Journal
ONCOGENE
Volume 38, Issue 2, Pages 244-260Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41388-018-0406-x
Keywords
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology [17H04282, 17K19698, 16K15615, 15H05791]
- Ministry of Education, Culture, Sports, Science, and Technology (P-DIRECT)
- Ministry of Education, Culture, Sports, Science, and Technology (P-CREATE)
- Ministry of Education, Culture, Sports, Science, and Technology (AMED-Japan Cancer Research Project)
- Grants-in-Aid for Scientific Research [17K19698, 17H04282, 16K15615, 15H05791] Funding Source: KAKEN
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Previous studies highlighted that aminopeptidase N (APN)/CD13 acts as a scavenger in the survival of hepatocellular carcinoma (HCC) stem cells by reducing reactive oxygen species (ROS) levels. Hence, it has been proposed that APN/CD13 inhibition can increase cellular ROS levels and sensitize cells to chemotherapeutic agents. Although ubenimex, also known as bestatin, competitively inhibits proteases such as APN/CD13 on the cellular membrane and it is clinically used for patients with acute myeloid leukemia and lymphedema, research has demonstrated that higher concentrations of the agent induce the death of APN/CD13(+) HCC stem cells. In this study, we developed a poly(ethylene glycol)-poly(lysine) block copolymer-ubenimex conjugate (PEG-b-PLys(Ube)) to increase the efficacy of reagents in APN/CD13(+) cancer stem cells. Exposure to PEG-b-PLys(Ube) increased the intracellular ROS concentration by inhibiting APN enzyme activity, permitting the induction of apoptosis and attenuation of HCC cell proliferation. In addition, PEG-b-PLys(Ube) exhibited a relatively stronger antitumor effect in mice than PEG-b-PLys alone or phosphate-buffered saline. Moreover, an isobologram analysis revealed that combinations of fluorouracil, cisplatin, or doxorubicin with PEG-b-PLys(Ube) exhibited synergistic effects. This study demonstrated that PEG-b-PLys(Ube) does not impair the properties of ubenimex and exerts a potent antitumor effect.
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