Suppression of hormone-refractory prostate cancer by a novel nuclear factor kappaB inhibitor in nude mice.
We have synthesized and explored the feasibility of using a novel nuclear factor (NF) kappaB inhibitor, a dehydroxymethylepoxyquinomicin designated as DHMEQ, against prostate cancer. The activity of NFkappaB, evaluated by transient transfection of a luciferase reporter DNA containing a specific binding sequence for NFkappaB, was inhibited by DHMEQ in three human hormone-refractory prostate cancer cell lines, DU145, JCA-1, and PC-3. Statistically significant growth inhibition was achieved by 20 micro g/ml of DHMEQ, and marked levels of apoptosis were induced 48 h after DHMEQ administration in vitro. Electrophoretic mobility shift assay showed that DHMEQ completely inhibited NFkappaB DNA binding activity in JCA-1 cells. Furthermore, i.p. administrations of DHMEQ significantly inhibited pre-established JCA-1 s.c. tumor growth in nude mice without any side effects. Our result indicates the possibility of using a novel NFkappaB activation inhibitor, DHMEQ, as a new treatment strategy against hormone-refractory prostate cancer.
Kikuchi
Eiji
E
Department of Urology, Keio University, School of Medicine, Tokyo 160-8582, USA.
Horiguchi
Yutaka
Y
Nakashima
Jun
J
Kuroda
Kenji
K
Oya
Mototsugu
M
Ohigashi
Takashi
T
Takahashi
Nozomu
N
Shima
Yutaka
Y
Umezawa
Kazuo
K
Murai
Masaru
M
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000627:therapeutic use*; D002455:Cell Division / Q000187:drug effects; D003512:Cyclohexanones / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D014407:Tumor Cells, Cultured
D001549:Benzamides; D003512:Cyclohexanones; D016328:NF-kappa B; C464444:dehydroxymethylepoxyquinomicin