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

Abstract

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.

• Authors: Irina I Zaitseva, Sergei V Zaitsev, Per-Olof Berggren
• Journal: Investigational new drugs (Invest New Drugs) Vol. 34 Issue 4 Pg. 522-9 (08 2016) ISSN: 1573-0646 [Electronic] United States
• PMID: 27221730 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-(2-imidazolin-2-yl)-1-phenyl-1H-indole
• Antineoplastic Agents
• BL 11282
• Imidazoles
• Indoles
• Ribonucleosides
• Aminoimidazole Carboxamide
• acadesine
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (metabolism)
• Aminoimidazole Carboxamide (analogs & derivatives, pharmacology)
• Animals
• Antineoplastic Agents (pharmacology)
• Cell Death (drug effects)
• Cell Line
• Imidazoles (pharmacology)
• Indoles (pharmacology)
• Insulin-Secreting Cells (drug effects)
• Insulinoma (drug therapy, metabolism)
• Mice, Obese
• Phosphorylation (drug effects)
• Ribonucleosides (pharmacology)