MnTE-2-PyP as a radioprotector in prostate cancer therapy

MnTE-2-PyP 作为前列腺癌治疗中的放射防护剂

• 批准号: 8923175
• 负责人: REBECCA E OBERLEY-DEEGAN
• 金额: $ 31.94万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-08 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8923175
• 关键词: Adverse effects; Affect; Animals; Antioxidants; Atrophic; Cell Proliferation; Cells; Cessation of life; Chronic; Data; Development; Dose; EP300 gene; Employee Strikes; Enzymes; Erectile dysfunction; FDA approved; Fibroblasts; Fibrosis; Free Radicals; Gene Expression; Generations; Genes; Genitourinary system; Growth; Health; Human; Hydrogen Peroxide; In Vitro; Incontinence; Inflammation; Inflammatory; Inflammatory Response; Injury; Laboratories; Lead; Left; Life; Malignant neoplasm of prostate; Measures; Mediating; Metabolic; Metabolism; NADPH Oxidase; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; Oxidative Stress; Pathway interactions; Patients; Pelvis; Pharmaceutical Preparations; Play; Process; Proctitis; Production; Prostate Cancer therapy; Prostatic Neoplasms; Quality of life; Radiation; Radiation induced damage; Radiation therapy; Radio; Reaction; Reactive Oxygen Species; Relative (related person); Role; Signal Transduction; Superoxides; Testing; Therapeutic; Time; Tissues; Treatment outcome; Tumor Tissue; Work; Xenograft Model; antitumor agent; cancer cell; cancer radiation therapy; cell killing; cytokine; histone acetyltransferase; in vivo; inhibitor/antagonist; irradiation; killings; men; migration; oxidative damage; prevent; prostate cancer cell; radiation-induced injury; response; small molecule; targeted treatment; transcription factor; tumor; tumor growth; tumor progression; Adverse effects; Affect; Animals; Antioxidants; Atrophic; Cell Proliferation; Cells; Cessation of life; Chronic; Data; Development; Dose; EP300 gene; Employee Strikes; Enzymes; Erectile dysfunction; FDA approved; Fibroblasts; Fibrosis; Free Radicals; Gene Expression; Generations; Genes; Genitourinary system; Growth; Health; Human; Hydrogen Peroxide; In Vitro; Incontinence; Inflammation; Inflammatory; Inflammatory Response; Injury; Laboratories; Lead; Left; Life; Malignant neoplasm of prostate; Measures; Mediating; Metabolic; Metabolism; NADPH Oxidase; Neoplasm Metastasis; Normal Cell; Normal tissue morphology; Oxidative Stress; Pathway interactions; Patients; Pelvis; Pharmaceutical Preparations; Play; Process; Proctitis; Production; Prostate Cancer therapy; Prostatic Neoplasms; Quality of life; Radiation; Radiation induced damage; Radiation therapy; Radio; Reaction; Reactive Oxygen Species; Relative (related person); Role; Signal Transduction; Superoxides; Testing; Therapeutic; Time; Tissues; Treatment outcome; Tumor Tissue; Work; Xenograft Model; antitumor agent; cancer cell; cancer radiation therapy; cell killing; cytokine; histone acetyltransferase; in vivo; inhibitor/antagonist; irradiation; killings; men; migration; oxidative damage; prevent; prostate cancer cell; radiation-induced injury; response; small molecule; targeted treatment; transcription factor; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Roughly 1.5 million US men living today have been treated with radiation therapy for prostate cancer and the number is expected to increase. The majority of these patients will suffer significant reduction in quality of life (i.e., erectile dysfunction, incontinence and proctitis) ad there are no FDA approved treatments to protect normal pelvic tissues from radiation-induced damage. Radiation exposure leads to free radical-mediated oxidative damage to normal tissues leading to fibrosis. The activation of p300 helps to drive persistent inflammation and fibrosis after irradiation. Cancer cells have increased metabolic production of reactive oxygen species (ROS) and p300 activity, relative to normal cells, which have been shown to drive cancer progression. Thus, suppressing radiation-induced ROS and p300 activity can act as both a radio-protector in normal tissues while inhibiting pro-survival and progression pathways in cancer cells. MnTE-2-PyP is a small molecule antioxidant, which scavenges a variety of ROS and reduces p300 activity. Preliminary data demonstrate that MnTE-2-PyP protects urogenital tissues from radiation-induced damage, while enhancing prostate cancer killing. The overall hypothesis of this proposal is that MnTE-2-PyP both scavenges ROS and inhibits p300 activity, which protects normal tissue injury by suppressing fibrosis while at the same time inhibiting tumor progression. Specific Aim 1 will determine whether MnTE-2-PyP protects normal pelvic tissues from radiation-induced inflammation by inhibiting both NADPH oxidase derived ROS and p300 activity. We will determine whether: 1. MnTE-2-PyP protects normal tissues from radiation damage by inhibiting ROS and p300 2. MnTE-2-PyP through ROS scavenging and p300 inhibition prevents pro-fibrotic signaling in fibroblasts exposed to irradiation 3. MnTE-2-PyP protects normal tissues by inhibiting Th2 inflammatory response by inhibiting NADPH oxidase- derived ROS and p300 activity. Specific Aim 2 will determine whether MnTE-2-PyP inhibits the progression of irradiated prostate cancer cells both in vitro and in vivo via ROS scavenging and p300 inhibition. In this aim it will be demonstrated that: 1. MnTE-2-PyP sensitizes prostate cancer cells to irradiation in vitro and in vivo 2. The manipulation of p300 and/or ROS affects the ability of MnTE-2-PyP to inhibit pro-survival and pro-angiogenic pathways necessary for tumor survival. 3. MnTE-2-PyP inhibits tumor growth and metastasis in an irradiated orthotopic xenograft model while protecting normal tissues. The completion of the studies will provide an in depth mechanistic understanding of the mechanisms by which MnTE-2-PyP inhibits normal tissue injury, while reducing prostate cancer growth during prostate cancer radiotherapy. Understanding how MnTE-2-PyP works as a radio-protector, can lead to the development more targeted therapies to enhance treatment outcomes in prostate cancer radiotherapy.

描述（由申请人提供）： 当今居住的大约有150万美国男性接受了前列腺癌的放射治疗，预计该数量将增加。这些患者中的大多数将大大降低生活质量（即勃起功能障碍，尿失禁和前进性炎）AD没有FDA批准的治疗方法可以保护正常的骨盆组织免受辐射诱导的损伤。辐射暴露会导致对正常组织的自由基介导的氧化损伤，从而导致纤维化。 p300的激活有助于辐射后持续的炎症和纤维化。相对于正常细胞，癌细胞的代谢生产增加了活性氧（ROS）和p300活性，这些细胞已证明促进了癌症的进展。因此，抑制辐射诱导的ROS和p300活性可以在正常组织中充当无线电组，同时抑制癌细胞中的促生存和进展途径。 MNTE-2-PYP是一种小分子抗氧化剂，它清除了各种ROS并减少P300活性。初步数据表明，MNTE-2-PYP可以保护泌尿生殖组织免受辐射诱导的损伤，同时增强了前列腺癌的杀戮。该提议的总体假设是MNTE-2-PYP既清除ROS又抑制P300活性，从而通过抑制纤维化来保护正常组织损伤，同时抑制肿瘤进展。特定的目标1将通过抑制NADPH氧化酶衍生的ROS和P300活性来确定MNTE-2-PYP是否可以保护正常的骨盆组织免受辐射诱导的炎症。我们将确定：1。MNTE-2-pyp是否通过抑制ROS和p300 2来保护正常组织免受辐射损伤。通过ROS清除和p300抑制，MNTE-2-pyp和p300抑制作用可防止暴露于辐照的成纤维细胞中促纤维细胞的促纤维细胞3。mnte-2-pyp可通过抑制ROS的NADPASE和ph3 nADD nADDINAD nADDIND nADDIND iNADDIND iNADDIND iNADDIND iNADPASE ind iNADS nADDIND iNADDIND iNADDIND iNADPASE。具体目标2将通过ROS清除和p300抑制在体外和体内抑制辐照前列腺癌细胞的进展。在此目的中，将证明：1。MNTE-2-PYP使前列腺癌细胞在体外和体内辐射2。 MNTE-2-pyp抑制肿瘤存活所必需的促生存和促血管生成途径的能力。 3。MNTE-2-PYP在保护正常组织的同时，在辐照的原位异种移植模型中抑制肿瘤的生长和转移。研究的完成将为MNTE-2-PYP抑制正常组织损伤的机制提供深入的机理理解，同时减少前列腺癌放射疗法期间前列腺癌的生长。了解MNTE-2-PYP如何作为无线电组件的工作方式，可以导致更具针对性的疗法，以增强前列腺癌放射疗法的治疗结果。