Heme oxygenase-1 and its metabolites affect pancreatic tumor growth <it>in vivo</it>

• Main Authors: Nuhn Philipp, Künzli Beat M, Hennig René, Mitkus Tomas, Ramanauskas Tadas, Nobiling Rainer, Meuer Stefan C, Friess Helmut, Berberat Pascal O
• Format: Article
• Language: English
• Published: BMC 2009-06-01
• Series: Molecular Cancer
• Online Access: http://www.molecular-cancer.com/content/8/1/37

<p>Abstract</p> <p>Background</p> <p>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 <it>in vitro</it>.</p> <p>Therefore, we investigated the effects of HO-1 and its metabolites biliverdin, carbon monoxide and iron on PaCa cells.</p> <p>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 <it>in vivo </it>and <it>in vitro</it>.</p> <p>Results</p> <p>High HO-1 expression in PaCa cell lines was associated with increased chemoresistance <it>in vitro</it>. 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 <it>in vivo </it>significantly. Furthermore, biliverdin and iron promoted PaCa resistance to chemotherapy. Consequently, specific iron chelation by desferrioxamine revealed profound anticancerous effects.</p> <p>Conclusion</p> <p>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 <it>in vivo</it>. 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.</p>