TY - JOUR
T1 - HMN-176, an Active Metabolite of the Synthetic Antitumor Agent HMN-214, Restores Chemosensitivity to Multidrug-Resistant Cells by Targeting the Transcription Factor NF-Y
AU - Tanaka, Hideki
AU - Ohshima, Nobuko
AU - Ikenoya, Mami
AU - Komori, Kinuyo
AU - Katoh, Fumitaka
AU - Hidaka, Hiroyoshi
PY - 2003/10/15
Y1 - 2003/10/15
N2 - HMN-176 ((E)-4-{[2-N-[4-methoxybenzenesulfonyl]amino]stilbazole}1-oxide) is an active metabolite of HMN-214 ((E)-4-{2-[2-(N-acetyl-N-[4methoxybenzenesulfonyl]amino)stilbazole]}1-oxide), which has a potent antitumor activity in mouse xenograft models. In this study, we show that HMN-176 circumvents multidrug resistance in a K2 human ovarian cancer subline selected for Adriamycin resistance (K2/ARS). Upon treatment of K2/ARS cells with 3 μM HMN-176, the GI50 of Adriamycin for the cells decreased by ∼50%. To explore the molecular mechanism of this effect, we assessed the expression of the multidrug resistance gene (MDR1), which is constitutive in K2/ARS cells, at both the protein and the mRNA level. Western and reverse transcription-PCR analysis revealed that the expression of MDR1 was significantly suppressed by treatment with HMN-176. Furthermore, when administered p.o., HMN-214 suppressed the expression of MDR1 mRNA in a mouse xenograft model implanted with KB-A.1, an Adriamycin-resistant cell line. Luciferase reporter fusion gene analysis demonstrated that HMN-176 inhibited the Y-box-dependent promoter activity of the MDR1 gene in a dose-dependent manner. Moreover, we show by electrophoretic mobility shift assay that HMN-176 inhibits the binding of NF-Y, which is thought to be an essential factor for the basal expression of MDR1, to its target Y-box consensus sequence in the MDR-1 promoter. Inhibition of MDR-1 expression was achieved with pharmacological concentrations of HMN-176, suggesting that HMN-176 may act by two different mechanisms-cytotoxicity and MDR1 down-regulation-simultaneously. The data presented strongly suggest that the antitumor mechanism of HMN-176 (or its prodrug HMN-214 in vivo) is quite different from those of known antitumor agents.
AB - HMN-176 ((E)-4-{[2-N-[4-methoxybenzenesulfonyl]amino]stilbazole}1-oxide) is an active metabolite of HMN-214 ((E)-4-{2-[2-(N-acetyl-N-[4methoxybenzenesulfonyl]amino)stilbazole]}1-oxide), which has a potent antitumor activity in mouse xenograft models. In this study, we show that HMN-176 circumvents multidrug resistance in a K2 human ovarian cancer subline selected for Adriamycin resistance (K2/ARS). Upon treatment of K2/ARS cells with 3 μM HMN-176, the GI50 of Adriamycin for the cells decreased by ∼50%. To explore the molecular mechanism of this effect, we assessed the expression of the multidrug resistance gene (MDR1), which is constitutive in K2/ARS cells, at both the protein and the mRNA level. Western and reverse transcription-PCR analysis revealed that the expression of MDR1 was significantly suppressed by treatment with HMN-176. Furthermore, when administered p.o., HMN-214 suppressed the expression of MDR1 mRNA in a mouse xenograft model implanted with KB-A.1, an Adriamycin-resistant cell line. Luciferase reporter fusion gene analysis demonstrated that HMN-176 inhibited the Y-box-dependent promoter activity of the MDR1 gene in a dose-dependent manner. Moreover, we show by electrophoretic mobility shift assay that HMN-176 inhibits the binding of NF-Y, which is thought to be an essential factor for the basal expression of MDR1, to its target Y-box consensus sequence in the MDR-1 promoter. Inhibition of MDR-1 expression was achieved with pharmacological concentrations of HMN-176, suggesting that HMN-176 may act by two different mechanisms-cytotoxicity and MDR1 down-regulation-simultaneously. The data presented strongly suggest that the antitumor mechanism of HMN-176 (or its prodrug HMN-214 in vivo) is quite different from those of known antitumor agents.
UR - http://www.scopus.com/inward/record.url?scp=0142188694&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0142188694&partnerID=8YFLogxK
M3 - Article
C2 - 14583495
AN - SCOPUS:0142188694
SN - 0008-5472
VL - 63
SP - 6942
EP - 6947
JO - Cancer Research
JF - Cancer Research
IS - 20
ER -