TY - JOUR
T1 - Antitumor activity of cyclin-dependent kinase inhibitor alsterpaullone in Epstein-Barr virus-associated lymphoproliferative disorders
AU - Watanabe, Takahiro
AU - Sato, Yoshitaka
AU - Masud, H. M.Abdullah Al
AU - Takayama, Masahiro
AU - Matsuda, Hiroki
AU - Hara, Yuya
AU - Yanagi, Yusuke
AU - Yoshida, Masahiro
AU - Goshima, Fumi
AU - Murata, Takayuki
AU - Kimura, Hiroshi
N1 - Funding Information:
We are grateful to Drs. Eric Johannsen, Teru Kanda, Wolfgang Hammerschmidt, and Henri‐Jacques Delecluse for scientific discussions and materials. We also thank Drs. Masato Asai and Taku Nagai for technical assistance. The FACS and immunofluorescence analyses were carried out at the Division for Medical Research Engineering, Nagoya University Graduate School of Medicine. This work was supported by Grants‐in‐Aid from the Ministry of Education, Culture, Sports, Science and Technology, Japan (JP16H06867 to TW, JP16H06231 to YS, and 17H04081 to HK), by a grant from the Hori Sciences and Arts Foundation to HK and YS, and by the GSK Japan Research Grant to TW and YS.
PY - 2020/1/1
Y1 - 2020/1/1
N2 - Epstein-Barr virus (EBV) is a well-established tumor virus that has been implicated in a wide range of immunodeficiency-associated lymphoproliferative disorders (LPDs). Although rituximab, a CD20 mAb, has proven effective against EBV-associated LPDs, prolonged use of this drug could lead to resistance due to the selective expansion of CD20− cells. We have previously shown that cyclin-dependent kinase (CDK) inhibitors are able to specifically suppress the expression of viral late genes, particularly those encoding structural proteins; however, the therapeutic effect of CDK inhibitors against EBV-associated LPDs is not clear. In this study, we examined whether CDK inhibitors confer a therapeutic effect against LPDs in vivo. Treatment with alsterpaullone, an inhibitor of the CDK2 complex, resulted in a survival benefit and suppressed tumor invasion in a mouse model of LPDs. Inhibition of CDK efficiently induced G1 cell cycle arrest and apoptosis in EBV-positive B cells. These results suggest that alsterpaullone suppresses cell cycle progression, resulting in the antitumor effect observed in vivo.
AB - Epstein-Barr virus (EBV) is a well-established tumor virus that has been implicated in a wide range of immunodeficiency-associated lymphoproliferative disorders (LPDs). Although rituximab, a CD20 mAb, has proven effective against EBV-associated LPDs, prolonged use of this drug could lead to resistance due to the selective expansion of CD20− cells. We have previously shown that cyclin-dependent kinase (CDK) inhibitors are able to specifically suppress the expression of viral late genes, particularly those encoding structural proteins; however, the therapeutic effect of CDK inhibitors against EBV-associated LPDs is not clear. In this study, we examined whether CDK inhibitors confer a therapeutic effect against LPDs in vivo. Treatment with alsterpaullone, an inhibitor of the CDK2 complex, resulted in a survival benefit and suppressed tumor invasion in a mouse model of LPDs. Inhibition of CDK efficiently induced G1 cell cycle arrest and apoptosis in EBV-positive B cells. These results suggest that alsterpaullone suppresses cell cycle progression, resulting in the antitumor effect observed in vivo.
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U2 - 10.1111/cas.14241
DO - 10.1111/cas.14241
M3 - Article
C2 - 31743514
AN - SCOPUS:85076412708
VL - 111
SP - 279
EP - 287
JO - Cancer Science
JF - Cancer Science
SN - 1347-9032
IS - 1
ER -