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Pancreatic Neoplasms: HELP
Articles by Juan Du
Based on 13 articles published since 2009
(Why 13 articles?)
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Between 2009 and 2019, Juan DU wrote the following 13 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Article Enhanced Pharmacological Ascorbate Oxidation Radiosensitizes Pancreatic Cancer. 2019

Alexander, Matthew S / O'Leary, Brianne R / Wilkes, Justin G / Gibson, Adrienne R / Wagner, Brett A / Du, Juan / Sarsour, Ehab / Hwang, Rosa F / Buettner, Garry R / Cullen, Joseph J. ·a   Department of Surgery, University of Iowa, Iowa City, Iowa. · b   Free Radical and Radiation Biology Program, University of Iowa, Iowa City, Iowa. · c   Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas. · d   The University of Iowa Holden Comprehensive Cancer Center, Iowa City, Iowa. · e   Veterans Affairs Medical Center, Iowa City, Iowa. ·Radiat Res · Pubmed #30376411.

ABSTRACT: Pharmacologic ascorbate (P-AscH

2 Article Pharmacologic ascorbate (P-AscH 2018

Wilkes, Justin G / O'Leary, Brianne R / Du, Juan / Klinger, Adrienne R / Sibenaller, Zita A / Doskey, Claire M / Gibson-Corley, Katherine N / Alexander, Matthew S / Tsai, Susan / Buettner, Garry R / Cullen, Joseph J. ·Department of Radiation Oncology, University of Iowa Carver College of Medicine, Iowa City, IA, USA. · Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA. · Department of Pathology, University of Iowa Carver College of Medicine, Iowa City, IA, USA. · Holden Comprehensive Cancer Center, Iowa City, IA, USA. · The Medical College of Wisconsin, Milwaukee, WI, USA. · Department of Radiation Oncology, University of Iowa Carver College of Medicine, Iowa City, IA, USA. joseph-cullen@uiowa.edu. · Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA. joseph-cullen@uiowa.edu. · Holden Comprehensive Cancer Center, Iowa City, IA, USA. joseph-cullen@uiowa.edu. · Veterans Affairs Medical Center, Iowa City, IA, USA. joseph-cullen@uiowa.edu. · University of Iowa Hospitals and Clinics, 1528 JCP, 200 Hawkins Drive, Iowa City, IA, 52242, USA. joseph-cullen@uiowa.edu. ·Clin Exp Metastasis · Pubmed #29396728.

ABSTRACT: HIF-1α is a transcriptional regulator that functions in the adaptation of cells to hypoxic conditions; it strongly impacts the prognosis of patients with cancer. High-dose, intravenous, pharmacological ascorbate (P-AscH

3 Article Tumor cells have decreased ability to metabolize H 2016

Doskey, Claire M / Buranasudja, Visarut / Wagner, Brett A / Wilkes, Justin G / Du, Juan / Cullen, Joseph J / Buettner, Garry R. ·Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA 52242, USA. · Free Radical & Radiation Biology Program in the Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA. · Department of Surgery, The University of Iowa, Iowa City, IA 52242, USA. · Free Radical & Radiation Biology Program in the Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA; Department of Surgery, The University of Iowa, Iowa City, IA 52242, USA; Veterans Affairs Medical Center, Veterans Affairs Medical Center, Iowa City, IA 52246, USA. · Interdisciplinary Graduate Program in Human Toxicology, The University of Iowa, Iowa City, IA 52242, USA; Free Radical & Radiation Biology Program in the Department of Radiation Oncology, The University of Iowa, Iowa City, IA 52242, USA. Electronic address: garry-buettner@uiowa.edu. ·Redox Biol · Pubmed #27833040.

ABSTRACT: Ascorbate (AscH

4 Article Fluorine-18-Labeled Thymidine Positron Emission Tomography (FLT-PET) as an Index of Cell Proliferation after Pharmacological Ascorbate-Based Therapy. 2016

Cieslak, John A / Sibenaller, Zita A / Walsh, Susan A / Ponto, Laura L Boles / Du, Juan / Sunderland, John J / Cullen, Joseph J. ·a  Free Radical and Radiation Biology Program, Department of Radiation Oncology; Departments of. · b  Surgery; · d  Small Animal Imaging Core, University of Iowa Carver College of Medicine, Iowa City, Iowa; · c  Radiology and. · e  Holden Comprehensive Cancer Center, Iowa City, Iowa; and. · f  Iowa City Veterans Affairs Medical Center, Iowa City, Iowa. ·Radiat Res · Pubmed #26720803.

ABSTRACT: Pharmacological ascorbate (AscH(-)) induces cytotoxicity and oxidative stress selectively in pancreatic cancer cells compared with normal cells. Positron emission tomography (PET) with the thymidine analog 3'-deoxy-3'-((18)F) fluorothymidine (FLT) enables noninvasive imaging and quantification of the proliferation fraction of tumors. We hypothesized that the rate of tumor proliferation determined by FLT-PET imaging, would be inversely proportional to tumor susceptibility to pharmacological AscH(-)-based treatments. Indeed, there was decreased FLT uptake in human pancreatic cancer cells treated with AscH(-) in vitro, and this effect was abrogated by co-treatment with catalase. In separate experiments, cells were treated with AscH(-), ionizing radiation or a combination of both. These studies demonstrated that combined AscH(-) and radiation treatment resulted in a significant decrease in FLT uptake that directly correlated with decreased clonogenic survival. MicroPET (18)F-FLT scans of mice with pre-established tumors demonstrated that AscH(-) treatment induced radiosensitization compared to radiation treatment alone. These data support testing of pharmacological ascorbate as a radiosensitizer in pancreatic cancer as well as the use of FLT-PET to monitor response to therapy.

5 Article Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer. 2015

Du, Juan / Cieslak, John A / Welsh, Jessemae L / Sibenaller, Zita A / Allen, Bryan G / Wagner, Brett A / Kalen, Amanda L / Doskey, Claire M / Strother, Robert K / Button, Anna M / Mott, Sarah L / Smith, Brian / Tsai, Susan / Mezhir, James / Goswami, Prabhat C / Spitz, Douglas R / Buettner, Garry R / Cullen, Joseph J. ·Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa. · Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa. · Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, Iowa City, Iowa. · Holden Comprehensive Cancer Center, Iowa City, Iowa. · Medical College of Wisconsin, Milwaukee, Wisconsin. · Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, Iowa City, Iowa. · Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa. Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa. Holden Comprehensive Cancer Center, Iowa City, Iowa. Veterans Affairs Medical Center, Iowa City, Iowa. joseph-cullen@uiowa.edu. ·Cancer Res · Pubmed #26081808.

ABSTRACT: The toxicity of pharmacologic ascorbate is mediated by the generation of H2O2 via the oxidation of ascorbate. Because pancreatic cancer cells are sensitive to H2O2 generated by ascorbate, they would also be expected to become sensitized to agents that increase oxidative damage such as ionizing radiation. The current study demonstrates that pharmacologic ascorbate enhances the cytotoxic effects of ionizing radiation as seen by decreased cell viability and clonogenic survival in all pancreatic cancer cell lines examined, but not in nontumorigenic pancreatic ductal epithelial cells. Ascorbate radiosensitization was associated with an increase in oxidative stress-induced DNA damage, which was reversed by catalase. In mice with established heterotopic and orthotopic pancreatic tumor xenografts, pharmacologic ascorbate combined with ionizing radiation decreased tumor growth and increased survival, without damaging the gastrointestinal tract or increasing systemic changes in parameters indicative of oxidative stress. Our results demonstrate the potential clinical utility of pharmacologic ascorbate as a radiosensitizer in the treatment of pancreatic cancer.

6 Article Manganoporphyrins and ascorbate enhance gemcitabine cytotoxicity in pancreatic cancer. 2015

Cieslak, John A / Strother, Robert K / Rawal, Malvika / Du, Juan / Doskey, Claire M / Schroeder, Samuel R / Button, Anna / Wagner, Brett A / Buettner, Garry R / Cullen, Joseph J. ·Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IA 52242, USA; Department of Surgery, University of Iowa College of Medicine, Iowa City, IA 52242, USA. · Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IA 52242, USA. · Interdisciplinary Program in Human Toxicology, University of Iowa, Iowa City, IA 52242, USA. · Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA. · Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa College of Medicine, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA. · Department of Surgery, University of Iowa College of Medicine, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA; Veterans Affairs Medical Center, Iowa City, IA 52242, USA. Electronic address: joseph-cullen@uiowa.edu. ·Free Radic Biol Med · Pubmed #25725418.

ABSTRACT: Pharmacological ascorbate (AscH(-)) selectively induces cytotoxicity in pancreatic cancer cells vs normal cells via the generation of extracellular hydrogen peroxide (H2O2), producing double-stranded DNA breaks and ultimately cell death. Catalytic manganoporphyrins (MnPs) can enhance ascorbate-induced cytotoxicity by increasing the rate of AscH(-) oxidation and therefore the rate of generation of H2O2. We hypothesized that combining MnPs and AscH(-) with the chemotherapeutic agent gemcitabine would further enhance pancreatic cancer cell cytotoxicity without increasing toxicity in normal pancreatic cells or other organs. Redox-active MnPs were combined with AscH(-) and administered with or without gemcitabine to human pancreatic cancer cell lines, as well as immortalized normal pancreatic ductal epithelial cells. The MnPs MnT2EPyP (Mn(III)meso-tetrakis(N-ethylpyridinium-2-yl) porphyrin pentachloride) and MnT4MPyP (Mn(III)tetrakis(N-methylpyridinium-4-yl) porphyrin pentachloride) were investigated. Clonogenic survival was significantly decreased in all pancreatic cancer cell lines studied when treated with MnP + AscH(-) + gemcitabine, whereas nontumorigenic cells were resistant. The concentration of ascorbate radical (Asc(•-), an indicator of oxidative flux) was significantly increased in treatment groups containing MnP and AscH(-). Furthermore, MnP + AscH(-) increased double-stranded DNA breaks in gemcitabine-treated cells. These results were abrogated by extracellular catalase, further supporting the role of the flux of H2O2. In vivo growth was inhibited and survival increased in mice treated with MnT2EPyP, AscH(-), and gemcitabine without a concomitant increase in systemic oxidative stress. These data suggest a promising role for the use of MnPs in combination with pharmacologic AscH(-) and chemotherapeutics in pancreatic cancer.

7 Article Extracellular superoxide dismutase suppresses hypoxia-inducible factor-1α in pancreatic cancer. 2014

Sibenaller, Zita A / Welsh, Jessemae L / Du, Changbin / Witmer, Jordan R / Schrock, Hannah E / Du, Juan / Buettner, Garry R / Goswami, Prabhat C / Cieslak, John A / Cullen, Joseph J. ·Department of Surgery, The University of Iowa College of Medicine, Iowa City, IA 52242, USA. · Department of Radiation Oncology, The University of Iowa College of Medicine, Iowa City, IA 52242, USA. · Department of Radiation Oncology, The University of Iowa College of Medicine, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA. · Department of Surgery, The University of Iowa College of Medicine, Iowa City, IA 52242, USA; Department of Radiation Oncology, The University of Iowa College of Medicine, Iowa City, IA 52242, USA; Holden Comprehensive Cancer Center, Iowa City, IA 52242, USA; Veterans Affairs Medical Center, Iowa City, IA 52242, USA. Electronic address: joseph-cullen@uiowa.edu. ·Free Radic Biol Med · Pubmed #24509158.

ABSTRACT: Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that governs cellular responses to reduced oxygen availability by mediating crucial homeostatic processes and is a major survival determinant for tumor cells growing in a low-oxygen environment. Clinically, HIF-1α seems to be important in pancreatic cancer, as HIF-1α correlates with metastatic status of the tumor. Extracellular superoxide dismutase (EcSOD) inhibits pancreatic cancer cell growth by scavenging nonmitochondrial superoxide. We hypothesized that EcSOD overexpression leads to changes in the O2(-)/H2O2 balance modulating the redox status affecting signal transduction pathways. Both transient and stable overexpression of EcSOD suppressed the hypoxic accumulation of HIF-1α in human pancreatic cancer cells. This suppression of HIF-1α had a strong inverse correlation with levels of EcSOD protein. Coexpression of the hydrogen peroxide-removing protein glutathione peroxidase did not prevent the EcSOD-induced suppression of HIF-1α, suggesting that the degradation of HIF-1α observed with high EcSOD overexpression is possibly due to a low steady-state level of superoxide. Hypoxic induction of vascular endothelial growth factor (VEGF) was also suppressed with increased EcSOD. Intratumoral injections of an adenoviral vector containing the EcSOD gene into preestablished pancreatic tumors suppressed both VEGF levels and tumor growth. These results demonstrate that the transcription factor HIF-1α and its important gene target VEGF can be modulated by the antioxidant enzyme EcSOD.

8 Article Pharmacological ascorbate and ionizing radiation (IR) increase labile iron in pancreatic cancer. 2013

Moser, Justin C / Rawal, Malvika / Wagner, Brett A / Du, Juan / Cullen, Joseph J / Buettner, Garry R. ·Free Radical and Radiation Biology Program and ESR Facility, Department of Radiation Oncology, The University of Iowa, Iowa City, IA, USA. · Free Radical and Radiation Biology Program and ESR Facility, Department of Radiation Oncology, The University of Iowa, Iowa City, IA, USA ; Department of Surgery, The University of Iowa, Iowa City, IA, USA ; Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, USA. · Free Radical and Radiation Biology Program and ESR Facility, Department of Radiation Oncology, The University of Iowa, Iowa City, IA, USA ; Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, IA, USA. ·Redox Biol · Pubmed #24396727.

ABSTRACT: Labile iron, i.e. iron that is weakly bound and is relatively unrestricted in its redox activity, has been implicated in both the pathogenesis as well as treatment of cancer. Two cancer treatments where labile iron may contribute to their mechanism of action are pharmacological ascorbate and ionizing radiation (IR). Pharmacological ascorbate has been shown to have tumor-specific toxic effects due to the formation of hydrogen peroxide. By catalyzing the oxidation of ascorbate, labile iron can enhance the rate of formation of hydrogen peroxide; labile iron can also react with hydrogen peroxide. Here we have investigated the magnitude of the labile iron pool in tumor and normal tissue. We also examined the ability of pharmacological ascorbate and IR to change the size of the labile iron pool. Although a significant amount of labile iron was seen in tumors (MIA PaCa-2 cells in athymic nude mice), higher levels were seen in murine tissues that were not susceptible to pharmacological ascorbate. Pharmacological ascorbate and irradiation were shown to increase the labile iron in tumor homogenates from this murine model of pancreatic cancer. As both IR and pharmacological ascorbate may rely on labile iron for their effects on tumor tissues, our data suggest that pharmacological ascorbate could be used as a radio-sensitizing agent for some radio-resistant tumors.

9 Article Manganoporphyrins increase ascorbate-induced cytotoxicity by enhancing H2O2 generation. 2013

Rawal, Malvika / Schroeder, Samuel R / Wagner, Brett A / Cushing, Cameron M / Welsh, Jessemae L / Button, Anna M / Du, Juan / Sibenaller, Zita A / Buettner, Garry R / Cullen, Joseph J. ·Department of Radiation Oncology, The University of Iowa Carver College of Medicine, Iowa City, IA, USA. ·Cancer Res · Pubmed #23764544.

ABSTRACT: 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 H2O2. We hypothesized that catalytic manganoporphyrins (MnP) would increase AscH- oxidation rates, thereby increasing H2O2 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 [Asc•-] 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 Asc•- 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-. We concluded that MnPs increase the rate of oxidation of AscH- to leverage H2O2 flux and ascorbate-induced cytotoxicity.

10 Article Regulation of pancreatic cancer growth by superoxide. 2013

Du, Juan / Nelson, Elke S / Simons, Andrean L / Olney, Kristen E / Moser, Justin C / Schrock, Hannah E / Wagner, Brett A / Buettner, Garry R / Smith, Brian J / Teoh, Melissa L T / Tsao, Ming-Sound / Cullen, Joseph J. ·Departments of Radiation Oncology, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA. ·Mol Carcinog · Pubmed #22392697.

ABSTRACT: K-ras mutations have been identified in up to 95% of pancreatic cancers, implying their critical role in the molecular pathogenesis. Expression of K-ras oncogene in an immortalized human pancreatic ductal epithelial cell line, originally derived from normal pancreas (H6c7), induced the formation of carcinoma in mice. We hypothesized that K-ras oncogene correlates with increased non-mitochondrial-generated superoxide (O 2.-), which could be involved in regulating cell growth contributing to tumor progression. In the H6c7 cell line and its derivatives, H6c7er-Kras+ (H6c7 cells expressing K-ras oncogene), and H6c7eR-KrasT (tumorigenic H6c7 cells expressing K-ras oncogene), there was an increase in hydroethidine fluorescence in cell lines that express K-ras. Western blots and activity assays for the antioxidant enzymes that detoxify O 2.- were similar in these cell lines suggesting that the increase in hydroethidine fluorescence was not due to decreased antioxidant capacity. To determine a possible non-mitochondrial source of the increased levels of O 2.-, Western analysis demonstrated the absence of NADPH oxidase-2 (NOX2) in H6c7 cells but present in the H6c7 cell lines expressing K-ras and other pancreatic cancer cell lines. Inhibition of NOX2 decreased hydroethidine fluorescence and clonogenic survival. Furthermore, in the cell lines with the K-ras oncogene, overexpression of superoxide dismutases that detoxify non-mitochondrial sources of O 2.-, and treatment with the small molecule O 2.- scavenger Tempol, also decreased hydroethidine fluorescence, inhibited clonogenic survival and inhibited growth of tumor xenografts. Thus, O 2.- produced by NOX2 in pancreatic cancer cells with K-ras, may regulate pancreatic cancer cell growth.

11 Article Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer. 2010

Du, Juan / Martin, Sean M / Levine, Mark / Wagner, Brett A / Buettner, Garry R / Wang, Sih-han / Taghiyev, Agshin F / Du, Changbin / Knudson, Charles M / Cullen, Joseph J. ·Department of Surgery, University of Iowa College of Medicine, Iowa City, Iowa 52242, USA. ·Clin Cancer Res · Pubmed #20068072.

ABSTRACT: 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 H(2)O(2) 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 H(2)O(2). 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.

12 Article [Clinical pathological analysis in 14 cases of pancreatic solid-pseudopapillary tumors]. 2009

Mei, Fang / DU, Juan / Ma, Xiao-long. ·Department of Pathology, Peking University School of Basic Medical Sciences, Beijing 100191, China. meifangmail@yahoo.com.cn ·Beijing Da Xue Xue Bao Yi Xue Ban · Pubmed #20019775.

ABSTRACT: OBJECTIVE: To observe clinical and pathological features of pancreatic solid-pseudopapillary tumor (SPPT), and to find some useful immunohistochemical methods for its differential diagnosis. METHODS: The clinical features of 14 SPPT patients were obtained. Each case underwent microscopic observation and immunohistochemical staining. The primary antibodies were CgA, Syn, E-cadherin, beta-catenin and Cyclin D1. These results were compared with 5 pancreatic well-differentiated tumors and well-differentiated carcinomas (WET/WEC). RESULTS: SPPT mainly involved young women, and the head of pancreas was the commonest location. Tumors were always in solid and cystic gross appearance. Although the tumor's borderlines seemed clear, focal infiltrations could often be identified. The histological features of SPPT were similar in some aspects to those of WET/WEC, especially the solid pattern of WET/WEC. Both of them could express CgA and Syn. But all SPPTs lost E-cadherin membranous signals, and even had some nuclear signals(5/14), while all WET/WECs remained the same staining pattern with normal pancreas cells. beta-catenin positive signals in SPPTs were located both in nuclei and plasmas. WET/WECs' positive signals were all in membranes and plasmas, but negative ones in nuclei. Perinuclear dot-like signals could also be seen in the majority cells, which were similar to normal islet cells' staining pattern. SPPTs' nuclear positive rates of Cyclin D1 were usually more than 70% (12/14). WET/WECs' rates were all lower than 30%. CONCLUSION: Comprehensive analysis of patients' clinical, pathological features and immunohistochemistry results, including E-cadherin, beta-catenin and Cyclin D1, was helpful to the diagnosis of SPPT and its differential diagnosis of WET/WEC.

13 Article Mitochondrial DNA depletion induces radioresistance by suppressing G2 checkpoint activation in human pancreatic cancer cells. 2009

Cloos, Carla R / Daniels, David H / Kalen, Amanda / Matthews, Katee / Du, Juan / Goswami, Prabhat C / Cullen, Joseph J. ·Departments of Surgery, Iowa City, Iowa, USA. ·Radiat Res · Pubmed #19580493.

ABSTRACT: We hypothesized that mitochondrial function regulates cell cycle checkpoint activation and radiosensitivity. Human pancreatic tumor cells (MiaPaCa-2, rho(+)) were depleted of mitochondrial DNA (rho degrees ) by culturing cells in the presence of ethidium bromide. Depletion of mitochondrial DNA was verified by PCR amplification of total DNA using primer pairs specific for mitochondrial DNA. Loss of mitochondrial DNA decreased plating efficiency and the percentage of cells in S phase. Exponential cultures were irradiated with 2, 4 and 6 Gy (dose rate: 0.83 Gy/min) of ionizing radiation and harvested for determination of cell viability, growth and cell cycle phase distributions. Rho degrees cells were radioresistant compared to rho(+) cells, with a dose-modifying factor (DMF) of 1.6. Although cell growth was significantly inhibited in irradiated rho(+) cells compared to unirradiated control cells, the inhibition in Rho degrees cells was minimal. In addition, mitochondrial DNA depletion suppressed radiation-induced G(2) checkpoint activation, which was accompanied by increases in both cyclin B1 and CDK1. These results suggest that mitochondrial function may regulate cell cycle checkpoint activation and radiosensitivity in pancreatic cancer cells.