Betulinic acid impairs metastasis and reduces immunosuppressive cells in breast cancer models
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An-Qi Zeng1,*, Yan Yu1,*, Yu-Qin Yao1,*, Fang-Fang Yang1, Mengya Liao2, Lin-Jiang Song1, Ya-Li Li1, Yang Yu3, Yu-Jue Li1, Yuan-Le Deng1, Shu-Ping Yang1, Chen-Juan Zeng1,4, Ping Liu5, Yong-Mei Xie1, Jin-Liang Yang1, Yi-Wen Zhang1, Ting-Hong Ye1 and Yu-Quan Wei1
1Laboratory of Liver Surgery, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China
2Sichuan Nursing Vocational College, Chengdu 610100, China
3Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital Affiliated to the Capital Medical University, Beijing 100038, China
4Sichuan Scientist Biotechnology Co., Ltd, Chengdu 610041, China
5Department of Gynecology and Obstetrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children of the Ministry of Education, West China Second Hospital, Sichuan University, Chengdu 610041, China
*These authors contributed equally to this work
Ting-Hong Ye, email: [email protected]
Yi-Wen Zhang, email: [email protected]
Keywords: betulinic acid; breast cancer; migration and invasion; pulmonary metastases; MDSCs
Received: May 19, 2017 Accepted: November 27, 2017 Published: December 17, 2017
Breast cancer is the most common female cancer with considerable metastatic potential, explaining the need for new candidates that inhibit tumor metastasis. In our study, betulinic acid (BA), a kind of pentacyclic triterpenoid compound derived from birch trees, was evaluated for its anti-metastasis activity in vitro and in vivo. BA decreased the viability of three breast cancer cell lines and markedly impaired cell migration and invasion. In addition, BA could inhibit the activation of stat3 and FAK which resulted in a reduction of matrix metalloproteinases (MMPs), and increase of the MMPs inhibitor (TIMP-2) expression. Moreover, in our animal experiment, intraperitoneal administration of 10 mg/kg/day BA suppressed 4T1 tumor growth and blocked formation of pulmonary metastases without obvious side effects. Furthermore, histological and immunohistochemical analyses showed a decrease in MMP-9 positive cells, MMP-2 positive cells and Ki-67 positive cells and an increase in cleaved caspase-3 positive cells upon BA administration. Notably, BA reduced the number of myeloid-derived suppressor cells (MDSCs) in the lungs and tumors. Interestingly, in our caudal vein model, BA also obviously suppressed 4T1 tumor pulmonary metastases. These findings suggested that BA might be a potential agent for inhibiting the growth and metastasis of breast cancer.
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