The Aurora kinase inhibitor VE-465 has anticancer effects in pre-clinical studies of human hepatocellular carcinoma.
OBJECTIVE
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide and novel therapies are urgently needed. Recently, aberrant expression of Aurora kinases has been reported in various human cancers including HCC. We sought to investigate the potential of a potent and selective Aurora kinase inhibitor, VE-465, for targeted therapy of HCC.


METHODS
Cytotoxicity effects of VE-465 were tested in Huh-7 and HepG2 cell lines. Inhibition of Aurora kinase activity was demonstrated by Western blotting and immunofluorescence staining. Mitotic perturbation was visualized by confocal microscopy. Cell cycle profiles and apoptosis were assessed by flow cytometry. In vivo efficacy was determined in nude mice with human HCC xenografts.


RESULTS
We demonstrated that VE-465 induced proliferation blockade, histone H3 (Ser10) dephosphorylation, mitotic disturbance, endoreduplication, and apoptosis in Huh-7 and HepG2 cells. We also found that VE-465 suppressed Aurora kinase activity, prevented tumor growth, and induced apoptosis in a Huh-7 xenograft model.


CONCLUSIONS
These findings show that VE-465 has potent anticancer effects in human HCC. Inhibitors of Aurora kinases may deserve further exploration as molecular targeted agents against HCC.
Lin
Zhong-Zhe
ZZ
National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan.
Hsu
Hey-Chi
HC
Hsu
Chih-Hung
CH
Yeh
Pei-Yen
PY
Huang
Chi-Ying F
CY
Huang
Yung-Feng
YF
Chen
Te-Jung
TJ
Kuo
Sung-Hsin
SH
Hsu
Chiun
C
Hu
Fu-Chang
FC
Jeng
Yung-Ming
YM
Chung
Ying
Y
Cheng
Ann-Lii
AL
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D064127:Aurora Kinases; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008938:Mitosis / Q000187:drug effects; D010879:Piperazines / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines
D000970:Antineoplastic Agents; D064127:Aurora Kinases; D006657:Histones; D010879:Piperazines; D017346:Protein Serine-Threonine Kinases; C484810:tozasertib; D003521:Cyclopropanes; D011720:Pyrazoles; D011743:Pyrimidines