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Molecular Cancer
Published in: Molecular Cancer 1/2009

Open Access 01-12-2009 | Research

Heme oxygenase-1 and its metabolites affect pancreatic tumor growth in vivo

Authors: Philipp Nuhn, Beat M Künzli, René Hennig, Tomas Mitkus, Tadas Ramanauskas, Rainer Nobiling, Stefan C Meuer, Helmut Friess, Pascal O Berberat

Published in: Molecular Cancer | Issue 1/2009

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Abstract

Background

Pancreatic cancer (PaCa) is a fatal human cancer due to its exceptional resistance to all current anticancer therapies. The cytoprotective enzyme heme oxygenase-1 (HO-1) is significantly overexpressed in PaCa and seems to play an important role in cancer resistance to anticancer treatment. The inhibition of HO-1 sensitized PaCa cells to chemo- and radiotherapy in vitro.
Therefore, we investigated the effects of HO-1 and its metabolites biliverdin, carbon monoxide and iron on PaCa cells.
PaCa cell lines with divergent HO-1 expression patterns were used in a murine orthotopic cancer model. HO-1 expression and activity was regulated by zinc (inhibition) and cobalt (induction) protoporphyrin. Furthermore, the influence of cellular HO-1 levels and its metabolites on effects of standard chemotherapy with gemcitabine was tested in vivo and in vitro.

Results

High HO-1 expression in PaCa cell lines was associated with increased chemoresistance in vitro. Chemoresistance to gemcitabine was increased during HO-1 induction in PaCa cells expressing low levels of HO-1. The inhibition of HO-1 activity in pancreatic tumors with high HO-1 boosted chemotherapeutic effects in vivo significantly. Furthermore, biliverdin and iron promoted PaCa resistance to chemotherapy. Consequently, specific iron chelation by desferrioxamine revealed profound anticancerous effects.

Conclusion

In summary, the inhibition of HO-1 and the chelation of iron in PaCa cells were associated with increased sensitivity and susceptibility of pancreatic tumors to chemotherapy in vivo. The metabolites biliverdin and iron seem to be involved in HO-1-mediated resistance to anticancer treatment. Therefore, HO-1 inhibition or direct interference with its metabolites may evolve new PaCa treatment strategies.
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Metadata
Title
Heme oxygenase-1 and its metabolites affect pancreatic tumor growth in vivo
Authors
Philipp Nuhn
Beat M Künzli
René Hennig
Tomas Mitkus
Tadas Ramanauskas
Rainer Nobiling
Stefan C Meuer
Helmut Friess
Pascal O Berberat
Publication date
01-12-2009
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2009
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-8-37

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