PMID- 22285179
OWN - NLM
STAT- MEDLINE
DCOM- 20130307
LR  - 20131121
IS  - 1879-0852 (Electronic)
IS  - 0959-8049 (Linking)
VI  - 48
IP  - 15
DP  - 2012 Oct
TI  - Rapamycin blocks hepatoblastoma growth in vitro and in vivo implicating new 
      treatment options in high-risk patients.
PG  - 2442-50
LID - S0959-8049(12)00007-X [pii]
LID - 10.1016/j.ejca.2011.12.032 [doi]
AB  - Activation of the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) 
      signalling pathway plays a central role in the formation of hepatoblastoma (HB), 
      the most common liver cancer in childhood. Blocking this pathway with specific 
      mTOR inhibitors such as the immunosuppressant rapamycin is being currently tested 
      for a variety of cancers. Here, we report that rapamycin treatment induced a 
      significant dose-dependent inhibition of cell viability and promoted apoptosis in 
      HB cells in vitro. Moreover, rapamycin inhibited AKT/mTOR signalling by 
      dephosphorylation of the downstream target p70S6 kinase (p70S6K). Most 
      importantly, treating subcutaneous HUH6 xenograft tumour bearing mice orally with 
      5mg/kg/day rapamycin for three weeks resulted in a striking reduction of tumour 
      growth, as evidenced by reduced volume and weight, and moderately lowered 
      tumour-specific alpha-fetoprotein (AFP) serum levels. The anti-tumourigenic 
      effect was primarily ascribed to a significantly reduced proliferation rate upon 
      p70S6K dephosphorylation, as microvascular density of rapamycin-treated compared 
      to vehicle-treated tumours stayed grossly unchanged. Of uttermost clinical 
      importance, we found no evidence for a feedback-loop activation of AKT in vivo. 
      In conclusion, we demonstrate that rapamycin effectively inhibits HB growth both 
      in vitro and in vivo by blocking AKT/mTOR signalling at the level of p70S6K and 
      that rapamycin should be considered to treat HB patients especially those to be 
      indicated for liver transplantation to benefit from its anti-tumourigenic and 
      immunosuppressive properties.
CI  - Copyright (c) 2012 Elsevier Ltd. All rights reserved.
FAU - Wagner, Ferdinand
AU  - Wagner F
AD  - Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, 
      Ludwig-Maximilians-University Munich, D-80337 Munich, Federal Republic of 
      Germany.
FAU - Henningsen, Bente
AU  - Henningsen B
FAU - Lederer, Christine
AU  - Lederer C
FAU - Eichenmuller, Melanie
AU  - Eichenmuller M
FAU - Godeke, Jan
AU  - Godeke J
FAU - Muller-Hocker, Josef
AU  - Muller-Hocker J
FAU - von Schweinitz, Dietrich
AU  - von Schweinitz D
FAU - Kappler, Roland
AU  - Kappler R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120128
PL  - England
TA  - Eur J Cancer
JT  - European journal of cancer (Oxford, England : 1990)
JID - 9005373
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Apoptosis/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Cell Survival/drug effects
MH  - Female
MH  - Hep G2 Cells
MH  - Hepatoblastoma/*drug therapy/pathology
MH  - Humans
MH  - Immunohistochemistry
MH  - Liver Neoplasms/*drug therapy/pathology
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Mice, Nude
MH  - Risk Factors
MH  - Sirolimus/*pharmacology
EDAT- 2012/01/31 06:00
MHDA- 2013/03/08 06:00
CRDT- 2012/01/31 06:00
PHST- 2011/09/19 00:00 [received]
PHST- 2011/12/14 00:00 [revised]
PHST- 2011/12/28 00:00 [accepted]
PHST- 2012/01/31 06:00 [entrez]
PHST- 2012/01/31 06:00 [pubmed]
PHST- 2013/03/08 06:00 [medline]
AID - S0959-8049(12)00007-X [pii]
AID - 10.1016/j.ejca.2011.12.032 [doi]
PST - ppublish
SO  - Eur J Cancer. 2012 Oct;48(15):2442-50. doi: 10.1016/j.ejca.2011.12.032. Epub 2012 
      Jan 28.