Energy metabolism transition in multi‐cellular human tumor spheroids

Abstract

It is thought that glycolysis is the predominant energy pathway in cancer, particularly in solid and poorly vascularized tumors where hypoxic regions develop. To evaluate whether glycolysis does effectively predominate for ATP supply and to identify the underlying biochemical mechanisms, the glycolytic and oxidative phosphorylation (OxPhos) fluxes, ATP/ADP ratio, phosphorylation potential, and expression and activity of relevant energy metabolism enzymes were determined in multi-cellular tumor spheroids, as a model of human solid tumors. In HeLa and Hek293 young-spheroids, the OxPhos flux and cytochrome c oxidase protein content and activity were similar to those observed in monolayer cultured cells, whereas the glycolytic flux increased two- to fourfold; the contribution of OxPhos to ATP supply was 60%. In contrast, in old-spheroids, OxPhos, ATP content, ATP/ADP ratio, and phosphorylation potential diminished 50-70%, as well as the activity (88%) and content (3 times) of cytochrome c oxidase. Glycolysis and hexokinase increased significantly (both, 4 times); consequently glycolysis was the predominant pathway for ATP supply (80%). These changes were associated with an increase (3.3 times) in the HIF-1alpha content. After chronic exposure, both oxidative and glycolytic inhibitors blocked spheroid growth, although the glycolytic inhibitors, 2-deoxyglucose and gossypol (IC(50) of 15-17 nM), were more potent than the mitochondrial inhibitors, casiopeina II-gly, laherradurin, and rhodamine 123 (IC(50) > 100 nM). These results suggest that glycolysis and OxPhos might be considered as metabolic targets to diminish cellular proliferation in poorly vascularized, hypoxic solid tumors.

Continuously perfused microbubble array for 3D tumor spheroid model

“…They have been investigated in the contexts of experimental radiotherapy, photodynamic treatment, hyperthermia, and target specific chemotherapy and immunotherapy. [10][11][12][13][14] Moreover, recent studies have shown that the gene expression profiles, 15,16 growth kinetics and metabolic rates 16 of MCTSs are similar to clinical conditions and hence, are believed to mimic in vivo solid tumors in their response to new drug targets and immunological factors. Therefore, MCTSs could help eliminate less efficient cancer drugs and therapies in earlier stages of testing before they enter expensive animal testing, and promote innovative drug targets that would otherwise fail in the traditional drug screening assays.…”

Loss of VOPP1 overexpression in squamous carcinoma cells induces apoptosis through oxidative cellular injury

“…Of particular interest is the notion that mitochondrial functions such as oxidative phosphorylation become dysregulated in the neoplastic condition. [32][33][34][35][36][37][38][39] VOPP1 overexpression in neoplasia may function to somehow neutralize ROS that form as a by-product of dysregulated mitochondrial function, potentially through the vesicular structures to which this protein has been localized. 3 supported by a gift provided to the University of Virginia by Philip Morris (PM) USA.…”

Detection and Quantification of the Evolution Dynamics of Apoptosis Using the PET Voltage Sensor 18F-Fluorobenzyl Triphenyl Phosphonium

“…A significant drop in breast tumor standardized uptake value, however, may occur late in the treatment, by the end of the first cycle of chemotherapy (31) and as early as 8 d after treatment in responders (32). The mechanisms contributing to the delay of 18 F-FDG response are still far from clear, but may be attributed to the unique metabolic plasticity of the regeneration of adenosine triphosphate by the cancer cell via both oxidative phosphorylation and glycolysis (33,34). The present study provides evidence that 18 F-FBnTP permits the detection of the apoptotic action of docetaxel earlier than that afforded by 18 F-FDG.…”