Effect of heat-shock protein-90 (HSP90) inhibition on human hepatocytes and on liver regeneration in experimental models.
BACKGROUND
Targeting heat shock protein 90 (HSP90) has gained great interest for cancer therapy. However, in view of novel multimodality therapy approaches for treating hepatic metastases, concerns have raised regarding the impact of targeted therapies on liver regeneration and repair. In this study, we investigated the impact of HSP90 inhibition on liver regeneration in murine models.


METHODS
Effects of HSP90 inhibition on the activation of signaling intermediates, expression of vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) were investigated in primary human hepatocytes (PHHs) in vitro. Effects of HSP90 inhibition on liver regeneration and repair were determined in a murine hepatectomy model and in a model with acute carbon tetrachloride (CCl(4))-induced liver damage.


RESULTS
Inhibition of HSP90 effectively diminished the constitutive phosphorylation of Akt, Erk, and STAT3 in PHHs. Conversely, inhibition of HSP90 significantly increased the expression of both VEGF and HGF mRNA, and induced HSP70 protein in PHH cultures in vitro. In vivo, HSP90 inhibition significantly upregulated constitutive VEGF mRNA and HSP70 in murine livers and did not impair liver re-growth after 70% hepatectomy. Furthermore, BrdUrd-staining and histological quantification of necrotic areas revealed that HSP90 inhibition did not impair liver regeneration following partial hepatectomy, or liver repair that occurs after toxic liver injury with CCl(4).


CONCLUSIONS
Targeting HSP90 does not negatively affect the multifactorial process of liver regeneration and repair in vivo. Hence, the use of inhibitors to HSP90 appears to be a valid option for neoadjuvant therapy of liver metastases when subsequent surgery is intended.
Hackl
Christina
C
Department of Surgery, University of Regensburg Medical Center, Regensburg, Germany.
Mori
Akira
A
Moser
Christian
C
Lang
Sven A
SA
Dayoub
Rania
R
Weiss
Thomas S
TS
Schlitt
Hans J
HJ
Geissler
Edward K
EK
Hellerbrand
Claus
C
Stoeltzing
Oliver
O
D000208:Acute Disease; D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000188:drug therapy*; D015179:Colorectal Neoplasms / Q000473:pathology; D004195:Disease Models, Animal; D018841:HSP90 Heat-Shock Proteins / Q000494:pharmacology*; D006498:Hepatectomy; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000556:secondary; D008115:Liver Regeneration / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C066855:HGF protein, human; D018841:HSP90 Heat-Shock Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D017228:Hepatocyte Growth Factor; D002251:Carbon Tetrachloride