TY - JOUR
T1 - Poly(ethylene glycol)–poly(lysine) block copolymer–ubenimex conjugate targets aminopeptidase N and exerts an antitumor effect in hepatocellular carcinoma stem cells
AU - Toshiyama, Reishi
AU - Konno, Masamitsu
AU - Eguchi, Hidetoshi
AU - Takemoto, Hiroyasu
AU - Noda, Takehiro
AU - Asai, Ayumu
AU - Koseki, Jun
AU - Haraguchi, Naotsugu
AU - Ueda, Yuji
AU - Matsushita, Katsunori
AU - Asukai, Kei
AU - Ohashi, Tomofumi
AU - Iwagami, Yoshifumi
AU - Yamada, Daisaku
AU - Sakai, Daisuke
AU - Asaoka, Tadafumi
AU - Kudo, Toshihiro
AU - Kawamoto, Koichi
AU - Gotoh, Kunihito
AU - Kobayashi, Shogo
AU - Satoh, Taroh
AU - Doki, Yuichiro
AU - Nishiyama, Nobuhiro
AU - Mori, Masaki
AU - Ishii, Hideshi
N1 - Publisher Copyright:
© 2018, Springer Nature Limited.
PY - 2019/1/10
Y1 - 2019/1/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85052540239&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85052540239&partnerID=8YFLogxK
U2 - 10.1038/s41388-018-0406-x
DO - 10.1038/s41388-018-0406-x
M3 - Article
C2 - 30089817
AN - SCOPUS:85052540239
SN - 0950-9232
VL - 38
SP - 244
EP - 260
JO - Oncogene
JF - Oncogene
IS - 2
ER -
