Additive Antiproliferative and Antiangiogenic Effects of Metformin and Pemetrexed in a Non-Small-Cell Lung Cancer Xenograft Model

Frontiers in Cell and Developmental Biology

Theresa Staniczek¹  Chih-Ching Yen²  Yung-An Tsou³  Jiun-Long Wang⁴  Yi-Ting Tsai⁵  Ying-Cheng Chen⁶  Ying-Wei Lan⁶  Chuan-Mu Chen⁷ 

[1] Department of Dermatology, Venereology and Allergology, Center of Excellence in Dermatology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany;Department of Internal Medicine, China Medical University Hospital, College of Health Care, China Medical University, Taichung, Taiwan;Department of Otolaryngology-Head and Neck Surgery, China Medical University Hospital, Taichung, Taiwan;Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan;Division of Endocrinology and Metabolism, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan;Ph.D. Program in Translational Medicine, Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan;The iEGG and Animal Biotechnology Center, Rong Hsing Research Center for Translational Medicine, National Chung Hsing University, Taichung, Taiwan;

关键词: metformin;    pemetrexed;    lung cancer;    angiogenesis;    orthotopic xenograft;    chorioallantoic membrane;   

DOI  :  10.3389/fcell.2021.688062

来源: DOAJ

【 摘 要 】

Lung cancer is heterogeneous and challenging to cope with once it has progressed. Chemotherapy is the first step once no active driver mutation has been discovered. Non-antitumor drugs have been found to be beneficial when used as adjuvants to chemotherapy. In this study, the additive effect and mechanism of metformin combined with pemetrexed in non-small-cell lung cancer (NSCLC) cells were elucidated. Three NSCLC cell lines, A549, H1975, and HCC827, were used to analyze tumor cell proliferation, colony formation and the cell cycle in vitro when exposed to metformin alone, pemetrexed alone or their combination. We found that combination treatment in three cell lines exerted antiproliferative effects through cell cycle arrest in the S phase. An ex vivo chicken chorioallantoic membrane (CAM) assay was used to examine the antiangiogenic effect of metformin combined with pemetrexed on vascular structure formation. We further created an A549 orthotopic xenograft model with an in vivo imaging system (IVIS) and explored the associated indicators involved in the tumorigenic process. The in vitro results showed that the combination of metformin and pemetrexed exhibited an antiproliferative effect in reducing cell viability and colony formation, the downregulation of cyclin D1 and A2 and the upregulation of CDKN1B, which are involved in the G1/S phase. For antiangiogenic effects, the combination therapy inhibited the vascular structure, as proven by the CAM assay. We elucidated that combination therapy could target VEGFA and Endoglin by RT-qPCR, ELISA and histopathological findings in an A549 orthotopic NSCLC xenograft model. Our research demonstrated the additive antiproliferative and antiangiogenic effects of the combination of metformin with pemetrexed in NSCLC and could be applied to clinical lung cancer therapy.

【 授权许可】

Unknown