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: 10265344
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265344
• 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.

军事人员暴露于高剂量的紫外线辐射（UVR）， 训练或演习，或部署到太阳辐射高的地方。所以我们的 退伍军人特别容易在一生中患上皮肤癌， 和基底细胞癌，因为过度暴露于UVR，这是不可避免的，由于 服兵役的要求和性质。UVB也需要维生素D3（D3）的生产 在皮肤中，它提供了>90%的身体对这种激素原的需求。由于有毒 （钙离子）的影响，1，25（OH）2D 3在药理剂量下的治疗用途严重 有限公司我们发现了一种替代途径，它由CYP 11 A1的作用开始， 类固醇生成酶，以产生20（OH）D3，其进一步羟基化产生几种 （OH）nD 3代谢物。它们都表达受细胞谱系影响的生物活性， 羟基的位置。20（OH）D3及其代谢产物存在于表皮、肾上腺 并且在人血清中，大多数其他代谢物也可在体内检测到。这些开环甾类化合物 证明生物效价等于或高于1，25（OH）2D 3。其中一些是 在超药理剂量下无钙血症/无毒。它们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，新的CYP 11 A1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，并作为抗癌化合物。的 假设将在两个具体目标进行测试。具体目标1：我们将定义临床前疗效 CYP 11 A1衍生的D3-羟基衍生物，并确定其作用机制 UVB诱发的表皮皮肤癌。在其Subaim 1中，我们将定义 20（OH）D3及其下游（OH）nD 3代谢产物对永生化或恶性人的抗肿瘤作用 和鼠表皮角质形成细胞。在Subaim 2中，我们将定义 选择的（OH）nD 3衍生物。具体目标2：我们将测试20（OH）D3的临床前疗效， 在Ptch+/-/SKH-1中，两种最有效的（OH）nD 3衍生物对抗UVB诱导的癌症 小鼠模型。预期的结果是提供证据，证明选定的CYP 11 A1衍生物 开环甾类化合物可以减弱或逆转UVB诱导的病理学， 光致癌作用我们还将确定其抗癌作用的作用机制 并确定在UV暴露之前或之后局部施用的相似性和差异性。的 最终的目标是局部或肌肉注射最佳的非钙甾类化合物， 在为时已晚之前，治疗当前和未来的军事人员对抗UVB诱导的皮肤癌。