Aminopeptidase N inhibitor 4cc synergizes antitumor effects of 5-fluorouracil on human liver cancer cells through ROS-dependent CD13 inhibition |
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| Institution: | 1. Key Laboratory of Applied Pharmacology in Universities of Shandong, Department of Pharmacology, School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong, China;2. Department of Medical Chemistry, School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong, China;3. Department of Medicinal Chemistry, School of Pharmacy, Weifang Medical University, Weifang 261053, Shandong, China;4. Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China;1. Department of Human Communication, Trinity University, San Antonio, Texas;2. Audie L. Murphy Veterans Hospital, San Antonio, Texas;3. Division of Dermatology and Cutaneous Surgery, University of Texas Health Science Center–San Antonio, San Antonio, Texas;1. Pharmaleads, Paris BioPark, 11 rue Watt, 75013 Paris, France;2. Université Paris-Descartes, 4 Avenue de l''Observatoire, 75006 Paris, France;3. Jiangsu Engineering Research Center for microRNA Biology and Biotechnology, State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, 22 Hankou Road, Nanjing, Jiangsu 210093, China;4. Comprehensive Cancer Center of Drum Tower Hospital affiliated with Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing, Jiangsu 210008, China;5. Department of Thoracic and Cardiovascular surgery, Drum Tower Hospital affiliated with Medical School of Nanjing University, Nanjing, Jiangsu 210008, China;1. Department of General Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China;2. Biliary Tract Disease Center of Zhongshan Hospital, Fudan University, Shanghai 200032, China;3. Cancer Center, Zhongshan Hospital, Fudan University, Shanghai 200032, China;4. Biliary Tract Disease Institute, Fudan University, Shanghai 200032, China;5. Shanghai Biliary Tract Minimal Invasive Surgery and Materials Engineering Research Center, Shanghai 200032, China;6. Department of General Surgery, Shanghai Xuhui Central Hospital, Zhongshan-Xuhui Hospital, Fudan University, Shanghai 200032, China;1. UCL Cancer Institute, University College London, London WC1E 6BT, UK;1. Department of Pathology, Program in Dermatopathology, Brigham and Women''s Hospital, Boston, MA, USA;2. Harvard Medical School, Boston, MA, USA;3. Endocrinology Division, Department of Medicine, Brigham and Women''s Hospital, Boston, MA, USA;4. Department of Dermatology, Brigham and Women''s Hospital, Boston, MA, USA;5. Dana Farber Cancer Institute, Boston, MA, USA |
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| Abstract: | Aminopeptidase N (APN, also known as CD13) is involved in cellular processes of various types of tumors and a potential anti-cancer therapeutic target. Here, we report the effect of an APN inhibitor 4cc in enhancing sensitivity of hepatocellular carcinoma (HCC) cell lines and xenograft model in response to 5-fluorouracil (5-FU) in vivo and in vitro. The treatment of the combination of 4cc with 5-FU, compared to the combination of bestain with 5-FU, markedly suppressed cell growth and induced apoptosis of HCC cells, accompanying the increase in the level of reactive oxygen species (ROS) and followed by a decrease in the mitochondrial membrane potential (ΔΨM). Furthermore, the combination of 4cc and 5-FU showed a significant inhibitory effect on the growth of HCC xenograft tumors. In addition, following the treatment of 4cc, APN activity and clonogenic formation and the number of CD13-positive cells in PLC/PRF/5 cells were significantly decreased, suggesting that 4cc may also inhibit liver cancer stem cells by CD13 inhibition. These results showed that the APN inhibitor 4cc synergizes antitumor effects of 5-FU on human liver cancer cells via ROS-mediated drug resistance inhibition and concurrent activation of the mitochondrial pathways of apoptosis. |
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| Keywords: | CD13 4cc 5-FU Drug combination ROS ΔΨM Apotosis Liver cancer |
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