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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

Discovery Research Laboratories, Nippon Shinyaku Co. Ltd., Kyoto 601-8550 [H. T., K. K., F. K.]; Division of Biochemistry, Aichi Cancer Center Research Institute, Nagoya 464-8681 [N. O.]; Division of Demyelinating Disease and Aging, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502 [M. I.]; and D. Western Therapeutics Institute, Nagoya 466-0825 [H. H.], Japan

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-[4-methoxybenzenesulfonyl]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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