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1.
Cancers (Basel) ; 15(5)2023 Feb 23.
Article in English | MEDLINE | ID: mdl-36900207

ABSTRACT

(1) Background: the potency of drugs that interfere with glucose metabolism, i.e., glucose transporters (GLUT) and nicotinamide phosphoribosyltransferase (NAMPT) was analyzed in neuroendocrine tumor (NET, BON-1, and QPG-1 cells) and small cell lung cancer (SCLC, GLC-2, and GLC-36 cells) tumor cell lines. (2) Methods: the proliferation and survival rate of tumor cells was significantly affected by the GLUT-inhibitors fasentin and WZB1127, as well as by the NAMPT inhibitors GMX1778 and STF-31. (3) Results: none of the NET cell lines that were treated with NAMPT inhibitors could be rescued with nicotinic acid (usage of the Preiss-Handler salvage pathway), although NAPRT expression could be detected in two NET cell lines. We finally analyzed the specificity of GMX1778 and STF-31 in NET cells in glucose uptake experiments. As previously shown for STF-31 in a panel NET-excluding tumor cell lines, both drugs specifically inhibited glucose uptake at higher (50 µM), but not at lower (5 µM) concentrations. (4) Conclusions: our data suggest that GLUT and especially NAMPT inhibitors are potential candidates for the treatment of NET tumors.

2.
Cell Oncol (Dordr) ; 41(5): 485-494, 2018 Oct.
Article in English | MEDLINE | ID: mdl-29949049

ABSTRACT

BACKGROUND: Targeting glucose metabolism is a promising way to interfere with tumor cell proliferation and survival. However, controversy exists about the specificity of some glucose metabolism targeting anticancer drugs. Especially the potency of STF-31 has been debated. Here, we aimed to assess the impact of the glucose transporter (GLUT) inhibitors fasentin and WZB117, and the nicotinamide phosphoribosyltransferase (NAMPT) inhibitors GMX1778 and STF-31 on tumor cell proliferation and survival, as well as on glucose uptake. METHODS: Tumor-derived A172 (glioblastoma), BHY (oral squamous cell carcinoma), HeLa (cervix adenocarcinoma), HN (head neck cancer), HT-29 (colon carcinoma) and MG-63 (osteosarcoma) cells were treated with fasentin, WZB117, GMX1778 and STF-31. Proliferation rates and cell viabilities were assessed using XTT, crystal violet and LDH assays. mRNA and protein expression of GLUT1 and NAPRT were assessed using qPCR and Western blotting, respectively. The effects of inhibiting compounds on glucose uptake were measured using [18F]-fluoro-deoxyglucose uptake experiments. RESULTS: Stimulation of tumor-derived cells with the different inhibitors tested revealed a complex pattern, whereby proliferation inhibiting and survival reducing concentrations varied in [18F]-fluoro-deoxyglucose uptake experiments more than one order of magnitude among the different cells tested. We found that the effects of GMX1778 and STF-31 could be partially abolished by (i) nicotinic acid (NA) only in nicotinic acid phosphoribosyltransferase (NAPRT) expressing cells and (ii) nicotinamide mononucleotide (NMN) in all cells tested, supporting the classification of these compounds as NAMPT inhibitors. In short-time [18F]-fluoro-deoxyglucose uptake experiments the application of WZB-117 was found to lead to an almost complete uptake inhibition in all cells tested, whereas the effect of fasentin was found to be cell type dependent with a maximum value of ~35% in A172, BHY, HeLa and HT-29 cells. We also found that STF-31 inhibited glucose uptake in all cells tested in a range of 25-50%. These data support the classification of STF-31 as a GLUT inhibitor. CONCLUSIONS: Our data reveal a dual mode of action of STF-31, serving either as a NAMPT or as a GLUT inhibitor, whereby the latter seems to be apparent only at higher STF-31 concentrations. The molecular basis of such a dual function and its appearance in compounds previously designated as NAMPT-specific inhibitors requires further investigation.


Subject(s)
Anilides/pharmacology , Biological Transport/drug effects , Glucose Transport Proteins, Facilitative/antagonists & inhibitors , Glucose Transport Proteins, Facilitative/metabolism , Glucose/metabolism , NAD/metabolism , Pyridines/pharmacology , Blotting, Western , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Humans , Hydroxybenzoates/pharmacology , Nicotinamide Phosphoribosyltransferase/metabolism
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