中藥複方JC-001透過調節免疫抑制腫瘤進展並增強腫瘤對順鉑的化學敏感性

The Chinese medicine JC-001 suppresses tumor progression and enhances the chemosensitivity of tumor to cisplatin by modulating the immune response

莊孟憲(Meng-Hsien Chuang)

指導教授 ： 呂鋒洲

中山醫學大學/醫學院/醫學研究所/博士(2017年)

摘要

中藥複方JC-001一直被用在治療肝臟疾病部分，但沒有任何研究顯示其對於癌症治療的功效。本研究利用一系列癌細胞株測試與免疫健全腫瘤動物模型分析其抗癌藥效與機制。細胞部分，JC-001並無顯著直接毒殺癌細胞能力。在Hepa 1-6肝癌腫瘤模型中，JC-001不但可以直接增強抗原專一性毒殺能力來毒殺標的細胞，更有效透過調節系統性Th1 / Th2 / Th17 / Treg變化，抑制腫瘤病程。在LLC1肺癌腫瘤模型中更顯示出可以透過活化腫瘤微環境Th1免疫反應增強腫瘤對順鉑（CDDP）的化學敏感性，並避免因化療劑量產生的副作用。另外，JC-001的免疫調節功能更可在藍皮素誘導KrasG12D+/wPdx-Cre+/-基因鼠胰臟癌模型中，抑制由發炎引起的癌症病程。此抗癌功效在免疫缺陷鼠上鮮少觀察到。而在脾臟細胞與標的細胞共培養的實驗，發現JC-001調控微環境中細胞激素分泌的現象可能是透過巨噬細胞的活化與調控。綜合上述，JC-001可以透過免疫調節功能在腫瘤的發生，腫瘤生長與化療輔助這三個方向改善癌症病程，建議JC-001可廣泛應用於各種腫瘤治療，並值得進一步的臨床試驗與評估。

關鍵字

中藥複方 ； 腫瘤微環境 ； 免疫調節 ； 癌症病程 ； 化學敏感性

並列摘要

JC-001 is a Chinese medicine that has been used to treat liver disease; however, its significance in cancer treatment has not been characterized. In this study, we used a series of cancer cell lines and immunocompetent tumor models to characterize the anti-tumor activity of JC-001. For in vitro data, the direct cytotoxic of JC-001 did not observe on most cancer cell lines. In Hepa 1-6 / C57BL / 6 immunocompetent tumor model, JC-001 not only can directly enhance the antigen-specific cytotoxic ability of target cells, more effective through the modulation of Th1 / Th2 / Th17 / Treg paradigm to reduce the tumor progression. In LLC1 / C57BL / 6 immunocompetent tumor model, JC-001 can enhance the chemosensitivity of CDDP via the promotion of Th1 immune response in tumor microenvironment, and avoid the nephrotoxicity caused by the dose of chemotherapy. In addition, the immunomodulation function of JC-001 also can suppress the tumor progression in KrasG12D+/wPdx-Cre+/- mice pancreatic tumor model induced by cerulein. This anti-cancer effect is rarely observed in immunodeficient mice. The data of co-culture assay show that JC-001 mediated the cytokine secretion in tumor microenvironment may be through macrophage activation and regulation. In summary, JC-001 can be used in various tumor treatments by immunoregulatory function in tumorigenesis, tumor growth and chemotherapy. We suggest that JC-001 can be widely used in various tumor treatments, which merits further clinical testing and assessments.

並列關鍵字

Chinese medicine ； tumor microenvironment ； immunomodulation ； tumor progression ； chemosensitivity

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