Aiphanol, a multi-targeting stilbenolignan, potently suppresses mouse lymphangiogenesis and lymphatic metastasis  

作　　者：Shan-mei Chen Chuan-ke Zhao Li-cheng Yao Li-xin Wang Yu-nan Ma Lin Meng Shao-qing Cai Cai-yun Liu Li-ke Qu Yan-xing Jia Cheng-chao Shou 

机构地区：[1]Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing),Department of Biochemistry and Molecular Biology,Peking University Cancer Hospital&Institute,Beijing,100142,China [2]State Key Laboratory of Natural and Biomimetic Drugs,School of Pharmaceutical Sciences,Peking University,Beijing,100191,China [3]Key Laboratory of Carcinogenesis and Translational Research(Ministry of Education/Beijing),Department of Laboratory Animal,Peking University Cancer Hospital&Institute,Beijing,100142,China

出　　处：《Acta Pharmacologica Sinica》2023年第1期189-200,共12页中国药理学报（英文版）

基　　金：This study was supported by the National Natural Science Foundation of China(81773219);National Basic Research Program of China(2015CB553906);the Digestive Medical Coordinated Development Center of Beijing Hospitals Authority(XXT21,China);Clinical Medicine Plus X-Young Scholars Project,Peking University;the Fundamental Research Funds for the Central Universities(PKU2022LCXQ021);the PKU-Baidu Fund(2019BD015,China)。

摘　　要：The high incidence of lymphatic metastasis is closely related to poor prognosis and mortality in cancers.Potent inhibitors to prevent pathological lymphangiogenesis and lymphatic spread are urgently needed.The VEGF-C-VEGFR3 pathway plays a vital role in driving lymphangiogenesis and lymph node metastasis.In addition,COX2 in tumor cells and tumor-associated macrophages(TAMs)facilitates lymphangiogenesis.We recently reported that aiphanol,a natural stilbenolignan,attenuates tumor angiogenesis by repressing VEGFR2 and COX2.In this study,we evaluated the antilymphangiogenic and antimetastatic potency of aiphanol using in vitro,ex vivo and in vivo systems.We first demonstrated that aiphanol directly bound to VEGFR3 and blocked its kinase activity with an half-maximal inhibitory concentration(IC50)value of 0.29μM in an in vitro ADP-Glo^(TM) kinase assay.Furthermore,we showed that aiphanol(7.5−30μM)dose-dependently counteracted VEGF-C-induced proliferation,migration and tubular formation of lymphatic endothelial cells(LECs),which was further verified in vivo.VEGFR3 knockdown markedly mitigated the inhibitory potency of aiphanol on lymphangiogenesis.In 4T1-luc breast tumor-bearing mice,oral administration of aiphanol(5 and 30 mg·kg^(−1)·d^(−1))dose-dependently decreased lymphatic metastasis and prolonged survival time,which was associated with impaired lymphangiogenesis,angiogenesis and,interestingly,macrophage infiltration.In addition,we found that aiphanol decreased the COX2-dependent secretion of PGE2 and VEGF-C from tumor cells and macrophages.These results demonstrate that aiphanol is an appealing agent for preventing lymphangiogenesis and lymphatic dissemination by synergistically targeting VEGFR3 and inhibiting the COX2-PGE2-VEGF-C signaling axis.

关 键 词：aiphanol SAR131675 LYMPHANGIOGENESIS LYMPHATICMETASTASIS VEGFR3 COX2 

分 类 号：O62[理学—有机化学]