Lin Ruohong,Cheng Jiaxing,Zhao Jinlong,Zhou Liang,Li Jian,Yang Xinchun
Background Colorectal cancer (CRC) is the third most common cancer globally, with advanced stages presenting significant treatment challenges. Recently years, drug combination therapy has become a promising strategy for cancer treatment. Objective To evaluate the therapeutic efficacy of the combination of the anti-angiogenic drug PEP06 ( TB01) and the cytotoxic drug Trifluridine/Tipiracil (TAS-102) in human CRC HCT-116 xenograft mouse model. And quantitative assessment of the interaction between TB01 and TAS-102 in the treatment based on pharmacological effects. Methods This study utilized the human CRC HCT-116 xenograft nude mouse model to evaluate the antitumor effects of TAS-102 and TB01, both as mono-therapies and in combination therapies. Results The combination therapy not only demonstrated significantly inhibited tumor growth in a dose-dependent manner, but also seems to reduce the common toxicity associated with such treatments, as shown by the maintenance of body weights in the treated mice. Conclusion The synergistic effect observed from the combined use of TAS-102 and TB01 suggests a promising new treatment avenue for refractory CRC patients, meriting further investigation and potential clinical application.
Background and Purpose PEP06, a polypeptide modified from endostatin, was investigated for its antitumour effects on colorectal cancer (CRC) and the possible mechanisms of this antitumour activity were examined in in vitro and in vivo models. Experimental Approach After PEP06 treatment, cell proliferation and migration assays were performed in CRC cells. Epithelial–mesenchymal transition (EMT) progression was determined by Western blotting, immunofluorescent staining and immunohistochemistry in vitro and in a residual xenograft model. MiRNAs regulated by PEP06 were identified by miRNA microarray and verified by in situ hybridization and quantitative real-time PCR. The interactions between PEP06 and integrin αvβ3 were determined with Biacore SA biochips. The cellular function of miR-146b-5p was validated by gain-of-function and loss-of-function approaches. A mouse model of lung metastasis was used to determine the effect of PEP06 on metastatic growth. Key Results PEP06 did not affect cell viability but reduced migration and EMT in SW620 and HCT116 cells. PEP06 significantly repressed the expression of miR-146b-5p in these two cell lines through binding to integrin αvβ3. MiR-146b-5p was shown to increase EMT by targeting Smad4, and the miR-146b-5p-Smad4 cascade regulated EMT in CRC. PEP06 also suppressed CRC pulmonary metastasis, increased survival of mice and hampered residual tumour growth by inhibiting EMT through down-regulating miR-146b-5p. Conclusions and Implications PEP06 is a polypeptide that inhibits the growth and metastasis of colon cancer through its RGD motif binding to integrin αvβ3, thereby down-regulating miR-146b-5p to inhibit EMT in vitro and in vivo . It might have potential as a therapeutic for CRC.
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