Testing feasibility of artemisinin-based synthetic-lethal suppression of skin pho

测试基于青蒿素的皮肤光合成致死抑制的可行性

• 批准号: 8450745
• 负责人: Georg T Wondrak
• 金额: $ 7.58万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8450745
• 关键词: Animal Disease Models; Antimalarials; Antineoplastic Agents; Artemisia; Artemisia annua; Artemisinins; Biological Factors; Breast Carcinoma; Cancerous; Cell Survival; Cells; Chemoprevention; Clinical; Clinical Research; Cutaneous; Cutaneous Melanoma; Data; Development; Disease; Drug Kinetics; Epithelial Cells; Future; Genetic; Homeostasis; Human; Human papilloma virus infection; Hypersensitivity; Inbred HRS Mice; Incidence; Intervention; Ions; Iron; Lead; Libraries; Light; Malignant - descriptor; Malignant Neoplasms; Modeling; Molecular; Mus; Mutate; Mutation; Oncogene Activation; Oncogenes; Oncogenic; Oxidation-Reduction; Oxidative Stress; Pharmaceutical Preparations; Pharmacodynamics; Pilot Projects; Premalignant; Public Health; Research; Sesquiterpenes; Skin; Skin Cancer; Skin Carcinogenesis; Skin Carcinoma; Squamous cell carcinoma; Staging; Testing; The Sun; Time; Toxic effect; Tumor Suppressor Genes; Tumor Suppressor Proteins; UVB induced; Ultraviolet Rays; United States; Virus; absorption; anticancer activity; artemisinine; base; cancer cell; cancer chemoprevention; carcinogenesis; cell transformation; chemotherapy; cytotoxic; cytotoxicity; design; in vivo; innovation; keratinocyte; killings; loss of function; loss of function mutation; mouse model; novel; novel strategies; outcome forecast; pharmacophore; preclinical efficacy; preclinical study; prototype; residence; screening; transforming virus; ultraviolet

DESCRIPTION (provided by applicant): Nonmelanoma skin cancer (NMSC) is the most common malignancy in the United States presenting a public health burden of considerable magnitude. Chemoprevention strategies that involve pharmacological suppression of skin photocarcinogenesis have shown promise in preclinical and clinical studies, but more efficacious agents are needed. Recent research indicates that oncogene expression in premalignant and cancerous cells may represent a specific molecular vulnerability that can be targeted by personalized genetic or pharmacological intervention without impairing viability of cells that do not express the specific oncogene, a mode of conditional cytotoxicity referred to as 'synthetic-lethal'. Our recent research has identified artemisinins, an important class of redox-anti-malarials in clinical use worldwide, as synthetic- lethal anticancer agents that target disruption of cellular iron homeostasis, a common alteration of transformed cells that causes hypersensitivity to cytotoxic oxidative stress. In continuation of our current research aiming at elucidating molecular mechanisms underlying targeted inactivation of nonmelanoma and melanoma skin cancer cells by artemisinins, we propose pilot experimentation that tests the hypothesis that artemisinin-based topical intervention can suppress skin photocarcinogenesis by synthetic-lethal elimination of premalignant and malignant cutaneous keratinocytes. First, skin pharmacokinetics (cutaneous absorption profile) of artemisinin-derivatives will be established using an ex-vivo mouse skin chamber model (aim #1). Second, feasibility of artemisinin-based topical suppression of photocarcinogenesis will then be tested in the SKH-1 murine model of solar ultraviolet B-induced squamous cell carcinoma (aim #2). Critical proof-of-principle data will be generated guiding the rational design of future mechanistic and preclinical studies that validate synthetic-lethal approaches for photochemoprevention.

描述（由申请人提供）：非黑色素瘤皮肤癌（NMSC）是美国最常见的恶性肿瘤，对公共卫生造成相当大的负担。涉及药物抑制皮肤光致癌作用的化学预防策略已在临床前和临床研究中显示出前景，但需要更有效的药物。最近的研究表明，癌基因在癌前病变和癌细胞中的表达可能代表了一种特定的分子脆弱性，可以通过个性化的遗传或药理学干预来靶向该分子脆弱性，而不会损害不表达特定癌基因的细胞的活力，这是一种被称为“合成致死”的条件性细胞毒性模式。我们最近的研究已经确定了青蒿素，一种在世界范围内临床使用的重要类别的氧化还原抗疟疾药，作为靶向破坏细胞铁稳态的合成致死抗癌剂，这是转化细胞的一种常见改变，导致对细胞毒性氧化应激的超敏反应。在继续我们目前的研究，旨在阐明青蒿素靶向灭活非黑色素瘤和黑色素瘤皮肤癌细胞的分子机制，我们提出了试点实验，测试的假设，青蒿素为基础的局部干预可以抑制皮肤光致癌的癌前和恶性皮肤角质形成细胞的合成-致死消除。首先，将使用离体小鼠皮肤室模型建立青蒿素衍生物的皮肤药代动力学（皮肤吸收曲线）（目的#1）。第二，然后将在太阳紫外线B诱导的鳞状细胞癌的SKH-1鼠模型中测试基于青蒿素的局部抑制光致癌作用的可行性（目的#2）。关键的原理证明数据将产生指导合理设计未来的机制和临床前研究，验证合成致死方法的光化学预防。