TY - JOUR
T1 - Targeting glucose and glutamine metabolism combined with radiation therapy in non-small cell lung cancer
AU - Meijer, Tineke W. H.
AU - Peeters, Wenny J. M.
AU - Dubois, Ludwig J.
AU - van Gisbergen, Marike W.
AU - Biemans, Rianne
AU - Venhuizen, Jan-Hendrik
AU - Span, Paul N.
AU - Bussink, Johan
PY - 2018/12
Y1 - 2018/12
N2 - Purpose: Metabolic inhibition might sensitize tumors to irradiation. Here, we examined the effect of lonidamine (several metabolic effects, inhibiting hexokinase amongst others) and/or 968 (glutaminase inhibitor) on tumor cell metabolism, cell growth, cytotoxicity and radiosensitivity in NSCLC cell lines in vitro in relation to histology.Materials and methods: Adeno- (H23, HCC827, H1975) and squamous cell carcinoma (H520, H292, SW900) NSCLC cells were treated with lonidamine and/or 968 for 72 h under physiological levels of glucose (1.5 mM). Cells were irradiated with 0, 4 or 8 Gy. Cell growth of H2B-mCherry transduced cells and cytotoxicity (CellTox (TM) Green Cytotoxicity Assay) were measured using live cell imaging (IncuCyte). Inhibitory effects on metabolic profiles was determined using the Seahorse XF96 extracellular Flux analyzer.Results: NSCLC cell lines responded differently to glycolysis (lonidamine) and/or glutaminase (968) inhibition, largely corresponding with changes in glycolytic and mitochondrial metabolism upon treatment. Response patterns were not related to histology. 968 was cytotoxic in cell lines with high glutaminase C expression (H1975 and H520), whereas combination treatment was cytotoxic in KRAS mutated cell lines SW900 and H23. H292 and HCC827 were resistant to combination treatment. Treatment with 968 and especially lonidamine resulted in radiosensitization of H292 and HCC827 in terms of decreased relative cell growth and increased cytotoxicity.Conclusion: NSCLC is a heterogeneous disease, which is reflected in the response of different cell lines to the treatment (combinations) reported here. Only a part of NSCLC patients may benefit from the combination of radiation therapy and metabolic inhibition, making stratification necessary.
AB - Purpose: Metabolic inhibition might sensitize tumors to irradiation. Here, we examined the effect of lonidamine (several metabolic effects, inhibiting hexokinase amongst others) and/or 968 (glutaminase inhibitor) on tumor cell metabolism, cell growth, cytotoxicity and radiosensitivity in NSCLC cell lines in vitro in relation to histology.Materials and methods: Adeno- (H23, HCC827, H1975) and squamous cell carcinoma (H520, H292, SW900) NSCLC cells were treated with lonidamine and/or 968 for 72 h under physiological levels of glucose (1.5 mM). Cells were irradiated with 0, 4 or 8 Gy. Cell growth of H2B-mCherry transduced cells and cytotoxicity (CellTox (TM) Green Cytotoxicity Assay) were measured using live cell imaging (IncuCyte). Inhibitory effects on metabolic profiles was determined using the Seahorse XF96 extracellular Flux analyzer.Results: NSCLC cell lines responded differently to glycolysis (lonidamine) and/or glutaminase (968) inhibition, largely corresponding with changes in glycolytic and mitochondrial metabolism upon treatment. Response patterns were not related to histology. 968 was cytotoxic in cell lines with high glutaminase C expression (H1975 and H520), whereas combination treatment was cytotoxic in KRAS mutated cell lines SW900 and H23. H292 and HCC827 were resistant to combination treatment. Treatment with 968 and especially lonidamine resulted in radiosensitization of H292 and HCC827 in terms of decreased relative cell growth and increased cytotoxicity.Conclusion: NSCLC is a heterogeneous disease, which is reflected in the response of different cell lines to the treatment (combinations) reported here. Only a part of NSCLC patients may benefit from the combination of radiation therapy and metabolic inhibition, making stratification necessary.
KW - Glycolysis
KW - Glutamine metabolism
KW - Metabolic inhibition
KW - Radiotherapy
KW - Non-small cell lung cancer
KW - MITOCHONDRIAL
KW - ADENOCARCINOMA
KW - RADIOTHERAPY
KW - EXPRESSION
KW - CLASSIFICATION
KW - DEPENDENCIES
KW - SENSITIVITY
KW - GLUTATHIONE
KW - INHIBITION
KW - LONIDAMINE
U2 - 10.1016/j.lungcan.2018.10.016
DO - 10.1016/j.lungcan.2018.10.016
M3 - Article
C2 - 30527190
SN - 0169-5002
VL - 126
SP - 32
EP - 40
JO - Lung Cancer
JF - Lung Cancer
ER -