织中PI3K/Akt/mTOR通路中三个信号蛋白的表达,有效地下调了端粒酶催化亚单位的表达及降低了端粒酶活性。
结论：“肺复康”联合化疗具有增效解毒的作用,其抗肿瘤作用有可能是通过下调PI3K/Akt/mTOR通路和端粒酶催化亚单位表达及活性而实现的。
Objective:To investigate the effect of FeiFuKang combined with chemotherapy in treating non-small cell lung cancer (NSCLC). To probe the implication of FeiFuKan on the PI3K/Akt/mTOR pathway, the expression of telomerase catalytic subunit and activity of telomerase, and its synergistic detoxification effect in treating mice bearing Lewis lung cancer, in order to provide theoretical basis for reinforcing Qi and nourishing Yin combined with chemotherapy in treating advanced NSCLC.
Methods:48 patients with two syndrome types of traditional Chinese medicine (TCM) including asthenia of both Qi and Yin and Yin deficiency with internal heat were randomly divided into two groups, one group received FeiFuKang combined with chemotherapy, and the other chemotherapy alone. We observed the changes of TCM symptoms and QOL (quality of life) improvement, objective response rate, side effect, and T lymphocyte subsets. We established the models of 60 mice bearing Lewis lung cancer, and divided them into 6 groups, which included 3 FeiFuKang (small, middle, and high dose) groups, combined group(middle dose combined with chemotherapy), chemotherapy group, and control group. The peripheral blood and T lymphocyte subset were analyzed with Hematology analyzer and Flow cytometer respectively. The expression and distribution characteristics of PI3K/Akt/mTOR in Lewis lung cancer cell were detected by immunohistochemistry and western blot respectively. The expression of telomerase catalytic subunit was detected by RT-PCR, and activity of telomerase was inspected by TRAP-ELISA.
Results:In treating advanced NSCLC, FeiFuKang combined with chemotherapy can significantly improve the TCM symptoms, QOL, objective response, and cellular immune function respectively, and reduce the gastrointestinal tract and bone marrow toxicity. In treating mice bearing Lewis lung cancer, FeiFuKang can significantly inhibit the growth of tumor xenograft, protect the survival status, bone marrow and cellular immune function, and effectively down-regulate the expression of signal proteins PI3K, Akt and mTOR, and effectively down-regulate the expression of telomerase catalytic subunit and telomerase activity.
Conclusion:FeiFuKang combined with chemotherapy has Synergistic detoxification effect in treating NSCLC, which may be achieved from its down-regulation of PI3K/Akt/mTOR pathway, expression of telomerase catalytic subunit and telomerase activity.
方法：针对临床上证型为气阴两虚和阴虚内热的晚期非小细胞肺癌患者,分别给予“肺复康”联合化疗或单纯化疗,观察中医证候及生活质量的改善状况,观察客观有效率和毒性反应的不同及人淋巴细胞亚群变化。复制荷Lewis肺癌小鼠模型,将其分为中药大中小3个剂量组、联合组、化疗组和荷瘤对照组共6组,采用流式细胞分析、免疫组织化学分析、Western blot、逆转录PCR (RT-PCR)、活性光密度酶联免疫测定(TRAP-ELISA)等方法,对Lewis肺癌小鼠的外周血象、淋巴细胞亚群,小鼠Lewis肺癌组织中PI3K、Akt、mTOR三个信号分子的表达分布特征和表达量,小鼠Lewis肺癌组织中端粒酶表达及其活性进行了检测。
结果：“肺复康”联合化疗能够改善晚期非小细胞肺癌患者的中医证候及生活质量评分,提高客观有效率,减轻骨髓和胃肠道毒性反应,提高细胞免疫功能状态。“肺复康”治疗Lewis肺癌小鼠,具有显著的抑制肿瘤生长的作用,同时改善了荷瘤小鼠的生存状态,保护了化疗药物对骨髓和免疫功能的破坏,有效地下调了Lewis肺癌组织中PI3K/Akt/mTOR通路中三个信号蛋白的表达,有效地下调了端粒酶催化亚单位的表达及降低了端粒酶活性。
结论：“肺复康”联合化疗具有增效解毒的作用,其抗肿瘤作用有可能是通过下调PI3K/Akt/mTOR通路和端粒酶催化亚单位表达及活性而实现的。
Objective:To investigate the effect of FeiFuKang combined with chemotherapy in treating non-small cell lung cancer (NSCLC). To probe the implication of FeiFuKan on the PI3K/Akt/mTOR pathway, the expression of telomerase catalytic subunit and activity of telomerase, and its synergistic detoxification effect in treating mice bearing Lewis lung cancer, in order to provide theoretical basis for reinforcing Qi and nourishing Yin combined with chemotherapy in treating advanced NSCLC.
Methods:48 patients with two syndrome types of traditional Chinese medicine (TCM) including asthenia of both Qi and Yin and Yin deficiency with internal heat were randomly divided into two groups, one group received FeiFuKang combined with chemotherapy, and the other chemotherapy alone. We observed the changes of TCM symptoms and QOL (quality of life) improvement, objective response rate, side effect, and T lymphocyte subsets. We established the models of 60 mice bearing Lewis lung cancer, and divided them into 6 groups, which included 3 FeiFuKang (small, middle, and high dose) groups, combined group(middle dose combined with chemotherapy), chemotherapy group, and control group. The peripheral blood and T lymphocyte subset were analyzed with Hematology analyzer and Flow cytometer respectively. The expression and distribution characteristics of PI3K/Akt/mTOR in Lewis lung cancer cell were detected by immunohistochemistry and western blot respectively. The expression of telomerase catalytic subunit was detected by RT-PCR, and activity of telomerase was inspected by TRAP-ELISA.
Results:In treating advanced NSCLC, FeiFuKang combined with chemotherapy can significantly improve the TCM symptoms, QOL, objective response, and cellular immune function respectively, and reduce the gastrointestinal tract and bone marrow toxicity. In treating mice bearing Lewis lung cancer, FeiFuKang can significantly inhibit the growth of tumor xenograft, protect the survival status, bone marrow and cellular immune function, and effectively down-regulate the expression of signal proteins PI3K, Akt and mTOR, and effectively down-regulate the expression of telomerase catalytic subunit and telomerase activity.
Conclusion:FeiFuKang combined with chemotherapy has Synergistic detoxification effect in treating NSCLC, which may be achieved from its down-regulation of PI3K/Akt/mTOR pathway, expression of telomerase catalytic subunit and telomerase activity.
引文
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