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

Hideki Tanaka, Nobuko Oshima, Mami Ikenoya, Kinuyo Komori, Fumitaka Katoh, Hiroyoshi Hidaka

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)6942-6947
Number of pages6
JournalCancer Research
Volume63
Issue number20
Publication statusPublished - 15-10-2003

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Antineoplastic Agents
Transcription Factors
Doxorubicin
Heterografts
(E)-4-(2-(2-(N-acetyl-N-(4-methoxybenzenesulfonyl)amino)stilbazole)) 1-oxide
(E)-4-((2-N-(4-methoxybenzenesulfonyl)amino)stilbazole)1-oxide
MDR Genes
Messenger RNA
Consensus Sequence
Prodrugs
Multiple Drug Resistance
Electrophoretic Mobility Shift Assay
Luciferases
Reporter Genes
Ovarian Neoplasms
Oxides
Reverse Transcription
Down-Regulation
Pharmacology
Cell Line

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Tanaka, Hideki ; Oshima, Nobuko ; Ikenoya, Mami ; Komori, Kinuyo ; Katoh, Fumitaka ; Hidaka, Hiroyoshi. / 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. In: Cancer Research. 2003 ; Vol. 63, No. 20. pp. 6942-6947.
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abstract = "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.",
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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. / Tanaka, Hideki; Oshima, Nobuko; Ikenoya, Mami; Komori, Kinuyo; Katoh, Fumitaka; Hidaka, Hiroyoshi.

In: Cancer Research, Vol. 63, No. 20, 15.10.2003, p. 6942-6947.

Research output: Contribution to journalArticle

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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 - Oshima, Nobuko

AU - Ikenoya, Mami

AU - Komori, Kinuyo

AU - Katoh, Fumitaka

AU - Hidaka, Hiroyoshi

PY - 2003/10/15

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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.

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