CYP11A1-derived secosteroids as therapeutic agents in UVB induced skin cancer

CYP11A1 衍生的类固醇作为 UVB 诱导皮肤癌的治疗剂

• 批准号: 10436919
• 负责人: ANDRZEJ T SLOMINSKI
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436919
• 关键词: Actinic keratosis; Adrenal Glands; Affect; Animals; Antiinflammatory Effect; Attenuated; Basal cell carcinoma; Biological; CYP11A1 gene; Calcium; Carcinoma; Cell Lineage; Cells; Chemopreventive Agent; Cholecalciferol; Country; Dose; Drug Delivery Systems; Drug Kinetics; Enzymes; Epidermis; Evaluation; Exercise; Exposure to; Future; Geographic Locations; Goals; Histologic; Homeostasis; Human; Hydroxylation; Intramuscular; Location; Malignant - descriptor; Malignant Neoplasms; Measures; Military Personnel; Modeling; Molecular; Mus; Muscle; Nature; Nuclear Receptors; Outcome; Pathogenesis; Pathology; Pathway interactions; Pharmacology; Positioning Attribute; Precancerous Conditions; Preclinical Testing; Preventive; Production; Property; Radiation Protection; Regulation; Risk Factors; Route; Scheme; Secosteroids; Serum; Services; Skin; Skin Aging; Skin Cancer; Solar Energy; Squamous Cell; Squamous cell carcinoma; Steroid biosynthesis; Testing; Therapeutic Agents; Therapeutic Uses; Topical application; Toxic effect; Training; UV Radiation Exposure; UV carcinogenesis; UVB induced; Ultraviolet B Radiation; Ultraviolet Rays; Veterans; Vitamin D; Vitamin D3 Receptor; active duty; anti-cancer; experimental study; hydroxyl group; in vivo; irradiation; keratinocyte; keratinocyte differentiation; melanoma; military service; mouse model; novel; pleiotropism; preclinical efficacy; prevent; prohormone; protective effect; skin organogenesis; tumor; ultraviolet

Military personnel are unavoidably exposed to high doses of ultraviolet radiation (UVR) during training or exercise, or when deployed to locations with high solar radiation. Therefore, our veterans are particularly vulnerable to a lifetime development of skin cancers such as squamous and basal cell carcinomas, because of an excessive exposure to UVR that is inevitable due to the requirements and nature of military service. UVB is also required for vitamin D3 (D3) production in the skin, which supplies >90% of the body’s requirement for this prohormone. Due to the toxic (calcemic) effects, therapeutic uses of 1,25(OH)2D3 at pharmacological doses are severely limited. We discovered an alternative pathway that starts by the action of CYP11A1, rate limiting enzyme of steroidogenesis, to produce 20(OH)D3 with its further hydroxylation producing several (OH)nD3 metabolites. All of them express biological activities that are affected by cell lineage and position of hydroxyl group. 20(OH)D3 and its metabolites are present in the epidermis, adrenals and in human serum with majority of other metabolites also detectable in vivo. These secosteroids demonstrate biological potency equal or higher than that of 1,25(OH)2D3. Some of them are noncalcemic/nontoxic at supra-pharmacological doses. They induce keratinocyte differentiation, and initial experiments indicate that they have radio-protective and anti-skin cancer properties. Therefore, our hypothesis is that novel CYP11A1-derived vitamin D hydroxyderivatives can prevent and reverse UVB induced skin cancerogenesis and act as anti-cancer compounds. The hypothesis will be tested in two specific aims. Specific Aim 1: We will define the preclinical efficacy of CYP11A1-derived D3-hydroxyderivatives and determine their mechanism of action against UVB-induced epidermal skin cancers. In its Subaim 1 we will define the relative efficacy of 20(OH)D3 and its downstream (OH)nD3 metabolites against immortalized or malignant human and murine epidermal keratinocytes. In its Subaim 2 we will define the mechanism of action of selected (OH)nD3 derivatives. Specific Aim 2: We will test preclinical efficacy of 20(OH)D3 and the two most potent (OH)nD3 derivatives against UVB-induced cancer in the Ptch+/-/SKH-1 murine model. The expected outcome is to provide the proof that selected CYP11A1-derived secosteroids can attenuate or reverse UVB induced pathology acting as “guardians” against photocarcinogenesis. We will also define the mechanism of action for its anti-cancerogenic effects and establish similarities and differences for topical application prior to or after UV exposure. The final goal is to use topically or intra-muscularly optimal noncalcemic secosteroids to protect or treat current and future military personnel against UVB induced skin cancer before it is too late.

军事人员在执行任务期间不可避免地暴露于高剂量的紫外线辐射（UVR）下。 训练或锻炼，或部署到太阳辐射高的地方时，我们的。 退伍军人特别容易终生罹患皮肤癌，例如鳞状细胞癌 和基底细胞癌，因为过度暴露于 UVR，这是不可避免的 维生素 D3 (D3) 的生产也需要 UVB。 由于有毒，皮肤可以满足身体对这种激素原的需求的 90% 以上。 （血钙）效应，药理学剂量的 1,25(OH)2D3 的治疗用途是严重的 我们发现了一种由 CYP11A1 的作用（速率限制）启动的替代途径。 类固醇生成酶，产生 20(OH)D3，其进一步羟基化产生数种 (OH)nD3 代谢物均表达受细胞谱系和影响的生物活性。 20(OH)D3及其代谢物存在于表皮、肾上腺中。 在人血清中，大多数其他代谢物也可在体内检测到。 证明生物效力等于或高于 1,25(OH)2D3。 在超药理学剂量下，它们不会导致钙血症/无毒，它们会诱导角质形成细胞分化， 初步实验表明它们具有防辐射和抗皮肤癌的特性。 因此，我们的假设是新型 CYP11A1 衍生的维生素 D 羟基衍生物可以 预防和逆转 UVB 诱导的皮肤癌发生并充当抗癌化合物。 假设将在两个具体目标中进行检验 具体目标 1：我们将定义临床前疗效。 CYP11A1衍生的D3-羟基衍生物的研究并确定其作用机制 在其 Subaim 1 中，我们将定义 UVB 诱发的表皮皮肤癌的相对功效。 20(OH)D3 及其下游 (OH)nD3 代谢物对抗永生或恶性人类 在其 Subaim 2 中，我们将定义其作用机制。 选定的 (OH)nD3 衍生物 具体目标 2：我们将测试 20(OH)D3 和 20(OH)D3 的临床前功效。 Ptch+/-/SKH-1 中两种最有效的抗 UVB 诱导癌症的 (OH)nD3 衍生物 预期结果是提供选择 CYP11A1 衍生的证据。 隔离类固醇可以减弱或逆转 UVB 引起的病理，充当“守护者”的角色 我们还将定义其抗癌作用的作用机制。 并确定紫外线照射之前或之后局部应用的相似点和差异。 最终目标是使用局部或肌肉内最佳的非钙血症类固醇来保护或 尽早治疗当前和未来的军事人员，预防 UVB 诱发的皮肤癌。