Li Mingyue, Yue Grace Gar-Lee, Luo Lianxiang, Tsui Stephen Kwok-Wing, Fung Kwok-Pui, Ng Simon Siu-Man, Lau Clara Bik-San
School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
Institute of Chinese Medicine and State Key Laboratory of Research on Bioactivities and Clinical Applications of Medicinal Plants, The Chinese University of Hong Kong, Hong Kong, China.
Front Oncol. 2021 Jan 19;10:574827. doi: 10.3389/fonc.2020.574827. eCollection 2020.
Colorectal cancer is the third most frequently diagnosed cancer worldwide. Clinically, chemotherapeutic agents such as FOLFOX are the mainstay of colorectal cancer treatment. However, the side effects including toxicity of FOLFOX stimulated the enthusiasm for developing adjuvants, which exhibit better safety profile. Turmeric extract (TE), which has been previously shown to suppress the growth of human and murine colon xenografts, was further demonstrated here for its inhibitory effects on colon cancer patient-derived xenografts (PDX). PDX models were successfully established from tissues of colon cancer patients and the PDX preserved the heterogeneous architecture through passages. NOD/SCID mice bearing PDX were treated either with TE or FOLFOX and differential responses toward these treatments were observed. The growth of PDX, metastasis and tumor recurrence in PDX-bearing mice were suppressed after TE treatments with 60% anti-tumor response rate and 83.3% anti-metastasis rate. Mechanistic studies showed that TE reduced tumor cell proliferation, induced cell apoptosis, inhibited metastasis modulating multiple targets, such as molecules involved in Wnt and Src pathways, EMT and EGFR-related pathways. Nevertheless, FOLFOX treatments inhibited the PDX growth with sharp decreases of mice body weight and only mild anti-metastasis activities were observed. Furthermore, in order to have a better understanding of the underlying mechanisms, network pharmacology was utilized to predict potential targets and mechanism. In conclusion, the present study demonstrated for the first time that oral TE treatment was effective to suppress the growth of colon PDX and the recurrence of colon tumors in mice. The findings obtained from this clinically relevant PDX model would certainly provide valuable information for the potential clinical use of TE in colorectal cancer patients. The application of PDX model was well illustrated here as a good platform to verify the efficacy of multi-targeted herbal extracts.
结直肠癌是全球第三大常见癌症。临床上，诸如FOLFOX等化疗药物是结直肠癌治疗的主要手段。然而，FOLFOX的副作用包括毒性激发了人们开发佐剂的热情，这些佐剂具有更好的安全性。姜黄提取物（TE）此前已被证明可抑制人源和鼠源结肠异种移植瘤的生长，在此进一步证明了其对结肠癌患者来源的异种移植瘤（PDX）的抑制作用。从结肠癌患者的组织中成功建立了PDX模型，并且PDX在传代过程中保留了异质性结构。携带PDX的NOD/SCID小鼠分别用TE或FOLFOX进行治疗，并观察到对这些治疗的不同反应。用TE治疗后，携带PDX的小鼠中PDX的生长、转移和肿瘤复发受到抑制，抗肿瘤反应率为60%，抗转移率为83.3%。机制研究表明，TE可降低肿瘤细胞增殖、诱导细胞凋亡、抑制转移，调节多个靶点，如参与Wnt和Src途径、EMT和EGFR相关途径的分子。然而，FOLFOX治疗抑制了PDX的生长，小鼠体重急剧下降，仅观察到轻微的抗转移活性。此外，为了更好地理解潜在机制，利用网络药理学预测潜在靶点和机制。总之，本研究首次证明口服TE治疗可有效抑制小鼠结肠PDX的生长和结肠肿瘤的复发。从这个临床相关的PDX模型中获得的发现肯定会为TE在结直肠癌患者中的潜在临床应用提供有价值的信息。PDX模型作为验证多靶点草药提取物疗效的良好平台在此得到了很好的说明。
