Rosmarinic acid in combination with ginsenoside Rg1 suppresses colon cancer metastasis via co-inhition of COX-2 and PD1/PD-L1 signaling axis  

作　　者：Huan Liu Rui Deng Cheng-wei Zhu Hong-kuan Han Gang-fan Zong Lang Ren Peng Cheng Zhong-hong Wei Yang Zhao Su-yun Yu Yin Lu 

机构地区：[1]Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica,School of Pharmacy,Nanjing University of Chinese Medicine,Nanjing 210023,China [2]State Key Laboratory Cultivation Base for Traditional Chinese Medicine(TCM)Quality and Effcacy,Nanjing University of Chinese Medicine,Nanjing 210023,China [3]School of Medicine&Holistic Integrative Medicine,Nanjing University of Chinese Medicine,Nanjing 210023,China [4]Jiangsu Collaborative Innovation Center of Traditional Chinese Medicine(TCM)Prevention and Treatment of Tumor,Nanjing University of Chinese Medicine,Nanjing 210023,China

出　　处：《Acta Pharmacologica Sinica》2024年第1期193-208,共16页中国药理学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(81973734,81961128020 and 82204802);the Jiangsu Specially Appointed Professorship Foundation(013038021001);the Postgraduate Research and Practice Innovation Programof Jiangsu Province(KYCX22_2014).

摘　　要：Metastasis of colorectal cancer(CRC)is a leading cause of mortality among CRC patients.Elevated COX-2 and PD-L1 expression in colon cancer tissue has been linked to distant metastasis of tumor cells.Although cox-2 inhibitors and immune checkpoint inhibitors demonstrate improved anti-tumor efficacy,their toxicity and variable therapeutic effects in individual patients raise concerns.To address this challenge,it is vital to identify traditional Chinese medicine components that modulate COx-2 and PD-1/PD-L1:rosmarinic acid(RA)exerts striking inhibitory effect on COX-2,while ginsenoside Rg1(GR)possesses the potential to suppress the binding of PD-1/PD-L1.In this study we investigated whether the combination of RA and GR could exert antimetastatic effects against CRC.MC38 tumor xenograft mouse model with lung metastasis was established.The mice were administered RA(100 mg·kg^(-1)·d^(-1),i.g.)alone or in combination with GR(100 mg·kg^(-1)·d^(-1),i.p.).We showed that RA(50,100,150μM)or a COX-2 inhibitor Celecoxib(1,3,9μM)concentration-dependently inhibited the migration and invasion of MC38 cells in vitro.We further demonstrated that RA and Celecoxib inhibited the metastasis of MC38 tumors in vitro and in vivo via interfering with the COX-2-MYO10 signaling axis and inhibiting the generation of flopodia.In the MC38 tumor xenograft mice,RA administration significantly decreased the number of metastatic foci in the lungs detected by Micro CT scanning;RA in combination with GR that had inhibitory effect on the binding of PD-1 and PD-L1 further suppressed the lung metastasis of colon cancer.Compared to COX-2 inhibitors and immune checkpoint inhibitors,RA and GR displayed better safety profiles without disrupting the tissue structures of the liver,stomach and colon,offering insights into the lower toxic effects of clinical traditional Chinese medicine against tumors while retaining its efficacy.

关 键 词：colon cancer METASTASIS COX-2 MYO10 FILOPODIA rosmarinic acid ginsenoside Rg1 CELECOXIB PD-1/PD-L1 

分 类 号：R735.35[医药卫生—肿瘤]