PMID- 19085954
OWN - NLM
STAT- MEDLINE
DCOM- 20090312
LR  - 20211203
IS  - 1527-3350 (Electronic)
IS  - 0270-9139 (Linking)
VI  - 49
IP  - 2
DP  - 2009 Feb
TI  - Targeting heat-shock protein 90 improves efficacy of rapamycin in a model of 
      hepatocellular carcinoma in mice.
PG  - 523-32
LID - 10.1002/hep.22685 [doi]
AB  - Hepatocellular carcinoma (HCC) remains associated with a poor prognosis, but 
      novel targeted therapies in combination with anti-angiogenic substances may offer 
      new perspectives. We hypothesized that simultaneous targeting of tumor cells, 
      endothelial cells, and pericytes would reduce growth and angiogenesis of HCC, 
      which represents a highly vascularized tumor entity. Recently, because of their 
      anti-angiogenic properties, inhibitors of mammalian target of rapamycin (mTOR) 
      have entered clinical trials for therapy of HCC. However, treatment with mTOR 
      inhibitors may lead to paradoxical activation of Akt signaling in tumor cells via 
      insulin-like growth factor-I receptor (IGF-IR)-dependent and IGF-IR-independent 
      mechanisms. Because we have recently identified heat shock protein 90 (Hsp90) 
      antagonists to impair both oncogenic and angiogenic signaling cascades in tumor 
      cells, including Akt and IGF-IR, we sought to investigate whether Hsp90 blockade 
      could improve growth-inhibitory and anti-angiogenic effects of the mTOR inhibitor 
      rapamycin. Human HCC cells, a murine hepatoma cell line, endothelial cells (ECs), 
      and vascular smooth muscle cells (VSMC) were employed in experiments. Results 
      show that dual inhibition of mTOR and Hsp90 leads to effective disruption of 
      oncogenic signaling cascades and substantially improves growth-inhibitory effects 
      in vivo. Importantly, blocking Hsp90 abrogated the rapamycin-induced activation 
      of Akt and of the downstream effector nuclear factor kappa-B (NF-kappaB) in HCC 
      tumors. Furthermore, Hsp90 inhibition reduced the expression of platelet-derived 
      growth factor-receptor-beta (PDGF-Rbeta) on VSMCs, and diminished vascular 
      endothelial growth factor-receptor 2 (VEGFR-2) expression on ECs, which further 
      improves the anti-angiogenic capacity of this regimen. CONCLUSION: Blocking Hsp90 
      disrupts rapamycin-induced activation of alternative signaling pathways in HCCs 
      and substantially improves the growth-inhibitory effects of mTOR inhibition in 
      vivo. Hence, the concept of targeting tumor cells, ECs, and VSMCs by blocking 
      Hsp90/mTOR could prove valuable for treatment of HCC.
FAU - Lang, Sven A
AU  - Lang SA
AD  - Departments of Surgery and Surgical Oncology, University of Regensburg Medical 
      Center, Regensburg, Germany.
FAU - Moser, Christian
AU  - Moser C
FAU - Fichnter-Feigl, Stefan
AU  - Fichnter-Feigl S
FAU - Schachtschneider, Philipp
AU  - Schachtschneider P
FAU - Hellerbrand, Claus
AU  - Hellerbrand C
FAU - Schmitz, Volker
AU  - Schmitz V
FAU - Schlitt, Hans J
AU  - Schlitt HJ
FAU - Geissler, Edward K
AU  - Geissler EK
FAU - Stoeltzing, Oliver
AU  - Stoeltzing O
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Hepatology
JT  - Hepatology (Baltimore, Md.)
JID - 8302946
RN  - 0 (Antibiotics, Antineoplastic)
RN  - 0 (Carrier Proteins)
RN  - 0 (DNA Primers)
RN  - 0 (HSP90 Heat-Shock Proteins)
RN  - 0 (RNA, Neoplasm)
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.1 (mTOR protein, mouse)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Antibiotics, Antineoplastic/*therapeutic use
MH  - Carcinoma, Hepatocellular/*drug therapy/pathology
MH  - Carrier Proteins/antagonists & inhibitors
MH  - Cell Death/drug effects
MH  - Cell Movement/drug effects
MH  - DNA Fragmentation
MH  - DNA Primers
MH  - Disease Models, Animal
MH  - HSP90 Heat-Shock Proteins/*antagonists & inhibitors/genetics
MH  - Humans
MH  - Liver Neoplasms/*drug therapy/pathology
MH  - Mice
MH  - Phosphotransferases (Alcohol Group Acceptor)/antagonists & inhibitors
MH  - RNA, Neoplasm/genetics/isolation & purification
MH  - Sirolimus/*therapeutic use
MH  - TOR Serine-Threonine Kinases
MH  - Vascular Endothelial Growth Factor A/genetics
EDAT- 2008/12/17 09:00
MHDA- 2009/03/13 09:00
CRDT- 2008/12/17 09:00
PHST- 2008/12/17 09:00 [entrez]
PHST- 2008/12/17 09:00 [pubmed]
PHST- 2009/03/13 09:00 [medline]
AID - 10.1002/hep.22685 [doi]
PST - ppublish
SO  - Hepatology. 2009 Feb;49(2):523-32. doi: 10.1002/hep.22685.