Targeting glucose transport and the NAD pathway in tumor cells with STF-31: a re-evaluation
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.
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.
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.
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.
KeywordsFasentin Glucose transporter GMX1778 NAMPT STF-31 WZB117
Compliance with ethical standards
Conflict of interest
- 7.P.E. Porporato, S. Dhup, R.K. Dadhich, T. Copetti, P. Sonveaux, Anticancer targets in the glycolytic metabolism of tumors: A comprehensive review. Front Pharmacol 2, 49 (2011)Google Scholar
- 12.D.A. Chan, P.D. Sutphin, P. Nguyen, S. Turcotte, E.W. Lai, A. Banh, G.E. Reynolds, J.T. Chi, J. Wu, D.E. Solow-Cordero, M. Bonnet, J.U. Flanagan, D.M. Bouley, E.E. Graves, W.A. Denny, M.P. Hay, A.J. Giaccia, Targeting GLUT1 and the Warburg effect in renal cell carcinoma by chemical synthetic lethality. Sci Transl Med 3, 94ra70 (2011)PubMedPubMedCentralGoogle Scholar
- 14.E.M. Kropp, B.J. Oleson, K.A. Broniowska, S. Bhattacharya, A.C. Chadwick, A.R. Diers, Q. Hu, D.E. Sahoo, N. Hogg, K.R. Boheler, J.A. Corbett, R.L. Gundry, Inhibition of an NAD+ salvage pathway provides efficient and selective toxicity to human pluripotent stem cells. Stem Cells Transl Med 4, 483–493 (2015)CrossRefPubMedPubMedCentralGoogle Scholar
- 15.K.R. Boheler, S. Bhattacharya, E.M. Kropp, S. Chuppa, D.R. Riordon, D. Bausch-Fluck, P.W. Burridge, J.C. Wu, R.P. Wersto, G.C. Chan, S. Rao, B. Wollscheid, R.L. Gundry, A human pluripotent stem cell surface N-glycoproteome resource reveals markers, extracellular epitopes, and drug targets. Stem Cell Rep 3, 185–203 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
- 19.T. Murmann, C. Carrillo-García, N. Veit, C. Courts, A. Glassmann, V. Janzen, B. Madea, M. Reinartz, A. Harzen, M. Nowak, S. Perner, J. Winter, R. Probstmeier, Staurosporine and extracellular matrix proteins mediate the conversion of small cell lung carcinoma cells into a neuron-like phenotype. PLoS One 9, e86910 (2014)CrossRefPubMedPubMedCentralGoogle Scholar
- 21.M. Watson, A. Roulston, L. Bélec, X. Billot, R. Marcellus, D. Bédar, C. Bernier, S. Branchaud, H. Chan, K. Dairi, K. Gilbert, D. Goulet, M.O. Gratton, H. Isakau, A. Jang, A. Khadir, E. Koch, M. Lavoie, M. Lawless, M. Nguyen, D. Paquette, E. Turcotte, A. Berger, M. Mitchell, G.C. Shore, P. Beauparlant, The small molecule GMX1778 is a potent inhibitor of NAD+ biosynthesis: Strategy for enhanced therapy in nicotinic acid phosphoribosyltransferase 1-deficient tumors. Mol Cell Biol 29, 5872–5888 (2009)CrossRefPubMedPubMedCentralGoogle Scholar
- 22.Y. Xiao, K. Elkins, J.K. Durieux, L. Lee, J. Oeh, L.X. Yang, X. Liang, C. DelNagro, J. Tremayne, M. Kwong, B.M. Liederer, P.K. Jackson, L.D. Belmont, D. Sampath, T. O'Brien, dependence of tumor cell lines and patient-derived tumors on the NAD salvage pathway renders them sensitive to NAMPT inhibition with GNE-618. Neoplasia 15, 1151–1160 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
- 23.F. Sahm, I. Oezen, C.A. Opitz, B. Radlwimmer, A. von Deimling, T. Ahrendt, S. Adams, H.B. Bode, G.J. Guillemin, W. Wick, M. Platten, The endogenous tryptophan metabolite and NAD+ precursor quinolinic acid confers resistance of gliomas to oxidative stress. Cancer Res 73, 3225–3234 (2013)CrossRefPubMedGoogle Scholar
- 24.T. O'Brien, J. Oeh, Y. Xiao, X. Liang, A. Vanderbilt, A. Qin, L. Yang, L.B. Lee, J. Ly, E. Cosino, J.A. LaCap, A. Ogasawara, S. Williams, M. Nannini, B.M. Liederer, P. Jackson, P.S. Dragovich, D. Sampath, Supplementation of nicotinic acid with NAMPT inhibitors results in loss of in vivo efficacy in NAPRT1-deficient tumor models. Neoplasia 15, 1314–1329 (2013)CrossRefPubMedPubMedCentralGoogle Scholar
- 25.D.J. Stewart, G.P. Raaphorst, J. Yau, A.R. Beaubien, Active vs. passive resistance, dose-response relationships, high dose chemotherapy, and resistance modulation: A hypothesis. Investig New Drugs 14, 115–130 (1996)Google Scholar