Inhibition of heme oxygenase-1 enhances the cytotoxic effect of gemcitabine in urothelial cancer cells.
BACKGROUND
Elevated heme oxygenase-1 (HO-1) is associated with resistance to chemo- and radiotherapy through anti-apoptotic function. The present study evaluated whether the HO-1 inhibitor, zinc protoporphyrin IX (ZnPP), enhances the cytotoxic effect of gemcitabine in urothelial carcinoma (UC).


METHODS
The in vitro cytotoxic effect of combination treatment of gemcitabine and ZnPP on UC cells was examined. The in vivo growth inhibitory effects of intraperitoneal administration of gemcitabine and/or ZnPP on mouse subcutaneous tumours were examined. The apoptotic changes were analysed with the detection of DNA fragmentation and cleaved caspase-3.


RESULTS
HO-1 was up-regulated by both gemcitabine and irradiation treatment in vitro. ZnPP sensitised the UC cells to both therapies. Enhanced apoptosis was induced by the ZnPP combined with gemicitabine. ZnPP enhanced the antitumour effect of gemcitabine in vivo along with decreased numbers of proliferating cells and increased numbers of apoptotic cells.


CONCLUSIONS
These findings suggest that ZnPP combined with gemcitabine or irradiation therapy may be an effective therapeutic modality for UC patients.
Miyake
Makito
M
Department of Urology, Nara Medical University, Nara, 634-8522, Japan. mm-ulo@naramed-u.ac.jp
Fujimoto
Kiyohide
K
Anai
Satoshi
S
Ohnishi
Sayuri
S
Nakai
Yasushi
Y
Inoue
Takeshi
T
Matsumura
Yoshiaki
Y
Tomioka
Atsushi
A
Ikeda
Tomohiro
T
Okajima
Eijiro
E
Tanaka
Nobumichi
N
Hirao
Yoshihiko
Y
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D019610:Cytoprotection; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D005260:Female; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D011524:Protoporphyrins / Q000494:pharmacology; D011836:Radiation Tolerance; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
D000964:Antimetabolites, Antineoplastic; D011524:Protoporphyrins; D003841:Deoxycytidine; C017803:zinc protoporphyrin; D051547:Heme Oxygenase-1; D000093542:Gemcitabine