Molecularly targeted radiosensitization of human prostate cancer by modulating inhibitor of apoptosis.
OBJECTIVE
The inhibitor of apoptosis proteins (IAP) are overexpressed in hormone-refractory prostate cancer, rendering the cancer cells resistant to radiation. This study aims to investigate the radiosensitizing effect of small-molecule IAP inhibitor both in vitro and in vivo in androgen-independent prostate cancer and the possible mechanism of radiosensitization.


METHODS
Radiosensitization of SH-130 in human prostate cancer DU-145 cells was determined by clonogenic survival assay. Combination effect of SH-130 and ionizing radiation was evaluated by apoptosis assays. Pull-down and immunoprecipitation assays were employed to investigate the interaction between SH-130 and IAPs. DU-145 xenografts in nude mice were treated with SH-130, radiation, or combination, and tumor suppression effect was determined by caliper measurement or bioluminescence imaging. Nuclear factor-kappaB activation was detected by luciferase reporter assay and quantitative real-time PCR.


RESULTS
SH-130 potently enhanced radiation-induced caspase activation and apoptosis in DU-145 cells. Both X-linked IAP and cIAP-1 can be pulled down by SH-130 but not by inactive SH-123. Moreover, SH-130 interrupted interaction between X-linked IAP/cIAP-1 and Smac. In a nude mouse xenograft model, SH-130 potently sensitized the DU-145 tumors to X-ray radiation without increasing systemic toxicity. The combination therapy suppressed tumor growth more significantly than either treatment alone, with over 80% of complete tumor regression. Furthermore, SH-130 partially blocked tumor necrosis factor-alpha- and radiation-induced nuclear factor-kappaB activation in DU-145 cells.


CONCLUSIONS
Our results show that small-molecule inhibitors of IAPs can overcome apoptosis resistance and radiosensitize human prostate cancer with high levels of IAPs. Molecular modulation of IAPs may improve the outcome of prostate cancer radiotherapy.
Dai
Yao
Y
Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan 48109-0582, USA.
Liu
Meilan
M
Tang
Wenhua
W
DeSano
Jeffrey
J
Burstein
Ezra
E
Davis
Mary
M
Pienta
Kenneth
K
Lawrence
Theodore
T
Xu
Liang
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000528:radiation effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D047468:Immunoprecipitation; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D016328:NF-kappa B / Q000187:drug effects / Q000528:radiation effects; D009842:Oligopeptides / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000628:therapy*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D011878:Radiotherapy; D020133:Reverse Transcriptase Polymerase Chain Reaction; D023041:Xenograft Model Antitumor Assays
D051034:Inhibitor of Apoptosis Proteins; D016328:NF-kappa B; D009842:Oligopeptides; D011838:Radiation-Sensitizing Agents; C534849:SH-130