Enhancement of radiosensitivity by a unique novel NF-κB inhibitor, DHMEQ, in prostate cancer.
BACKGROUND
Inducible activation of nuclear factor (NF)-κB is one of the principal mechanisms through which resistant prostate cancer cells are protected from radiotherapy. We hypothesised that inactivation of inducible NF-κB with a novel NF-κB inhibitor, DHMEQ, would increase the therapeutic effects of radiotherapy.


METHODS
PC-3 and LNCaP cells were exposed to irradiation and/or DHMEQ. Cell viability, cell cycle analysis, western blotting assay, and NF-κB activity were measured. The antitumour effect of irradiation combined with DHMEQ in vivo was also assessed.


RESULTS
The combination of DHMEQ with irradiation resulted in cell growth inhibition and G2/M arrest relative to treatment with irradiation alone. Inducible NF-κB activity by irradiation was inhibited by DHMEQ treatment. The expression of p53 and p21 in LNCaP, and of 14-3-3σ in PC-3 cells, was increased in the combination treatment. In the in vivo study, 64 days after the start of treatment, tumour size was 85.1%, 77.1%, and 64.7% smaller in the combination treatment group than that of the untreated control, DHMEQ-treated alone, and irradiation alone groups, respectively.


CONCLUSIONS
Blockade of NF-κB activity induced by radiation with DHMEQ could overcome radio-resistant responses and may become a new therapeutic modality for treating prostate cancer.
Department of Urology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan.
N
N
Kozakai
E
E
Kikuchi
M
M
Hasegawa
E
E
Suzuki
H
H
Ide
A
A
Miyajima
Y
Y
Horiguchi
J
J
Nakashima
K
K
Umezawa
N
N
Shigematsu
M
M
Oya
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001549:Benzamides / Q000494:pharmacology* / Q000627:therapeutic use; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D002455:Cell Division / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D003512:Cyclohexanones / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D011836:Radiation Tolerance / Q000187:drug effects; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001549:Benzamides; D003512:Cyclohexanones; D016328:NF-kappa B; D011838:Radiation-Sensitizing Agents; C464444:dehydroxymethylepoxyquinomicin