title: Rapamycin blocks hepatoblastoma growth in vitro and in vivo implicating new treatment options in high-risk patients.
abstract: 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.
authors.affiliation: Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, D-80337 Munich, Federal Republic of Germany.
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Wagner
authors.forename: Bente
authors.initials: B
authors.lastname: Henningsen
authors.forename: Christine
authors.initials: C
authors.lastname: Lederer
authors.forename: Melanie
authors.initials: M
authors.lastname: Eichenmüller
authors.forename: Jan
authors.initials: J
authors.lastname: Gödeke
authors.forename: Josef
authors.initials: J
authors.lastname: Müller-Höcker
authors.forename: Dietrich
authors.initials: D
authors.lastname: von Schweinitz
authors.forename: Roland
authors.initials: R
authors.lastname: Kappler
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D056945:Hep G2 Cells; D018197:Hepatoblastoma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D012307:Risk Factors; D020123:Sirolimus / Q000494:pharmacology*
chemical_list: D020123:Sirolimus