Holden Comprehensive Cancer Center

Iowa City, IA, United States

Holden Comprehensive Cancer Center

Iowa City, IA, United States
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Cancer is a huge obstacle and challenge in the medical world and numerous studies have been done in order to find ways to cure or treat the deadly disease. Some researchers focus on developing drugs that would help patients cope with the harsh effects of chemotherapy, while others look into natural treatments. Tech Times reported on March 24 that a doctor stumbled upon a cure for sepsis and the key is vitamin C. We also reported on March 27 that researchers from the University of Salford Manchester tested different natural substances on cancer stem cells and found that vitamin C seems the most promising in obliterating them. Now a team of researchers from the University of Iowa released the results of their clinical trials and it backs up the vitamin C claim. A team of researchers from the Holden Comprehensive Cancer Center at the University of Iowa looked into the effect of vitamin C in cancer cells, specifically, brain cancer glioblastoma multiforme (GBM) and non-small cell lung cancer (NSCLC). The trials tested the idea that a regular high dose of vitamin C is a safe and effective anti-cancer agent when combined with chemotherapy and other radiation treatments. The researchers also focused on two specific forms of cancer that have the least improvement in terms of treatment. "These two diseases really haven't had a significant improvement in outcomes for two or three decades," study author and UI assistant professor of radiation oncology Bryan Allen said. There's a saying that anything in excess is bad for the body, but it seems the human body makes an exception when it comes to fighting cancer. This is because the dosage of vitamin C that is delivered intravenously is actually 1,000 times higher than the concentration a healthy person has in their blood stream, which is about 70 micromolar. How so? The target is to get the cancer patient's blood to have up to 20,000 micromolar of vitamin C. What happens is that the high concentration of vitamin C messes up the cancer cell metabolism by disrupting the iron levels in the cells. This, in turn, causes excess iron to react to the vitamin C and generate free radicals that can weaken and kill DNA. When this happens, the chemotherapy and radiation can easily kill the cancer cells. The best part is that the trials showed no serious side effects to the patients who participated and there was also an overall increase in the survival rate. The research, titled "O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate," was published in the journal Cancer Cell on March 30. It contains the results of the first phase of the clinical trials, as well as a small portion of the Phase II results. "Results look promising but we're not going to know if this approach really improves therapy response until we complete these phase II trials," Allen said. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.

Case A.J.,Holden Comprehensive Cancer Center | Madsen J.M.,Holden Comprehensive Cancer Center | Meyerholz D.K.,University of Iowa | Domann F.E.,Holden Comprehensive Cancer Center
Free Radical Biology and Medicine | Year: 2013

Heme synthesis partially occurs in the mitochondrial matrix; thus there is a high probability that enzymes and intermediates important in the production of heme will be exposed to metabolic by-products including reactive oxygen species. In addition, the need for ferrous iron for heme production, Fe/S coordination, and other processes occurring in the mitochondrial matrix suggests that aberrant fluxes of reactive oxygen species in this compartment might perturb normal iron homeostasis. Manganese superoxide dismutase (Sod2) is an antioxidant enzyme that governs steady-state levels of the superoxide in the mitochondrial matrix. Using hematopoietic stem cell-specific conditional Sod2 knockout mice we observed increased superoxide concentrations in red cell progeny, which caused significant pathologies including impaired erythrocytes and decreased ferrochelatase activity. Animals lacking Sod2 expression in erythroid precursors also displayed extramedullary hematopoiesis and systemic iron redistribution. Additionally, the increase in superoxide flux in erythroid precursors caused abnormal gene regulation of hematopoietic transcription factors, globins, and iron-response genes. Moreover, the erythroid precursors also displayed evidence of global changes in histone posttranslational modifications, a likely cause of at least some of the aberrant gene expression noted. From a therapeutic translational perspective, mitochondrially targeted superoxide-scavenging antioxidants partially rescued the observed phenotype. Taken together, our findings illuminate the superoxide sensitivity of normal iron homeostasis in erythrocyte precursors and suggest a probable link between mitochondrial redox metabolism and epigenetic control of nuclear gene regulation during mammalian erythropoiesis. © 2012 Elsevier Inc.

Welsh J.L.,University of Iowa | Button A.M.,Holden Comprehensive Cancer Center | Buettner G.R.,Holden Comprehensive Cancer Center | Cullen J.J.,University of Iowa | And 2 more authors.
Cancer Research | Year: 2013

Renewed interest in using pharmacological ascorbate (AscH-) to treat cancer has prompted interest in leveraging its cytotoxic mechanism of action. A central feature of AscH- action in cancer cells is its ability to act as an electron donor to O2 for generating H 2O2. We hypothesized that catalytic manganoporphyrins (MnP) would increase AscH- oxidation rates, thereby increasing H 2O2 fluxes and cytotoxicity. Three different MnPs were tested (MnTBAP, MnT2EPyP, and MnT4MPyP), exhibiting a range of physicochemical and thermodynamic properties. Of the MnPs tested, MnT4MPyP exerted the greatest effect on increasing the rate of AscH- oxidation as determined by the concentration of ascorbate radical [AscH-] and the rate of oxygen consumption. At concentrations that had minimal effects alone, combining MnPs and AscH- synergized to decrease clonogenic survival in human pancreatic cancer cells. This cytotoxic effect was reversed by catalase, but not superoxide dismutase, consistent with a mechanism mediated by H2O2. MnPs increased steady-state concentrations of AscH- upon ex vivo addition to whole blood obtained either from mice infused with AscH- or patients treated with pharmacologic AscH-. Finally, tumor growth in vivo was inhibited more effectively by combining MnT4MPyP with AscH -.Weconcluded that MnPs increase the rate of oxidation of AscH - to leverage H2O2 flux and ascorbateinduced cytotoxicity. © 2013 American Association for Cancer Research.

Navalkele P.,University of Iowa | O'Dorisio M.S.,Holden Comprehensive Cancer Center | Zamba G.K.,University of Iowa | Lynch C.F.,Holden Comprehensive Cancer Center
Pediatric Blood and Cancer | Year: 2011

Background: The incidence, survival, and prevalence of neuroendocrine tumors (NETs) in children were determined as a first step in improving diagnosis and therapy. Outcomes were compared with neuroblastoma, a pediatric malignancy that shares several biomarkers. Methods: Incidence rates, observed survival rates and 31-year limited duration prevalence counts were obtained from SEER*Stat for diagnosis years 1975 to 2006. These rates were compared between and within NETs and neuroblastoma for demographic and tumor-related variables from nine standard SEER registries for ages 0-29 years. Multivariate Cox regression was performed to identify prognostic factors for survival in NETs. Results: The number of NETs was 1,073 compared to 1,664 neuroblastomas. The most common NET sites were lung, breast, and appendix. NET 5-year observed survival rates increased from 83% between 1975 and 1979 to 84% for the 2000-2006 period, while analogous neuroblastoma survival rates steadily increased from 45-73%. Five-year observed survival was less than 30% in females with NETs of the cervix and ovary. The estimated 31-year limited duration prevalence for NETs as of January 1, 2006 in the U.S. population was 7,724 compared to 9,960 for neuroblastomas. Age-adjusted multivariate Cox Regression demonstrated small cell histology, primary location in the breast, and distant stage as major predictors of decreased survival. Conclusions: While survivorship has significantly increased for neuroblastoma, those diagnosed with NETs have shown no increase in survival during this 31-year period. NETs constitute an unrecognized cancer threat to children and young adults comparable to neuroblastoma in both number of affected persons and disease severity. © 2010 Wiley-Liss, Inc.

Allen B.G.,Holden Comprehensive Cancer Center | Bhatia S.K.,Holden Comprehensive Cancer Center | Buatti J.M.,Holden Comprehensive Cancer Center | Brandt K.E.,Holden Comprehensive Cancer Center | And 6 more authors.
Clinical Cancer Research | Year: 2013

Purpose: Ketogenic diets are high in fat and low in carbohydrates as well as protein which forces cells to rely on lipid oxidation and mitochondrial respiration rather than glycolysis for energy metabolism. Cancer cells (relative to normal cells) are believed to exist in a state of chronic oxidative stress mediated by mitochondrial metabolism. The current study tests the hypothesis that ketogenic diets enhance radiochemo- therapy responses in lung cancer xenografts by enhancing oxidative stress. Experimental Design: Mice bearing NCI-H292 and A549 lung cancer xenografts were fed a ketogenic diet (KetoCal 4:1 fats: proteins+carbohydrates) and treated with either conventionally fractionated (1.8-2 Gy) or hypofractionated (6 Gy) radiation as well as conventionally fractionated radiation combined with carboplatin. Mice weights and tumor size were monitored. Tumors were assessed for immunoreactive 4-hydroxy-2-nonenal-(4HNE)-modified proteins as a marker of oxidative stress as well as proliferating cell nuclear antigen (PCNA) and γH2AX as indices of proliferation and DNA damage, respectively. Results: The ketogenic diets combined with radiation resulted in slower tumor growth in both NCI-H292 and A549 xenografts (P < 0.05), relative to radiation alone. The ketogenic diet also slowed tumor growth when combined with carboplatin and radiation, relative to control. Tumors from animals fed a ketogenic diet in combination with radiation showed increases in oxidative damage mediated by lipid peroxidation as determined by 4HNE-modified proteins as well as decreased proliferation as assessed by decreased immunoreactive PCNA. Conclusions: These results show that a ketogenic diet enhances radio-chemo-therapy responses in lung cancer xenografts by a mechanism that may involve increased oxidative stress. © 2013 American Association for Cancer Research.

Du J.,University of Iowa | Martin S.M.,University of Iowa | Levine M.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases | Wagner B.A.,University of Iowa | And 9 more authors.
Clinical Cancer Research | Year: 2010

Purpose: Pharmacologic concentrations of ascorbate may be effective in cancer therapeutics. We hypothesized that ascorbate concentrations achievable with i.v. dosing would be cytotoxic in pancreatic cancer for which the 5-year survival is <3%. Experimental Design: Pancreatic cancer cell lines were treated with ascorbate (0, 5, or 10 mmol/L) for 1 hour, then viability and clonogenic survival were determined. Pancreatic tumor cells were delivered s.c. into the flank region of nude mice and allowed to grow at which time they were randomized to receive either ascorbate (4 g/kg) or osmotically equivalent saline (1 mol/L) i.p. for 2 weeks. Results: There was a time- and dose-dependent increase in measured H2O2 production with increased concentrations of ascorbate. Ascorbate decreased viability in all pancreatic cancer cell lines but had no effect on an immortalized pancreatic ductal epithelial cell line. Ascorbate decreased clonogenic survival of the pancreatic cancer cell lines, which was reversed by treatment of cells with scavengers of H2O2. Treatment with ascorbate induced a caspase-independent cell death that was associated with autophagy. In vivo, treatment with ascorbate inhibited tumor growth and prolonged survival. Conclusions: These results show that pharmacologic doses of ascorbate, easily achievable in humans, may have potential for therapy in pancreatic cancer. ©2010 AACR.

Du J.,University of Iowa | Cullen J.J.,University of Iowa | Cullen J.J.,Holden Comprehensive Cancer Center | Cullen J.J.,Veterans Affairs Medical Center | And 2 more authors.
Biochimica et Biophysica Acta - Reviews on Cancer | Year: 2012

Since the discovery of vitamin C, the number of its known biological functions is continually expanding. Both the names ascorbic acid and vitamin C reflect its antiscorbutic properties due to its role in the synthesis of collagen in connective tissues. Ascorbate acts as an electron-donor keeping iron in the ferrous state thereby maintaining the full activity of collagen hydroxylases; parallel reactions with a variety of dioxygenases affect the expression of a wide array of genes, for example via the HIF system, as well as via the epigenetic landscape of cells and tissues. In fact, all known physiological and biochemical functions of ascorbate are due to its action as an electron donor. The ability to donate one or two electrons makes AscH- an excellent reducing agent and antioxidant. Ascorbate readily undergoes pH-dependent autoxidation producing hydrogen peroxide (H2O2). In the presence of catalytic metals this oxidation is accelerated. In this review, we show that the chemical and biochemical nature of ascorbate contribute to its antioxidant as well as its prooxidant properties. Recent pharmacokinetic data indicate that intravenous (i.v.) administration of ascorbate bypasses the tight control of the gut producing highly elevated plasma levels; ascorbate at very high levels can act as prodrug to deliver a significant flux of H2O2 to tumors. This new knowledge has rekindled interest and spurred new research into the clinical potential of pharmacological ascorbate. Knowledge and understanding of the mechanisms of action of pharmacological ascorbate bring a rationale to its use to treat disease especially the use of i.v. delivery of pharmacological ascorbate as an adjuvant in the treatment of cancer. © 2012.

Cullen J.J.,University of Iowa | Cullen J.J.,Holden Comprehensive Cancer Center
Autophagy | Year: 2010

Ascorbate (ascorbic acid, vitamin C) is one of the early, unorthodox treatments for cancer. The evidence upon which people base the use of ascorbate in cancer treatment falls into two categories: clinical data on dose concentration relationships, and laboratory data describing potential cell toxicity with high concentrations of ascorbate in vitro. Clinical data show that when ascorbate is given orally, fasting plasma concentrations are tightly controlled by decreased absorption, increased urine excretion, and reduced ascorbate bioavailability. In contrast, when ascorbate is administered intravenously, concentrations in the millimolar level are achieved. Thus, it is clear that intravenous administration of ascorbate can yield very high plasma levels, while oral treatment does not. © 2010 Landes Bioscience.

Shepherd T.R.,University of Iowa | Klaus S.M.,University of Iowa | Liu X.,University of Iowa | Ramaswamy S.,University of Iowa | And 4 more authors.
Journal of Molecular Biology | Year: 2010

The T-cell lymphoma invasion and metastasis gene 1 (Tiam1) is a guanine exchange factor (GEF) for the Rho-family GTPase Rac1 that is crucial for the integrity of adherens junctions, tight junctions, and cell-matrix interactions. This GEF contains several protein-protein interaction domains, including a PDZ domain. Earlier studies identified a consensus PDZ-binding motif and a synthetic peptide capable of binding to the Tiam1 PDZ domain, but little is known about its ligand specificity and physiological role in cells. Here, we investigated the structure, specificity, and function of the Tiam1 PDZ domain. We determined the crystal structures of the Tiam1 PDZ domain free and in complex with a "model" peptide, which revealed the structural basis for ligand specificity. Protein database searches using the consensus PDZ-binding motif identified two eukaryotic cell adhesion proteins, Syndecan1 and Caspr4, as potential Tiam1 PDZ domain binding proteins. Equilibrium binding experiments confirmed that C-terminal peptides derived from Syndecan1 and Caspr4 bound the Tiam1 PDZ domain. NMR chemical shift perturbation experiments indicated that the Tiam1 PDZ/Syndecan1 and PDZ/Caspr4 complexes were structurally distinct and identified key residues likely to be responsible for ligand selectivity. Moreover, cell biological analysis established that Syndecan1 is a physiological binding partner of Tiam1 and that the PDZ domain has a function in cell-matrix adhesion and cell migration. Collectively, our data provide insight into the structure, specificity, and function of the Tiam1 PDZ domain. Importantly, our data report on a physiological role for the Tiam1 PDZ domain and establish a novel link between two previously unrelated signal transduction pathways, both of which are implicated in cancer. © 2010 Elsevier Ltd.

Shepherd T.R.,University of Iowa | Fuentes E.J.,University of Iowa | Fuentes E.J.,Holden Comprehensive Cancer Center
Methods in Enzymology | Year: 2011

Tiam-family guanine exchange proteins are activators of the Rho GTPase Rac1 and critical for cell morphology, adhesion, migration, and polarity. These modular proteins contain a variety of signaling domains, including a single postsynaptic density-95/discs large/zonula occludens-1 (PDZ) domain. Here, we show how structural and thermodynamic approaches applied to the Tiam1 PDZ domain can be used to gain unique insights into the affinity and specificity of PDZ-ligand interactions with peptides derived from Syndecan1 and Caspr4 proteins. First, we describe a fluorescence anisotropy-based assay that can be used to determine PDZ-ligand interactions, and describe important considerations in designing binding experiments. Second, we used site-specific mutagenesis in combination with double-mutant cycle analysis to probe the binding energetics and cooperativity of residues in two ligand binding pockets (S0 and S-2) that are involved in Tiam1 PDZ-ligand interactions. Peptide ligand binding results and double-mutant cycle analysis revealed that the S 0 pocket was important for Syndecan1 and Caspr4 peptide interactions and that the S-2 pocket provided selectivity for the Syndecan1 ligand. Finally, we devised a "peptide evolution" strategy whereby a Model consensus peptide was "evolved" into either the Syndecan1 or Caspr4 peptide by site-directed mutagenesis. These results corroborated the PDZ mutational analysis of the S0 pocket and identified the P -4 position in the ligand as critical for Syndecan1 affinity and selectivity. Together, these studies show that a combined structural and thermodynamic approach is powerful for obtaining insights into the origin of Tiam1 PDZ-ligand domain affinity and specificity. © 2011 Elsevier Inc.

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