Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Oncology, Cell Biology, transgenic mice, cilostazol, tissue array, KIT, cancer, C-KIT, GENE-EXPRESSION, CILOSTAZOL, MODEL, EFFICACY, ISOFORMS, IMATINIB, ORIGIN, SAFETY, PDE3A, Aged, Animals, Antineoplastic Agents, Biomarkers, Tumor, Cell Line, Tumor, Cell Survival, Cilostazol, Cyclic Nucleotide Phosphodiesterases, Type 3, Drug Synergism, Female, Gastrointestinal Stromal Tumors, HEK293 Cells, Humans, Imatinib Mesylate, Interstitial Cells of Cajal, Male, Mice, 129 Strain, Mice, Knockout, Middle Aged, Phosphodiesterase 3 Inhibitors, Pyridazines, Tetrazoles, 1112 Oncology and Carcinogenesis, 3211 Oncology and carcinogenesis

Abstract:

We previously identified phosphodiesterase 3A (PDE3A) as a marker for interstitial cells of Cajal (ICC) in adult mouse gut. However, PDE3A expression and function during gut development and in ICC-derived gastrointestinal stromal tumors (GIST) remained unknown. Here we found that PDE3A was expressed throughout ICC development and that ICC density was halved in PDE3A-deficient mice. In the human imatinib-sensitive GIST882 cell line, the PDE3 inhibitor cilostazol halved cell viability (IC50 0.35 μM) and this effect synergized with imatinib (Chou-Talalay's CI50 0.15). Recently the compound 6-(4-(diethylamino)-3-nitrophenyl)-5-methyl-4,5-dihydropyridazin-3(2H)-one, or DNMDP was found to be cytotoxic selectively for cells expressing both PDE3A and Schlafen12 (SLFN12) (de Waal L et al. Nat Chem Bio 2016), identifying a new, non-catalytic, role for PDE3A. 108 out of 117 (92%) of our human GIST samples displayed both PDE3A and SLFN12 immunoreactivity. GIST882 cells express both PDE3A and SLFN12 and DNMDP decreased their viability by 90%. Our results suggest a role for PDE3A during ICC development and open novel perspectives for PDE3A in targeted GIST therapy, on one hand by the synergism between imatinib and cilostazol, a PDE3 inhibitor already in clinical use for other indications, and, on the other hand, by the neomorphic, druggable, PDE3A-SLFN12 cytotoxic interplay.