Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants (CUHK), The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
Department of Surgery, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong.
Phytomedicine. 2019 Jul;60:152886. doi: 10.1016/j.phymed.2019.152886. Epub 2019 Mar 12.
Esophageal cancer (EC) is a malignant gastrointestinal cancer with high morbidity worldwide and is the fourth leading cause of cancer-related deaths in China. Even though surgery and/or chemotherapy/chemoradiation might achieve good therapeutic response, recurrence rate is high due to cancer metastasis. Hence, the use of alternative adjuvant treatments, such as herbal medicines, for metastatic EC remains a great desire of the patients. Our previous studies have demonstrated the anti-metastatic efficacy of hot water extract of Andrographis paniculata (APW) in human esophageal cancer cells and tumor-bearing nude mice.
In the present study, the immunomodulatory activities of APW were further evaluated in human peripheral blood mononuclear cells (PBMCs) and in a carcinogen-induced esophageal tumorigenesis model using immune-competent C57BL/6 mice. Besides, the inhibitory effects of APW on esophageal cancer cell line-based xenografts and patient-derived xenografts (PDX) were examined so as to illustrate the potential multi-targeted efficacies of APW in esophageal cancer in pre-clinical models.
In vitro results showed that APW could stimulate proliferation of PBMCs, as well as TNF-α and IFN-γproductions. In mice with 4-nitroquinoline 1-oxide-induced tumorigenesis, 21-day oral treatment with APW (1600 mg/kg) decreased the level of dysplasia in esophagus and significantly modulated the population of regulatory T cells. The cytokines productions by spleen lymphocytes of APW-treated mice were shifted towards normal resting state (i.e. unchallenged with carcinogen). Furthermore, APW treatment suppressed the growth of cell line-based xenografts by significantly increasing apoptosis in tumors, without causing severe body weight loss as chemotherapeutics did. Most importantly, the inhibitory effects of APW treatment on esophageal patient-derived xenografts growth were demonstrated for the first time. Besides, several diterpenes were detected in the plasma after oral administration of APW in mice, suggesting that multi-components of APW were bioavailable and might have contributed towards the varied pharmacological activities demonstrated in our studies.
APW was shown to possess anti-tumor, anti-metastatic and immunomodulatory activities in esophageal cancer cell-based and animal models, including immunocompromised mice model and clinically relevant PDX model. Our findings illustrated the potential multi-targeted efficacies of APW in esophageal cancer management.
食管癌（EC）是一种恶性胃肠道癌症，在全球范围内发病率较高，是中国癌症相关死亡的第四大原因。尽管手术和/或化疗/放化疗可能会取得良好的治疗反应，但由于癌症转移，复发率仍然很高。因此，对于转移性 EC，患者仍然非常希望使用替代辅助治疗方法，如草药。我们之前的研究已经证明了穿心莲热水提取物（APW）在人食管癌细胞和荷瘤裸鼠中的抗转移作用。
在本研究中，进一步评估 APW 在人外周血单核细胞（PBMC）中的免疫调节活性，并在免疫功能正常的 C57BL/6 小鼠的致癌物诱导食管肿瘤发生模型中进行评估。此外，还检查了 APW 对食管癌细胞系异种移植和患者来源异种移植（PDX）的抑制作用，以说明 APW 在临床前模型中对食管癌的多靶点疗效。
体外结果表明，APW 可以刺激 PBMC 的增殖，以及 TNF-α和 IFN-γ的产生。在 4-硝基喹啉 1-氧化物诱导的肿瘤发生模型中，21 天口服 APW（1600mg/kg）治疗可降低食管发育不良水平，并显著调节调节性 T 细胞的群体。APW 治疗小鼠脾淋巴细胞的细胞因子产生向正常静息状态（即未受到致癌物挑战）转变。此外，APW 治疗通过显著增加肿瘤中的细胞凋亡来抑制细胞系异种移植的生长，而不会像化疗药物那样导致严重的体重减轻。最重要的是，首次证明了 APW 治疗对食管患者来源异种移植生长的抑制作用。此外，在小鼠口服 APW 后检测到几种二萜类化合物在血浆中，表明 APW 的多种成分是生物可利用的，并且可能对我们研究中显示的各种药理活性做出了贡献。
APW 显示出在食管癌细胞模型和动物模型中具有抗肿瘤、抗转移和免疫调节活性，包括免疫功能低下的小鼠模型和临床相关的 PDX 模型。我们的研究结果说明了 APW 在食管癌治疗中的潜在多靶点疗效。
