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Cancer

Direct Therapeutic Applications of Calcium Electroporation to Effectively Induce Tumor Necrosis

By | Cancer

Direct Therapeutic Applications of Calcium Electroporation to Effectively Induce Tumor Necrosis

Stine Krog Frandsen, Hanne Gissel, Pernille Hojman, Trine Tramm, Jens Eriksen, and Julie Gehl

Electroporation of cells with short, high-voltage pulses causes a transient permeabilization of cell membranes that permits passage of otherwise nonpermeating ions and molecules. In this study, we illustrate how electro- poration with isotonic calcium can achieve highly effective cancer cell kill in vivo. Calcium electroporation elicited dramatic antitumor responses in which 89% of treated tumors were eliminated. Histologic analyses indicated complete tumor necrosis. Mechanistically, calcium electroporation caused acute ATP depletion likely due to a combination of increased cellular use of ATP, decreased production of ATP due to effects on the mitochondria, as well as loss of ATP through the permeabilized cell membrane. Taken together, our findings offer a preclinical proof of concept for the use of electroporation to load cancer cells with calcium as an efficient anticancer treat- ment. Electroporation equipment is already used clinically to enhance the delivery of chemotherapy to superficial tumors, with trials on internal tumors in progress, enabling the introduction of calcium electroporation to clini- cal use. Moreover, the safety profile, availability, and low cost of calcium facilitate access to this technology for many cancer patients in developed and developing countries.

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Dose-Dependent ATP Depletion and Cancer Cell Death following Calcium Electroporation, Relative Effect of Calcium Concentration and Electric Field Strength

By | Cancer

Dose-Dependent ATP Depletion and Cancer Cell Death following Calcium Electroporation, Relative Effect of Calcium Concentration and Electric Field Strength

Emilie Louise Hansen, Esin Bengisu Sozer, Stefania Romeo, Stine Krog Frandsen, P. Thomas Vernier, Julie Gehl

Electroporation, a method for increasing the permeability of membranes to ions and small molecules, is used in the clinic with chemotherapeutic drugs for cancer treatment (electro- chemotherapy). Electroporation with calcium causes ATP (adenosine triphosphate) deple- tion and cancer cell death and could be a novel cancer treatment. This study aims at understanding the relationship between applied electric field, calcium concentration, ATP depletion and efficacy.

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Calcium, Magnesium, and Colorectal Cancer

By | Cancer

Calcium, Magnesium, and Colorectal Cancer

Qi Dai, Robert S. Sandler, Elizabeth L. Barry, Robert W. Summers, Maria V. Grau, and
John A. Baron

High calcium consumption may confer a reduced risk of colorectal cancer.1,2 Dai and colleagues recently reported in a case-control study that intake of calcium may be associated with a decreased risk of colorectal adenoma only when the dietary calcium:magnesium intake ratio is low. This finding provides one possible interpretation for inconsistencies in previous studies of the association of calcium intake with risk of colorectal neoplasia.

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Interaction of Papillomavirus E6 Oncoproteins with a Putative Calcium-Binding Protein

By | Cancer

Interaction of Papillomavirus E6 Oncoproteins with a Putative Calcium-Binding Protein

Jason J. Chen, Carl E. Reid, Vir:nla Band, Elliot J. Androphy

Human papillomaviruses (HPVs) are associated with the majority of cervical cancers and encode a transforming protein, E6, that interacts with the tumor suppressor protein p53. Because E6 has p53-independent transforming activity, the yeast two-hybrid system was used to search for other E6-binding proteins. One such protein, E6BP, interacted with cancer-associated HPV E6 and with bovine papillomavirus type 1 (BPV-1) E6. The trans¬forming activity of BPV-1 E6 mutants correlated with their E6BP-binding ability. E6BP is identical to a putative calcium-binding protein, ERC-55, that appears to be localized in the endoplasmic reticulum.

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Recognition of the tumor suppressor protein p53 and other protein targets by the calcium-binding protein S100B

By | Cancer

Recognition of the tumor suppressor protein p53 and other protein targets by the calcium-binding protein S100B

Paul T. Wilder, Jing Lin, Catherine L. Bair, Thomas H. Charpentier, Dong Yang, Melissa Liriano, Kristen M. Varney, Andrew Lee, Amos. Oppenheim, Sankar Adhya, France Carrier, David J. Weber

S100B is an EF-hand containing calcium-binding protein of the S100 protein family that exerts its biological effect by binding and affecting various target proteins. A consensus sequence for S100B target proteins was published as (K/R)(L/I)xWxxIL and matches a region in the actin capping protein CapZ (V.V. Ivanenkov, G.A. Jamieson, Jr., E. Gruenstein, R.V. Dimlich, Characterization of S-100b binding epitopes. Identification of a novel target, the actin capping protein, CapZ, J. Biol. Chem. 270 (1995) 14651–14658). Several additional S100B targets are known including p53, a nuclear Dbf2 related (NDR) kinase, the RAGE receptor, neuromodulin, protein kinase C, and others. Examining the binding sites of such targets and new protein sequence searches provided additional potential target proteins for S100B including Hdm2 and Hdm4, which were both found to bind S100B in a calcium-dependent manner. The interaction between S100B and the Hdm2 and/or the Hdm4 proteins may be important physiologically in light of evidence that like Hdm2, S100B also contributes to lowering protein levels of the tumor suppressor protein, p53. For the S100B–p53 interaction, it was found that phosphorylation of specific serine and/or threonine residues reduces the affinity of the S100B–p53 interaction by as much as an order of magnitude, and is important for protecting p53 from S100B-dependent down- regulation, a scenario that is similar to what is found for the Hdm2–p53 complex.

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Calcium electroporation in three cell lines: a comparison of bleomycin and calcium, calcium compounds, and pulsing conditions

By | Cancer

Calcium electroporation in three cell lines: a comparison of bleomycin and calcium, calcium compounds, and pulsing conditions

Stine Krog Frandsen, Hanne Gissel, Pernille Hojman, Jens Eriksen, Julie Gehl

Background: Electroporation with calcium (calcium electroporation) can induce ATP depletion-associated cellu- lar death. In the clinical setting, the cytotoxic drug bleomycin is currently used with electroporation (electrochemotherapy) for palliative treatment of tumors. Calcium electroporation offers several advantages over standard treatment options: calcium is inexpensive and may readily be applied without special precautions, as is the case with cytostatic drugs. Therefore, details on the use of calcium electroporation are essential for carrying out clinical trials comparing calcium electroporation and electrochemotherapy.
Methods: The effects of calcium electroporation and bleomycin electroporation (alone or in combination) were compared in three different cell lines (DC-3F, transformed Chinese hamster lung fibroblast; K-562, human leuke- mia; and murine Lewis Lung Carcinoma). Furthermore, the effects of electrical pulsing parameters and calcium compound on treatment efficacy were determined.
Results: Electroporation with either calcium or bleomycin significantly reduced cell survival (p b 0.0001), without evidence of a synergistic effect. Cellular death following calcium or bleomycin treatment occurred at similar applied voltages, suggesting that similar parameters should be applied. At equimolar concentrations, calcium chloride and calcium glubionate resulted in comparable decreases in cell viability.
Conclusions: Calcium electroporation and bleomycin electroporation significantly reduce cell survival at similar applied voltage parameters. The effect of calcium electroporation is independent of calcium compound. General significance: This study strongly supports the use of calcium electroporation as a potential cancer therapy and the results may aid in future clinical trials.

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Calcium, Calcineurin and the Control of Transcription

By | Cancer

Calcium, Calcineurin and the Control of Transcription

Gerald R. Crabtree, The American Society for Biochemistry and Molecular Biology, Inc.

Calcineurin (PP2B), a serine threonine kinase controlled by cellular calcium, was originally identified by Klee and colleagues in extracts of mammalian brain. Within the past few years this phosphatase has been implicated in a wide variety of biological responses including lymphocyte activation, neuronal and muscle development, axonal pathfinding and morphogenesis of vertebrate heart valves. Progress in this area has been greatly accelerated by the drugs cyclosporin A and FK506, which use a unique mechanism of action to achieve near genome-specific nanamolar inhibition of calcineurin. This minireview will focus on the role of calcineurin in regulating transcription during development, primarily through its dephosphorylation of downstream targets, such as the cytoplasmic subunits of the NF-AT transcription complex.

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Regulation of calcium signaling in lung cancer

By | Cancer

Regulation of calcium signaling in lung cancer

Haihong Yang, Qi Zhang, Jianxing He, Wenju Lu

Lung cancer is the most common malignant tumor in the world. Calcium is a ubiquitous cellular signal, which is crucial in cancer. This re- view presents regulation of calcium signaling in lung cancer. Altered expression of specific Ca2+ channels and Ca2+-binding proteins are characterizing features of lung cancer, which regulate cell signaling pathway leading to cell proliferation or apoptosis. Chemoresistance is frequent in lung cancer. Altered endoplasmic reticulum Ca2+ homeostasis of lung cancer cell is correlated with drug resistance. Hypoxia has a vital role in tumor angiogenesis, metastasis, apoptosis. And Ca2+ channels are open induced by hypoxia with the increase of Ca2+ influx causing tumor growth.

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