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The imidazoline compound RX871024 promotes insulinoma cell death independent of AMP-activated protein kinase inhibition

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Summary

We have previously shown that the insulinotropic imidazoline compound RX871024 induces death of insulinoma MIN6 cells, an effect involving stimulation of c-Jun N-terminal kinase (JNK) and caspase 3. It has also been reported that AMP-activated protein kinase (AMPK) activates JNK and induces β-cell death. Here we show that RX871024, but not another insulinotropic imidazoline compound (BL11282), suppressed AMPK activity in MIN6 cells. The inhibitory effect of RX871024 on AMPK was supported by the observation that the imidazoline induced lipid droplet formation in the cytoplasm of MIN6 cells. This reflects stimulation of anabolic pathways and inhibition of catabolic pathways in the cell that happen under conditions when AMPK is inhibited. Activation of AMPK by 5-aminoimidazole-4-carboxamide riboside (AICAR) elevated basal and cytokine-induced death in primary β-cells and in insulinoma MIN6 cells. RX871024 aggravated AICAR-induced insulinoma MIN6 cell death regardless of the presence of pro-inflammatory cytokines. The specific cytotoxic effect of imidazoline compound RX871024 on insulinoma cell death but not primary β-cell death is independent of its action on AMPK and may suggest the possibility of using this type of compound in the treatment of insulinomas.

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Acknowledgments

This work was supported by Grant N5-2001-34 from the Juvenile Diabetes Foundation International, the Swedish Foundation for Strategic Research, the European Foundation for the Study of Diabetes, the Swedish Research Council, the Swedish Diabetes Association, the Novo Nordisk Foundation, The Family Erling-Persson Foundation, the Knut and Alice Wallenberg Foundation, Torsten and Ragnar Söderberg Foundation, Berth von Kantzow’s Foundation, the Stichting af Jochnick Foundation, the Strategic Research Program in Diabetes at Karolinska Institutet, Skandia Insurance Company, Ltd., Karolinska Institutet, and Novo Nordisk A/S.

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Authors and Affiliations

  1. The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Karolinska University Hospital, L1, 17176, Stockholm, SE, Sweden

    Irina I. Zaitseva, Sergei V. Zaitsev & Per-Olof Berggren

  2. Belozersky Institute of Physico-Chemical Biology and Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Moscow, 119992, Russia

    Sergei V. Zaitsev

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  1. Irina I. Zaitseva
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  2. Sergei V. Zaitsev
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  3. Per-Olof Berggren
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Correspondence to Sergei V. Zaitsev.

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All experiments involving animals were approved by the Animal Experiment Ethics Committee at Karolinska Institutet.

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Zaitseva, I.I., Zaitsev, S.V. & Berggren, PO. The imidazoline compound RX871024 promotes insulinoma cell death independent of AMP-activated protein kinase inhibition. Invest New Drugs 34, 522–529 (2016). https://doi.org/10.1007/s10637-016-0362-7

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  • DOI: https://doi.org/10.1007/s10637-016-0362-7

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