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

Abstract

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.The reprogramming of energy metabolism has recently been recognised as a hallmark of cancer 1 . Understanding metabolic differences between normal cells and cancer cells can provide opportunities for both cancer imaging and therapy. Imaging glycolytic shifts in tumours using 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET), which has been widely used in clinical oncology, is a notable example. To treat cancers by targeting tumour metabolism, 2-deoxyglucose (2-DG) inhibits glycolysis, depletes intracellular adenosine triphosphate, and induces autophagy in cancer cells 2 . However, as high concentrations of 2-DG are needed to inhibit the glycolytic metabolism of cancer cells 2,3 , approaches that can enhance the efficacy of 2-DG treatment are crucial.Until now, a lot of agents that can modulate cell cycle in cancer cells have been used or are under development for cancer therapy 4 . However, few studies have examined the effect of cell cycle synchronisation on glucose metabolism in cancer cells. We have previously reported that cell cycle arrest at G1 by T-type calcium channel blocker, mibefradil, induced a subsequent increase in cell population in S phase after drug removal, and increased glucose uptake s in breast cancer cells, which enhanced the therapeutic effects of 2-DG 5 .Peroxisome proliferator activated receptor-γ (PPARγ) is widely expressed in various tumours and cell lines, thus this receptor has become a target for developing new anticancer drugs that can take advantage of the antiproliferative effects mediated through PPAR. Thiazolidinediones (TZDs), such as troglitazone, pioglitazone, ciglitazone, and rosiglitazone are well-known PPARγ ligands. TZDs have been reported to exert anti-tumour effects,...

The troglitazone derivative EP13 disrupts energy metabolism through respiratory chain complex I inhibition in breast cancer cells and potentiates the antiproliferative effect of glycolysis inhibitors

“…In MDA-MB-231 and MCF-7 cells, the combination of 2-DG and metformin resulted in a marked increase in cell death compared to either agent alone [ 48 ]. Treatment with TGZ or PGZ with 2-DG enhanced the antitumour effect of 2-DG in vitro and in vivo [ 52 ]. Similarly, the combination of 2-DG and EP13, used at a constant ratio, showed a synergistic effect on the three breast cancer cell lines MDA-MB-231, Hs578T, and MCF-7.…”

Modulation of FDG Uptake by Cell Cycle Synchronization Using a T-Type Calcium Channel Inhibitor

“…Recently, we have reported that cell cycle synchronization using thiazolidinediones enhanced anticancer effects of 2-DDG [31]. Like mibefradil, troglitazone or pioglitazone induced cell cycle arrest at the G1 phase, and then the withdrawal of these drugs increased 24 h accumulated [ 3 H] DDG uptake and membranous glucose transporter-1 expression.…”

Role of adipocytokines in endometrial cancer progression

“…Thiazolidinediones (TZDs) (rosiglitazone, pioglitazone) are also reported to increase adiponectin levels and decrease leptin, tumor necrosis factor-α (TNF-α), and IL-6 levels through modulatory mechanisms ( Garikapati et al, 2019 ; Biondo et al, 2020 ). Moreover, TZDs have played important roles in preventing progression of hepatocellular carcinoma (HCC) ( Arvind et al, 2021 ), colon cancer ( Yoon et al, 2020 ), and lung cancer ( Konieczna et al, 2015 ). Atorvastatin reduces cardiovascular mortality by increasing levels of adiponectin, which is involved in insulin resistance ( Koh et al, 2005 ; Ando et al, 2008 ).…”