Role of OCT-3 on metformin action in oral carcinogenesis

OCT-3 对二甲双胍在口腔癌发生中的作用的作用

• 批准号: 8649805
• 负责人: Abraham Schneider
• 金额: $ 38.38万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8649805
• 关键词: Address; Affect; Antidiabetic Drugs; Antineoplastic Agents; Area; Biguanides; Carcinogens; Cell Differentiation process; Cell Line; Cell Proliferation; Cell membrane; Cells; Chemoprevention; Chemopreventive Agent; Chronic; Clinical; Dependence; Development; Diagnosis; Disease; Down-Regulation; Drug Costs; FDA approved; Future; Gene Family; Genetic; Goals; Hormonal; Hour; Human; Immunocompetent; In Vitro; Intervention; Intracellular Transport; Knowledge; Lesion; Link; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Membrane; Metformin; Modeling; Morbidity - disease rate; Mus; Nitroquinolines; Non-Insulin-Dependent Diabetes Mellitus; Normal tissue morphology; Operative Surgical Procedures; Oral; Organic Cation Transporter; Organic Cation Transporter 1; Outcome; Oxides; Patients; Persons; Pharmaceutical Preparations; Phenformin; Play; Premalignant; Reporting; Risk; Role; Screening for Oral Cancer; Site; Structure; Survival Rate; Testing; Therapeutic; Tissues; Toxic effect; United States; Work; anticancer research; cancer cell; cancer chemoprevention; cancer therapy; cancer type; chemoradiation; defined contribution; in vivo; insight; malignant mouth neoplasm; mortality; mouse model; mouth squamous cell carcinoma; neoplastic cell; non-diabetic; oral cancer prevention; oral carcinogenesis; oral dysplasia; overexpression; patient population; prevent; public health relevance; resistance mechanism; response; solute; standard care; tissue culture; tumor; tumor growth; tumor xenograft; uptake

"Role of OCT-3 on metformin action in oral carcinogenesis" The long-term goal of this proposal is to identify the target patient population who will benefit from the use of metformin, or related biguanides, in oral cancer prevention and treatment. In the United States, roughly one person dies every hour of each day because of complications associated with oral cancer, mainly oral squamous cell carcinoma (OSCC). Unfortunately, improvements in OSCC patient survival rates have remained unchanged for decades. Late diagnosis and "field cancerization" with multifocal potentially malignant dysplastic lesions or secondary primary OSCCs are major factors compromising standard treatments. In this regard, long- term chemopreventive targeting of "at risk" oral premalignant lesions may offer a great opportunity to control OSCC development and progression. We recently reported that metformin, a FDA-approved biguanide used as first-line treatment for type 2 diabetes, significantly prevented the conversion of carcinogen-induced oral premalignant lesions into OSCC tumors in immunocompetent mice. Despite significant progress, a critical issue that remains elusive is whether metformin acts directly on the tumor cells, or affects cancer development by controlling hormonal responses at extratumoral sites. This gap in knowledge holds significant clinical implications because, as a highly hydrophilic cationic drug, metformin intracellular uptake relies on tissue- specific mechanisms facilitated by a group of polyspecific cell membrane organic cation transporters (OCTs) belonging to the solute carrier 22A (SLC22A) gene family. Although, it is known that OCT-1, OCT-2 and OCT-3 mediate metformin uptake in different normal tissues, it is still unclear which role OCTs play on the antineoplastic effects of metformin, or other related biguanides. Our preliminary studies point to OCT-3 as the uptake transporter of metformin in oral carcinogenesis. We found variable OCT-3 expression in OSCC cell lines derived from human oral premalignant lesions and OSCC tumors. Interestingly, strong OCT-3 expression was commonly observed in oral dysplasias and well-differentiated OSCC, but progressively declined in more atypical, less differentiated OSCC tumors. These results suggest that OCT-3 expression is linked to the degree of tumor cell differentiation, and points to this previously unidentified association as a potential mechanism of resistance to metformin in oral carcinogenesis. In contrast, phenformin, a more hydrophobic biguanide, appears to be less dependent on OCT-3-mediated uptake and likely a better alternative to target established, OCT-3 negative OSCC tumors. Through in vitro and in vivo approaches, we will test the overall hypothesis that tumor growth inhibition by metformin or related biguanides such as phenformin is dependent on OCT-3 uptake activity at the primary site of oral carcinogenesis. Three specific aims are proposed. Aim 1 will define the contribution of OCT-3 on OSCC cell proliferation in response to metformin. Aim 2 will determine the impact of OCT-3 on metformin chemopreventive action in oral carcinogenesis. Aim 3 will identify dependence of OCT-3 for the antineoplastic activity of phenformin in oral carcinogenesis. By elucidating mechanisms of biguanide uptake and activity, we envision that the outcomes of the proposed studies may ultimately impact the selection of the most suitable patients who can benefit from these drugs in oral cancer chemoprevention and treatment.

“ OCT-3对二甲双胍作用在口服癌变中的作用” 该提案的长期目标是确定目标患者群体，他们将从使用中受益 口腔癌预防和治疗中的二甲双胍或相关的biguanides。在美国，大约一个 由于与口腔癌相关的并发症，人们每天每小时死亡，主要是口腔 鳞状细胞癌（OSCC）。不幸的是，OSCC患者存活率的提高仍在 几十年来保持不变。多灶性潜在恶性发育不良的晚期诊断和“现场癌化” 病变或次级原发性OSCC是损害标准处理的主要因素。在这方面，长期 术语化学预防靶向“处于危险”口腔前病变可能会提供一个很好的控制机会 OSCC的发展和进展。我们最近报道说，二甲双胍是FDA批准的Biguanide使用的 作为2型糖尿病的一线治疗 免疫能力小鼠中OSCC肿瘤的前病变。尽管取得了重大进展，但一个关键 仍然难以捉摸的问题是二甲双胍是直接在肿瘤细胞上作用还是影响癌症的发展 通过控制肿瘤外部位的激素反应。知识的差距具有重大的临床 含义是因为作为一种高度亲水性阳离子药，二甲双胍细胞内摄取依赖于组织 一组多元特异性细胞膜有机阳离子转运蛋白（OCT）促进的特定机制 属于溶质载体22A（SLC22A）基因家族。虽然，众所周知，Oct-1，Oct-2和Oct-3 介导不同正常组织中的二甲双胍摄取，目前尚不清楚OCT在 二甲双胍或其他相关Biguanides的抗塑性作用。我们的初步研究指向10月3日 口服癌变中二甲双胍的摄取转运蛋白。我们发现OSCC细胞系中的OCT-3表达可变 源自人口腔前病变和OSCC肿瘤。有趣的是，强烈的Oct-3表达是 通常在口服异常增生和差异良好的OSCC中观察到，但逐渐下降了 非典型，分化较少的OSCC肿瘤。这些结果表明OCT-3表达与程度有关 肿瘤细胞分化，并指出这种先前未鉴定的关联是 口服癌变中对二甲双胍的抗性。相比之下，苯甲酸苯甲酸苯甲酸苯甲酸苯胺苯甲酸苯甲酸苯甲酸酯，疏水性biguanide， 似乎不太依赖Oct-3介导的摄取，并且可能是建立目标的更好替代方案， OCT-3阴性OSCC肿瘤。通过体外和体内方法，我们将测试总体假设 二甲双胍或相关的biguanides（例如苯甲酸苯甲酸苯甲酸盐）抑制肿瘤生长的抑制作用取决于OCT-3摄取 口服癌变的主要部位的活性。提出了三个具体目标。 AIM 1将定义 OCT-3对二甲双胍的OSCC细胞增殖的贡献。 AIM 2将决定 OCT-3关于口服癌变中的二甲双胍化学预防作用。 AIM 3将确定Oct-3的依赖性 对于口服癌变中苯甲酸苯甲酸的抗塑性活性。通过阐明Biguanide的机制 吸收和活动，我们设想提出的研究的结果可能最终会影响选择 最合适的患者可以从这些药物中受益于口腔癌的化学预防和治疗。