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Radiosensitization by enzalutamide for human prostate cancer is mediated through the DNA damage repair pathway.
Sekhar KR, Wang J, Freeman ML, Kirschner AN
(2019) PLoS One 14: e0214670
MeSH Terms: Aged, Animals, Cell Line, Tumor, Cell Proliferation, DNA Damage, DNA Repair, Drug Resistance, Neoplasm, Humans, Male, Mice, Mice, Nude, Mice, Transgenic, Phenylthiohydantoin, Prostatic Neoplasms, Prostatic Neoplasms, Castration-Resistant, Radiation Tolerance, Radiation-Sensitizing Agents, Signal Transduction, Xenograft Model Antitumor Assays
Show Abstract · Added April 2, 2019
Radiation therapy is often combined with androgen deprivation therapy in the treatment of aggressive localized prostate cancer. However, castration-resistant disease may not respond to testosterone deprivation approaches. Enzalutamide is a second-generation anti-androgen with high affinity and activity that is used for the treatment of metastatic disease. Although radiosensitization mechanisms are known to be mediated through androgen receptor activity, this project aims to uncover the detailed DNA damage repair factors influenced by enzalutamide using multiple models of androgen-sensitive (LNCaP) and castration-resistant human prostate cancer (22Rv1 and DU145). Enzalutamide is able to radiosensitize both androgen-dependent and androgen-independent human prostate cancer models in cell culture and xenografts in mice, as well as a treatment-resistant patient-derived xenograft. The enzalutamide-mediated mechanism of radiosensitization includes delay of DNA repair through temporal prolongation of the repair factor complexes and halting the cell cycle, which results in decreased colony survival. Altogether, these findings support the use of enzalutamide concurrently with radiotherapy to enhance the treatment efficacy for prostate cancer.
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19 MeSH Terms
In Vivo Imaging of Retinal Hypoxia Using HYPOX-4-Dependent Fluorescence in a Mouse Model of Laser-Induced Retinal Vein Occlusion (RVO).
Uddin MI, Jayagopal A, McCollum GW, Yang R, Penn JS
(2017) Invest Ophthalmol Vis Sci 58: 3818-3824
MeSH Terms: Animals, Disease Models, Animal, Fluorescein Angiography, Fluoresceins, Fluorescent Dyes, Hypoxia, Image Processing, Computer-Assisted, Macular Edema, Male, Mice, Mice, Inbred C57BL, Nitroimidazoles, Radiation-Sensitizing Agents, Retinal Neovascularization, Retinal Vein, Retinal Vein Occlusion, Tomography, Optical Coherence
Show Abstract · Added December 21, 2017
Purpose - To demonstrate the utility of a novel in vivo molecular imaging probe, HYPOX-4, to detect and image retinal hypoxia in real time, in a mouse model of retinal vein occlusion (RVO).
Methods - Retinal vein occlusion was achieved in adult mice by photodynamic retinal vein thrombosis (PRVT). One or two major retinal vein(s) was/were occluded in close proximity to the optic nerve head (ONH). In vivo imaging of retinal hypoxia was performed using, HYPOX-4, an imaging probe developed by our laboratory. Pimonidazole-adduct immunostaining was performed and used as a standard ex vivo method for the detection of retinal hypoxia in this mouse RVO model. The retinal vasculature was imaged using fluorescein angiography (FA) and isolectin B4 staining. Retinal thickness was assessed by spectral-domain optical coherence tomography (SD-OCT) analysis.
Results - By application of the standard ex vivo pimonidazole-adduct immunostaining technique, retinal hypoxia was observed within 2 hours post-PRVT. The observed hypoxic retinal areas depended on whether one or two retinal vein(s) was/were occluded. Similar areas of hypoxia were imaged in vivo using HYPOX-4. Using OCT, retinal edema was observed immediately post-PRVT induction, resolving 8 days later. Nominal preretinal neovascularization was observed at 10 to 14 days post-RVO.
Conclusions - HYPOX-4 is an efficient probe capable of imaging retinal hypoxia in vivo, in RVO mice. Future studies will focus on its use in correlating retinal hypoxia to the onset and progression of ischemic vasculopathies.
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17 MeSH Terms
Targeting Enox1 in tumor stroma increases the efficacy of fractionated radiotherapy.
Smith CA, Mont S, Traver G, Sekhar KR, Crooks PA, Freeman ML
(2016) Oncotarget 7: 77926-77936
MeSH Terms: Animals, Cell Line, Tumor, Colorectal Neoplasms, Dose Fractionation, Radiation, HT29 Cells, Humans, Mice, Mice, Nude, Molecular Targeted Therapy, NADH, NADPH Oxidoreductases, Radiation-Sensitizing Agents, Xenograft Model Antitumor Assays
Show Abstract · Added March 17, 2017
The goal of this investigation was to clarify the question of whether targeting Enox1 in tumor stroma would synergistically enhance the survival of tumor-bearing mice treated with fractionated radiotherapy. Enox1, a NADH oxidase, is expressed in tumor vasculature and stroma. However, it is not expressed in many tumor types, including HT-29 colorectal carcinoma cells. Pharmacological inhibition of Enox1 in endothelial cells inhibited repair of DNA double strand breaks, as measured by γH2AX and 53BP1 foci formation, as well as neutral comet assays. For 4 consecutive days athymic mice bearing HT-29 hindlimb xenografts were injected with a small molecule inhibitor of Enox1 or solvent control. Tumors were then administered 2 Gy of x-rays. On day 5 tumors were administered a single 'top-up' fraction of 30 Gy, the purpose of which was to amplify intrinsic differences in the radiation fractionation regimen produced by Enox1 targeting. Pharmacological targeting of Enox1 resulted in 80% of the tumor-bearing mice surviving at 90 days compared to only 40% of tumor-bearing mice treated with solvent control. The increase in survival was not a consequence of reoxygenation, as measured by pimonidazole immunostaining. These results are interpreted to indicate that targeting of Enox1 in tumor stroma significantly enhances the effectiveness of 2 Gy fractionated radiotherapy and identifies Enox1 as a potential therapeutic target.
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12 MeSH Terms
Targeting nucleophosmin 1 represents a rational strategy for radiation sensitization.
Sekhar KR, Benamar M, Venkateswaran A, Sasi S, Penthala NR, Crooks PA, Hann SR, Geng L, Balusu R, Abbas T, Freeman ML
(2014) Int J Radiat Oncol Biol Phys 89: 1106-1114
MeSH Terms: Animals, Barbiturates, Carcinoma, Non-Small-Cell Lung, DNA Breaks, Double-Stranded, DNA Repair, Fibroblasts, Histones, Humans, Indoles, Lung Neoplasms, Mice, Mice, Inbred C57BL, Mice, Nude, Molecular Targeted Therapy, Neoplasm Proteins, Nuclear Proteins, Rad51 Recombinase, Radiation Tolerance, Radiation-Sensitizing Agents, Tissue Array Analysis, Tumor Cells, Cultured
Show Abstract · Added January 20, 2015
PURPOSE - To test the hypothesis that small molecule targeting of nucleophosmin 1 (NPM1) represents a rational approach for radiosensitization.
METHODS AND MATERIALS - Wilde-type and NPM1-deficient mouse embryo fibroblasts (MEFs) were used to determine whether radiosensitization produced by the small molecule YTR107 was NPM1 dependent. The stress response to ionizing radiation was assessed by quantifying pNPM1, γH2AX, and Rad51 foci, neutral comet tail moment, and colony formation. NPM1 levels in a human-derived non-small-cell lung cancer (NSCLC) tissue microarray (TMA) were determined by immunohistochemistry. YTR107-mediated radiosensitization was assessed in NSCLC cell lines and xenografts.
RESULTS - Use of NPM1-null MEFs demonstrated that NPM1 is critical for DNA double- strand break (DSB) repair, that loss of NPM1 increases radiation sensitivity, and that YTR107-mediated radiosensitization is NPM1 dependent. YTR107 was shown to inhibit NPM1 oligomerization and impair formation of pNPM1 irradiation-induced foci that colocalized with γH2AX foci. Analysis of the TMA demonstrated that NPM1 is overexpressed in subsets of NSCLC. YTR107 inhibited DNA DSB repair and radiosensitized NSCLC lines and xenografts.
CONCLUSIONS - These data demonstrate that YTR107-mediated targeting of NPM1 impairs DNA DSB repair, an event that increases radiation sensitivity.
Copyright © 2014 Elsevier Inc. All rights reserved.
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21 MeSH Terms
Phase I study of concurrent weekly docetaxel, high-dose intensity-modulated radiation therapy (IMRT) and androgen-deprivation therapy (ADT) for high-risk prostate cancer.
Chen RC, Rosenman JG, Hoffman LG, Chiu WK, Wang AZ, Pruthi RS, Wallen EM, Crane JM, Kim WY, Rathmell WK, Godley PA, Whang YE
(2012) BJU Int 110: E721-6
MeSH Terms: Aged, Androgen Antagonists, Antineoplastic Agents, Disease-Free Survival, Docetaxel, Dose-Response Relationship, Drug, Follow-Up Studies, Gonadotropin-Releasing Hormone, Humans, Male, Middle Aged, Neoplasm Staging, Prospective Studies, Prostate-Specific Antigen, Prostatic Neoplasms, Radiation-Sensitizing Agents, Radiotherapy Dosage, Radiotherapy, Intensity-Modulated, Taxoids, Treatment Outcome
Show Abstract · Added October 17, 2015
UNLABELLED - Study Type - Therapy (phase 1) Level of Evidence 2a What's known on the subject? and What does the study add? High-risk and locally advanced prostate cancers are difficult to cure with the standard regimen of radiation therapy (RT) with concurrent androgen-deprivation therapy (ADT). Multiple studies have explored the addition of docetaxel chemotherapy in attempt to improve patient outcomes. Prior Phase I studies have shown that docetaxel 20 mg/m(2) is a safe dose, when given concurrently with 70 Gy of radiation. But current standard RT for prostate cancer uses higher doses, and it is unclear if concurrent chemotherapy is safe with modern RT. This is a Phase I study that explored the addition of concurrent docetaxel chemotherapy to modern RT (intensity-modulated RT to 78 Gy) plus ADT. The study showed that weekly docetaxel at 20 mg/m(2) is safe with modern RT. At a median follow-up of 2.2 years, biochemical progression-free survival was 94%. This triple-therapy regimen is safe and promising for further evaluation in prospective trials.
OBJECTIVE - •  To evaluate in a phase I trial, the feasibility of adding concurrent weekly docetaxel chemotherapy to high-dose intensity modulated radiation therapy (IMRT) and androgen-deprivation therapy (ADT) for treatment of high-risk prostate cancer.
PATIENTS AND METHODS - •  Patients with high-risk prostate cancer were treated with a luteinising hormone-releasing hormone agonist (starting 2-3 months before IMRT and lasting 2 years), IMRT of 78 Gy to the prostate and seminal vesicles, and weekly docetaxel during RT. •  All patients had computed tomography and bone scans to exclude metastatic disease. •  A standard 3 + 3 design was used for docetaxel dose escalation. Successive patients were treated on dose levels of 10, 15, and 20 mg/m(2) of weekly docetaxel.
RESULTS - •  In all, 18 patients participated in the study: 15 (83%) had Gleason 8-10 disease; the other three had either clinical T3 disease and/or a prostate-specific antigen (PSA) level of >20 ng/mL. •  Grade 3 diarrhoea (a defined dose-limiting toxicity, DLT) occurred in one patient in each of the first two dose levels. However, when the cohorts were expanded, no further DLT was seen. •  Weekly docetaxel at 20 mg/m(2) (dose level 3) was successfully given without DLT. •  No patient had grade 4 or 5 toxicity. •  At a median follow-up of 2.2 years, all patients achieved a PSA nadir of <1 ng/mL, including 13 patients who had an undetectable PSA level. The 2-year biochemical progression-free survival was 94%.
CONCLUSION - •  A dose of 20 mg/m(2) of weekly docetaxel given concurrently with high-dose IMRT and ADT appears safe for further study in patients with high-risk prostate cancer.
© 2012 BJU INTERNATIONAL.
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20 MeSH Terms
Novel radiosensitizing anticancer therapeutics.
Linkous AG, Yazlovitskaya EM
(2012) Anticancer Res 32: 2487-99
MeSH Terms: Animals, Humans, Neoplasms, Neoplastic Stem Cells, Radiation-Sensitizing Agents
Show Abstract · Added August 21, 2013
In cancer treatment, radiation therapy is second only to surgery in terms of its curative potential. However, radiation-induced tumor cell death is limited by a number of factors, including the adverse response of the tumor microenvironment to radiation treatment and tumor-acquired mechanisms of evasive resistance. Recent attempts to enhance the therapeutic efficiency of ionizing radiation have produced promising results. In this review article, we discuss the development of novel therapeutic strategies for tumor sensitization to radiation therapy. These innovative approaches incorporate the involvement of the immune response and the role of cancer stem cells, as well as direct targeting of signal transduction pathways. Taken together, these concerted efforts demonstrate that the augmentation of radiotherapeutic efficacy results in significantly improved control not only of local disease, but also of metastatic spread and improved overall patient survival.
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5 MeSH Terms
Role of insulin-like growth factor-1 signaling pathway in cisplatin-resistant lung cancer cells.
Sun Y, Zheng S, Torossian A, Speirs CK, Schleicher S, Giacalone NJ, Carbone DP, Zhao Z, Lu B
(2012) Int J Radiat Oncol Biol Phys 82: e563-72
MeSH Terms: AC133 Antigen, Aldehyde Dehydrogenase, Animals, Antigens, CD, Apoptosis, Biomarkers, Tumor, Blotting, Western, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Cell Survival, Chemoradiotherapy, Cisplatin, Drug Resistance, Neoplasm, Female, Glycoproteins, Humans, Insulin-Like Growth Factor Binding Protein 3, Insulin-Like Growth Factor I, Lung Neoplasms, Mice, Mice, Nude, Microarray Analysis, Peptides, RNA, Small Interfering, Radiation Tolerance, Radiation-Sensitizing Agents, Receptor, IGF Type 1, Recombinant Proteins, Signal Transduction, Xenograft Model Antitumor Assays
Show Abstract · Added March 5, 2014
PURPOSE - The development of drug-resistant phenotypes has been a major obstacle to cisplatin use in non-small-cell lung cancer. We aimed to identify some of the molecular mechanisms that underlie cisplatin resistance using microarray expression analysis.
METHODS AND MATERIALS - H460 cells were treated with cisplatin. The differences between cisplatin-resistant lung cancer cells and parental H460 cells were studied using Western blot, MTS, and clonogenic assays, in vivo tumor implantation, and microarray analysis. The cisplatin-R cells were treated with human recombinant insulin-like growth factor (IGF) binding protein-3 and siRNA targeting IGF-1 receptor.
RESULTS - Cisplatin-R cells illustrated greater expression of the markers CD133 and aldehyde dehydrogenase, more rapid in vivo tumor growth, more resistance to cisplatin- and etoposide-induced apoptosis, and greater survival after treatment with cisplatin or radiation than the parental H460 cells. Also, cisplatin-R demonstrated decreased expression of insulin-like growth factor binding protein-3 and increased activation of IGF-1 receptor signaling compared with parental H460 cells in the presence of IGF-1. Human recombinant IGF binding protein-3 reversed cisplatin resistance in cisplatin-R cells and targeting of IGF-1 receptor using siRNA resulted in sensitization of cisplatin-R-cells to cisplatin and radiation.
CONCLUSIONS - The IGF-1 signaling pathway contributes to cisplatin-R to cisplatin and radiation. Thus, this pathway represents a potential target for improved lung cancer response to treatment.
Copyright © 2012 Elsevier Inc. All rights reserved.
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30 MeSH Terms
The novel chemical entity YTR107 inhibits recruitment of nucleophosmin to sites of DNA damage, suppressing repair of DNA double-strand breaks and enhancing radiosensitization.
Sekhar KR, Reddy YT, Reddy PN, Crooks PA, Venkateswaran A, McDonald WH, Geng L, Sasi S, Van Der Waal RP, Roti JL, Salleng KJ, Rachakonda G, Freeman ML
(2011) Clin Cancer Res 17: 6490-9
MeSH Terms: Animals, Barbiturates, Cell Line, Tumor, DNA Breaks, Double-Stranded, DNA Damage, DNA Repair, Humans, Indoles, Mice, Mice, Nude, Molecular Chaperones, Molecular Targeted Therapy, Neoplasms, Nuclear Proteins, Radiation Tolerance, Radiation-Sensitizing Agents, Random Allocation
Show Abstract · Added March 7, 2014
PURPOSE - Radiation therapy continues to be an important therapeutic strategy for providing definitive local/regional control of human cancer. However, oncogenes that harbor driver mutations and/or amplifications can compromise therapeutic efficacy. Thus, there is a need for novel approaches that enhance the DNA damage produced by ionizing radiation.
EXPERIMENTAL DESIGN - A forward chemical genetic approach coupled with cell-based phenotypic screening of several tumor cell lines was used to identify a novel chemical entity (NCE) that functioned as a radiation sensitizer. Proteomics, comet assays, confocal microscopy, and immunoblotting were used to identify the biological target.
RESULTS - The screening process identified a 5-((N-benzyl-1H-indol-3-yl)-methylene)pyrimidine-2,4,6(1H,3H,5H)trione as an NCE that radiosensitized cancer cells expressing amplified and/or mutated RAS, ErbB, PIK3CA, and/or BRAF oncogenes. Affinity-based solid-phase resin capture followed by liquid chromatography/tandem mass spectrometry identified the chaperone nucleophosmin (NPM) as the NCE target. SiRNA suppression of NPM abrogated radiosensitization by the NCE. Confocal microscopy showed that the NCE inhibited NPM shuttling to radiation-induced DNA damage repair foci, and the analysis of comet assays indicated a diminished rate of DNA double-strand break repair.
CONCLUSION - These data support the hypothesis that inhibition of DNA repair due to inhibition of NPM shuttling increases the efficacy of DNA-damaging therapeutic strategies.
©2011 AACR.
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17 MeSH Terms
Autotaxin and LPA receptors represent potential molecular targets for the radiosensitization of murine glioma through effects on tumor vasculature.
Schleicher SM, Thotala DK, Linkous AG, Hu R, Leahy KM, Yazlovitskaya EM, Hallahan DE
(2011) PLoS One 6: e22182
MeSH Terms: Animals, Cell Death, Cell Line, Tumor, Cell Movement, Cell Survival, Endothelial Cells, Glioma, Human Umbilical Vein Endothelial Cells, Humans, Lysophospholipids, Mice, Molecular Targeted Therapy, Neovascularization, Pathologic, Phosphoric Diester Hydrolases, Radiation-Sensitizing Agents, Receptors, Lysophosphatidic Acid, Signal Transduction
Show Abstract · Added August 21, 2013
Despite wide margins and high dose irradiation, unresectable malignant glioma (MG) is less responsive to radiation and is uniformly fatal. We previously found that cytosolic phospholipase A2 (cPLA(2)) is a molecular target for radiosensitizing cancer through the vascular endothelium. Autotaxin (ATX) and lysophosphatidic acid (LPA) receptors are downstream from cPLA(2) and highly expressed in MG. Using the ATX and LPA receptor inhibitor, α-bromomethylene phosphonate LPA (BrP-LPA), we studied ATX and LPA receptors as potential molecular targets for the radiosensitization of tumor vasculature in MG. Treatment of Human Umbilical Endothelial cells (HUVEC) and mouse brain microvascular cells bEND.3 with 5 µmol/L BrP-LPA and 3 Gy irradiation showed decreased clonogenic survival, tubule formation, and migration. Exogenous addition of LPA showed radioprotection that was abrogated in the presence of BrP-LPA. In co-culture experiments using bEND.3 and mouse GL-261 glioma cells, treatment with BrP-LPA reduced Akt phosphorylation in both irradiated cell lines and decreased survival and migration of irradiated GL-261 cells. Using siRNA to knock down LPA receptors LPA1, LPA2 or LPA3 in HUVEC, we demonstrated that knockdown of LPA2 but neither LPA1 nor LPA3 led to increased viability and proliferation. However, knockdown of LPA1 and LPA3 but not LPA2 resulted in complete abrogation of tubule formation implying that LPA1 and LPA3 on endothelial cells are likely targets of BrP-LPA radiosensitizing effect. Using heterotopic tumor models of GL-261, mice treated with BrP-LPA and irradiation showed a tumor growth delay of 6.8 days compared to mice treated with irradiation alone indicating that inhibition of ATX and LPA receptors may significantly improve malignant glioma response to radiation therapy. These findings identify ATX and LPA receptors as molecular targets for the development of radiosensitizers for MG.
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17 MeSH Terms
Cytosolic phospholipase A2 as a molecular target for the radiosensitization of ovarian cancer.
Schulte RR, Linkous AG, Hallahan DE, Yazlovitskaya EM
(2011) Cancer Lett 304: 137-43
MeSH Terms: Adenocarcinoma, Animals, Antineoplastic Agents, Arachidonic Acids, Blotting, Western, Combined Modality Therapy, Cytoplasm, Enzyme Activation, Enzyme Inhibitors, Female, Humans, Mice, Mice, Nude, Ovarian Neoplasms, Phospholipases A2, Cytosolic, Radiation-Sensitizing Agents, Signal Transduction, Xenograft Model Antitumor Assays
Show Abstract · Added August 21, 2013
In ovarian cancer, the molecular targeted chemotherapeutics could increase the efficiency of low-dose radiotherapy while decreasing injury to adjusted organs. In irradiated A2780 human ovarian carcinoma cells, cytosolic phospholipase A2 (cPLA(2)) inhibitor AACOCF(3) prevented activation of pro-survival Akt signaling and enhanced cell death. The potential molecular mechanisms of this effect could involve signaling through lysophosphatidic acid receptors. In the heterotopic A2780 tumor model using nude mice, cPLA(2) inhibition significantly delayed tumor growth compared to treatment with radiation or vehicle alone. These results identify cPLA(2) as a molecular target to enhance the therapeutic ratio of radiation in ovarian cancer.
Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.
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18 MeSH Terms