Cell cycle synchronisation using thiazolidinediones affects cellular glucose metabolism and enhances the therapeutic effect of 2-deoxyglucose in colon cancer

• Published in: Scientific reports Vol. 10; no. 1; p. 4713
• Main Authors: Yoon, Joon-Kee, Byeon, Hye Eun, Ko, Seung Ah, Park, Bok-Nam, An, Young-Sil, Lee, Ho-Young, Lee, Youn Woo, Lee, Su Jin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13.03.2020; Nature Publishing Group
• Subjects: 631/337; 631/67; 692/4017; 692/4028; Animal models; Animals; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cell cycle; Cell Cycle Checkpoints - drug effects; Cell Cycle Checkpoints - genetics; Cell survival; Colon cancer; Colonic Neoplasms - drug therapy; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Cyclin D1; Cyclin D1 - genetics; Cyclin D1 - metabolism; Cyclin-dependent kinase 4; Cyclin-Dependent Kinase 4 - genetics; Cyclin-Dependent Kinase 4 - metabolism; Deoxyglucose; Deoxyglucose - pharmacology; Deoxyglucose - therapeutic use; Drug Synergism; Drug Therapy, Combination; G1 phase; Gene Expression - drug effects; Glucose; Glucose - metabolism; Glucose Transporter Type 1 - genetics; Glucose Transporter Type 1 - metabolism; Humanities and Social Sciences; Humans; Metabolism; Mice; multidisciplinary; Pioglitazone; Science; Science (multidisciplinary); Thiazolidinediones; Thiazolidinediones - pharmacology; Thiazolidinediones - therapeutic use; Troglitazone; Tumor Cells, Cultured; Tumors; Xenografts
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-61661-4

The effect of cell cycle synchronisation on glucose metabolism in cancer cells is not known. We assessed how cell cycle synchronisation by thiazolidinediones (TZDs) can affect glucose uptake by cancer cells and investigated the anti-cancer effect of combination therapy with TZDs and 2-deoxy-glucose (2-DG) in colon cancer cells and in mouse xenograft models. Troglitazone (58.1 ± 2.0 vs 48.6 ± 1.3%, p  = 0.002) or pioglitazone (82.9 ± 1.9 vs 61.6 ± 3.4%, p  < 0.001) induced cell cycle arrest in SW480 cells at G1 phase. Western blot analysis showed the degradation of cyclin D1 and CDK4, and an increase in the expression levels of p21 and p27 after TZDs treatment. Withdrawal of troglitazone treatment induced significant increase in cellular 3 H-DG uptake (141.5% ± 12.9% of controls) and membrane GLUT1 expression levels (146.3% of controls) by 24 h; 1 mM 2-DG treatment alone decreased cell survival by 5.8% as compared with the controls.; however, combination therapy enhanced the anti-tumour effects to 34.6% or 20.3% as compared with control cells. In vivo , each combination treatment group showed significant anti-tumour effects unlike the 2-DG alone group. Cell cycle synchronisation using TZDs induced cellular glucose uptake, which significantly enhanced the therapeutic effect of 2-DG in colon cancer.