Poly(ethylene glycol)–poly(lysine) block copolymer–ubenimex conjugate targets aminopeptidase N and exerts an antitumor effect in hepatocellular carcinoma stem cells

Reishi Toshiyama, Masamitsu Konno, Hidetoshi Eguchi, Hiroyasu Takemoto, Takehiro Noda, Ayumu Asai, Jun Koseki, Naotsugu Haraguchi, Yuji Ueda, Katsunori Matsushita, Kei Asukai, Tomofumi Ohashi, Yoshifumi Iwagami, Daisaku Yamada, Daisuke Sakai, Tadafumi Asaoka, Toshihiro Kudo, Koichi Kawamoto, Kunihito Gotoh, Shogo KobayashiTaroh Satoh, Yuichiro Doki, Nobuhiro Nishiyama, Masaki Mori, Hideshi Ishii

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)244-260
Number of pages17
JournalOncogene
Volume38
Issue number2
DOIs
Publication statusPublished - Jan 10 2019
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Fingerprint

Dive into the research topics of 'Poly(ethylene glycol)–poly(lysine) block copolymer–ubenimex conjugate targets aminopeptidase N and exerts an antitumor effect in hepatocellular carcinoma stem cells'. Together they form a unique fingerprint.

Cite this