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


CONCLUSIONS
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.
Nuhn
Philipp
P
Department of Surgery, Technische Universität München, Munich, Germany. nuhn.philipp@gmail.com
Künzli
Beat M
BM
Hennig
René
R
Mitkus
Tomas
T
Ramanauskas
Tadas
T
Nobiling
Rainer
R
Meuer
Stefan C
SC
Friess
Helmut
H
Berberat
Pascal O
PO
D000704:Analysis of Variance; D000818:Animals; D001664:Biliverdine / Q000378:metabolism; D002248:Carbon Monoxide / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003035:Cobalt / Q000378:metabolism; D003676:Deferoxamine / Q000378:metabolism; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005260:Female; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007501:Iron / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D017262:Siderophores / Q000378:metabolism; D015032:Zinc / Q000378:metabolism
D017262:Siderophores; D003035:Cobalt; D002248:Carbon Monoxide; D007501:Iron; D051547:Heme Oxygenase-1; D003676:Deferoxamine; D015032:Zinc; D001664:Biliverdine