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

军事人员不可避免地暴露在高剂量紫外线辐射(UVR)中 训练或锻炼，或部署到太阳辐射高的地方。因此，我们的 退伍军人特别容易患上终生皮肤癌，如鳞状细胞癌 和基底细胞癌，因为UVR的过度暴露是不可避免的，因为 兵役的要求和性质。维生素D3(D3)的生产也需要UVB 在皮肤中，它提供了人体对这种前激素90%的需求。由于有毒的 (钙化)作用，药理剂量的1，25(OH)2D3治疗用途严重 有限的。我们发现了另一种途径，它由Cyp11a1的作用开始，即速率限制 类固醇生成的酶，产生20(OH)D3，然后进一步羟化生成几个 (OH)Nd3代谢物。它们都表达受细胞谱系影响的生物活性，并 羟基的位置。20(OH)D3及其代谢物存在于表皮、肾上腺 而在人体血清中与大多数其他代谢物在体内也可检测到。这些皮质类固醇 证明生物效力等于或高于1，25(OH)2D3。他们中的一些人 无钙/无毒，超过药理剂量。它们诱导角质形成细胞分化， 初步实验表明，它们具有辐射防护和抗皮肤癌的特性。 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 预防和逆转中波紫外线诱导的皮肤癌变，并作为抗癌化合物。这个 假设将在两个具体目标中得到检验。具体目标1：我们将定义临床前疗效 Cyp11a1衍生的D3-羟基衍生物及其抗肿瘤作用机制的研究 中波紫外线诱发的表皮皮肤癌。在其Subaim 1中，我们将定义 20(OH)D3及其下游(OH)Nd3代谢物对永生化或恶性人的作用 和小鼠表皮角质形成细胞。在其Subaim 2中，我们将定义 精选的(OH)Nd3衍生物。具体目标2：我们将测试20(OH)D3和 两种最有效的(OH)Nd3衍生物在PTCH+/-/SKH-1中抗UVB诱癌作用 小鼠模型。预期的结果是提供证据，证明选定的Cyp11a1派生 赛克类固醇可减轻或逆转中波紫外线诱导的病理变化，起到保护作用 光致癌。我们还将确定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使用的相似和不同之处。这个 最终目标是使用局部或肌肉内最佳的非钙血症性Secosterid来保护或 及时治疗现有和未来的军事人员对抗UVB诱发的皮肤癌。

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.