Inhibition of mTOR in combination with doxorubicin in an experimental model of hepatocellular carcinoma

Piguet, Anne-Christine; Semela, David; Keogh, Adrian; Wilkens, Ludwig; Stroka, Deborah; Stoupis, Christoforos; St-Pierre, Marie V; Dufour, Jean-François (2008). Inhibition of mTOR in combination with doxorubicin in an experimental model of hepatocellular carcinoma. Journal of hepatology, 49(1), pp. 78-87. Amsterdam: Elsevier 10.1016/j.jhep.2008.03.024

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BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) is resistant to chemotherapy. We reported that sirolimus, an mTOR inhibitor, has antiangiogenic properties in HCC. Since antiangiogenic therapy may enhance chemotherapy effects, we tested the antitumorigenic properties of sirolimus combined with doxorubicin in experimental HCC. METHODS: Morris Hepatoma (MH) cells were implanted into livers of syngeneic rats. Animals were assigned to sirolimus, pegylated liposomal doxorubicin, both combined or control groups. Tumoral growth was followed by MRI. Antiangiogenic effects were assessed by CD31 immunostaining and capillary tube formation assays. Cell proliferation was monitored in vitro by thymidine incorporation. Expression of p21 and phosphorylated MAPKAP kinase-2 was quantified by immunoblotting. RESULTS: Animals treated with the combination developed smaller tumors with decreased tumor microvessel density compared to animals that received monotherapies. In vitro, inhibition of mTOR further impaired capillary formation in the presence of doxorubicin. Doxorubicin reduced endothelial cell proliferation; inhibition of mTOR accentuated this effect. Doxorubicin stimulated p21 expression and the phosphorylation of MAPKAP kinase-2 in endothelial cells. Addition of mTOR inhibitor down-regulated p21, but did not decrease MAPKAP kinase-2 phosphorylation. CONCLUSIONS: Sirolimus has additive antitumoral and antiangiogenic effects when administered with doxorubicin. These findings offer a rationale for combining mTOR inhibitors with chemotherapy in HCC treatment.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Service Sector > Institute of Clinical Pharmacology and Visceral Research [discontinued] 04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery 04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Hepatology
UniBE Contributor:	Piguet, Anne Christine, Keogh, Adrian, Stroka, Deborah, St-Pierre, Marie, Dufour, Jean-François
ISSN:	0168-8278
ISBN:	18486258
Publisher:	Elsevier
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 15:05
Last Modified:	05 Dec 2022 14:20
Publisher DOI:	10.1016/j.jhep.2008.03.024
PubMed ID:	18486258
Web of Science ID:	000257484300011
URI:	https://boris.unibe.ch/id/eprint/28357 (FactScience: 120267)