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对二甲双胍在口腔癌发生中的作用” 该提案的长期目标是确定将从使用 二甲双胍或相关的双胍在口腔癌预防和治疗中的应用。在美国，大约有一个 每天每小时都有一个人死于与口腔癌有关的并发症，主要是口腔癌。 鳞状细胞癌（OSCC）。不幸的是，口腔鳞状细胞癌患者的生存率仍在提高， 几十年不变。多灶性潜在恶性异型增生的晚期诊断和“野癌变” 病变或继发性原发性OSCC是影响标准治疗的主要因素。在这方面，长- 长期化学预防靶向“高危”口腔癌前病变可能提供一个很好的机会， OSCC的发展和进展。我们最近报道了二甲双胍，一种FDA批准的双胍， 作为2型糖尿病的一线治疗，显著防止了致癌物诱导的口服 癌前病变转化为OSCC肿瘤。尽管取得了重大进展， 二甲双胍是否直接作用于肿瘤细胞或影响癌症发展仍是一个难以解释的问题 通过控制肿瘤外部位的激素反应。这种知识上的差距具有重大的临床意义 因为作为一种高度亲水性的阳离子药物，二甲双胍的细胞内摄取依赖于组织- 一组多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22 A（SLC 22 A）基因家族。虽然，已知OCT-1、OCT-2和OCT-3 尽管OCT介导不同正常组织中的二甲双胍摄取，但仍不清楚OCT在二甲双胍摄取中的作用。 二甲双胍或其他相关双胍类药物的副作用。我们的初步研究指出，OCT-3是 二甲双胍摄取转运蛋白在口腔癌发生中的作用我们发现OCT-3在OSCC细胞系中的表达是可变的 来源于人口腔癌前病变和OSCC肿瘤。有趣的是，OCT-3的强表达是由于 在口腔发育不良和分化良好的口腔鳞状细胞癌中常见，但在更多的 非典型、低分化的OSCC肿瘤。这些结果表明，OCT-3的表达与肿瘤的程度有关。 肿瘤细胞分化，并指出这种以前未被确定的协会作为一个潜在的机制， 口服致癌作用中对二甲双胍的耐药性。相比之下，苯丙氨酸，一种更疏水的双胍， 似乎不太依赖OCT-3介导的摄取，并且可能是既定靶点的更好替代方案， 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， 二甲双胍或相关的双胍类如苯丙氨酸对肿瘤生长的抑制依赖于OCT-3的摄取 在口腔癌发生的主要部位的活性。提出了三个具体目标。目标1将定义 OCT-3对OSCC细胞增殖的贡献。目标2将决定 OCT-3对二甲双胍在口腔癌发生中的化学预防作用。目标3将确定OCT-3的依赖性 在口腔癌发生过程中，通过阐明双胍的作用机制， 吸收和活动，我们设想，拟议的研究结果可能最终影响选择 最适合的患者谁可以受益于这些药物在口腔癌化学预防和治疗。