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Effect of calcium electroporation in combination with metformin in vivo and correlation between viability and intracellular ATP level after calcium electroporation in vitro.

ABSTRACT: BACKGROUND:Calcium electroporation is a new experimental anti-cancer treatment where calcium is internalized into cells by application of short, high voltage pulses. Calcium electroporation has been shown to induce tumor necrosis associated with ATP depletion while the effect on normal fibroblasts was limited when investigated in a 3D in vitro spheroid model. We aimed to investigate the effect of calcium electroporation in combination with metformin, a drug that affects intracellular ATP level. We also aimed to study the relationship between the viability and intracellular ATP levels after calcium electroporation in vitro. METHODS:In this study, we investigated the effect of calcium electroporation with metformin on NMRI-Foxn1nu mice in vivo on tumor size, survival, and intracellular ATP. We further investigated viability and intracellular ATP level in vitro after calcium electroporation in two human cancer cell lines: Breast (MDA-MB231) and colon (HT29), and in normal human fibroblasts (HDF-n), as well as investigating viability in human bladder cancer cells (SW780) and human small cell lung cancer cells (H69) where we have previously published intracellular ATP levels. RESULTS:Calcium electroporation significantly reduced the size and ATP level of bladder cancer tumors treated in vivo but no increased effect of metformin combined with calcium electroporation was shown on neither tumor size, survival, nor ATP level. Calcium electroporation in vitro significantly decreased viability compared with calcium alone (p<0.0001 for calcium concentrations from 0.5 mM for H69, HDF-n, and MDA-MB231; p<0.0001 for calcium concentrations from 1 mM for HT29 and SW780). Intracellular ATP levels decreased significantly after calcium electroporation (p<0.05), however no correlation between intracellular ATP level and viability after treatment was observed. CONCLUSION:Calcium electroporation caused reduced tumor size, increased survival, and acute ATP depletion in vivo. This effect was not augmented by metformin. Calcium electroporation is a possible novel anti-cancer treatment that has been shown to cause cell death associated with acute ATP depletion in vitro and in vivo.

SUBMITTER: Frandsen SK

PROVIDER: S-EPMC5526525 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Effect of calcium electroporation in combination with metformin in vivo and correlation between viability and intracellular ATP level after calcium electroporation in vitro.

Frandsen Stine Krog SK Gehl Julie J

PloS one 20170725 7

<h4>Background</h4>Calcium electroporation is a new experimental anti-cancer treatment where calcium is internalized into cells by application of short, high voltage pulses. Calcium electroporation has been shown to induce tumor necrosis associated with ATP depletion while the effect on normal fibroblasts was limited when investigated in a 3D in vitro spheroid model. We aimed to investigate the effect of calcium electroporation in combination with metformin, a drug that affects intracellular ATP ...[more]

PMID: 28742810

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Project description:Intracellular Ca2+ release through the Inositol 1,4,5-Triphosphate Receptor (InsP3R) is a feature of all multicellular organisms in which it shapes the temporal and spatial aspects of calcium signaling in cells, affecting several developmental and physiological processes. Mutants in the InsP3R gene of Drosophila (itpr) exhibit a range of defects which include growth defects and larval lethality.The Drosophila Insulin-like peptides (ILPs) are encoded by multigene families that are expressed in the brain and other tissues. Upon secretion, these peptides likely serve as hormones, neurotransmitters, and growth factors. In Drosophila melanogaster, molecular genetic studies have revealed Drosophila ILPs as elements of a conserved insulin signaling pathway, and as in other animal models, it appears to play a key role in metabolism, growth, reproduction, and aging. Previous work from our group has shown that InsP3R function can be rescued by ectopically expressing InsP3R in dilp cells or can be compensated by altering the activity of Sarco-Endoplasmic Reticulum Calcium-ATPase (SERCA). To understand the molecular basis of larval lethality and growth defect in Drosophila InsP3R mutants and to decipher possible cross talk of itpr gene with other signaling pathways we have carried out genome wide microarray experiments. We have compared the transcript profiles of i) itpr mutant larvae and wild type larvae, ii) dilp rescue larvae with itpr mutant larvae iii) itpr and SERCA double mutant larvae with itpr mutant larvae. By this we have identified genes whose levels are altered in itpr mutants and are restored towards wild type in dilp rescue larvae with itpr mutant larvae and itpr and SERCA double mutants. Our experiments help in identify genes that are regulated by changes in intracellular Ca2+ in the context of larval viability may contribute to the better understanding of the major human pathologies caused by calcium misbalance or by dysregulation of the insulin/IGF pathway. The 8x60k array AMADID: 27326 slide was scanned immediately by PerkinElmer Scan array Gx Microarray scanner. The Scan array software (PerkinElmer) was used for grid wise normalization of array images. Three were used with Mutant, three for Dilp Rescue and two for Kum Rescue experiments . The data was analysed by GeneSpring GX Agilent . The differential expression was considered if the Log 2 mean of at least -1 for the down regulated genes and +1 for the upregulated genes. We considered only the genes that were reproducible from biological triplicates for Mutant, biological treplicates for Dilp Rescue and biological duplicates for Kum Rescue.

Dataset Information

Effect of calcium electroporation in combination with metformin in vivo and correlation between viability and intracellular ATP level after calcium electroporation in vitro.

Publications

Effect of calcium electroporation in combination with metformin in vivo and correlation between viability and intracellular ATP level after calcium electroporation in vitro.

Similar Datasets

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