Mechanism of Activity of Lonidamine

氯尼达明的活性机制

基本信息

批准号：
8707409
负责人：
JERRY D GLICKSON
金额：
$ 54.54万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8707409
关键词：
Address Alkylating Agents Anthracyclines Antineoplastic Agents Biochemical Pathway Biochemistry Bioenergetics Bioreactors Cardiac Cell membrane Cells Characteristics Clinical Collaborations Data Detection Development Disease Doxorubicin Electron Transport Electrons Energy Metabolism Funding Glycolysis Glycolysis Inhibition Goals Grant Heart Hexokinase 2 Human Isolated limb perfusion Isotopes Kinetics Label Lactic acid Liver Liver Mitochondria Lonidamine Magnetic Resonance Spectroscopy Malignant Neoplasms Measures Mechlorethamine Mediating Melanoma Cell Melphalan Metabolic Metabolism Methods Mitochondria Monitor Monocarboxylic Acid Transporters Mustard Nude Mice Oxidation-Reduction Oxidative Phosphorylation Pharmaceutical Preparations Pharmacologic Substance Phospholipid Metabolism Production Protein Isoforms Pyruvate Radiation Tolerance Rana Respiration Skin Cancer Staging Systemic Therapy Techniques Testing Therapeutic Agents Time Tissues Translations Tumor Oxygenation Universities Virulent Warburg Effect Xenograft procedure Xenopus laevis base cancer cell cancer therapy chemotherapeutic agent chemotherapy clinical practice design egg glucose metabolism improved in vivo inhibitor/antagonist liquid chromatography mass spectrometry melanoma metabolomics monolayer neoplastic cell network models novel public health relevance pyruvate carrier research clinical testing response tumor tumor metabolism tumor microenvironment tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Melanoma remains one of the deadliest of human cancers with no effective method for treating the disseminated disease. While targeted therapies have shown some efficacy, they have thus far proven to be noncurative, which points to the need for other forms of systemic therapy. This proposal is part of a long-term effort to develop methods for systemic therapy of melanoma. We have recently shown that administration of lonidamine (LND, 100 mg/kg) substantially enhances the activity of melphalan and have now extended this finding to doxorubicin treatment. As a key step towards eventual clinical translation, we will now examine the detailed mechanism of LND activity. We and others have shown that LND produces tumor specific intracellular acidification and a substantial decrease in tumor energy status (NTP/Pi). A number of mechanisms have been proposed for LND: 1) inhibition of hexokinase II, 2) interference with mitochondrial electron transport, 3) inhibition of cellular lactate export through the monocarboxylate transporters (MCT). We are proposing a fourth mechanism to explain the bioenergetic decline of the tumor following treatment with LND: 4) inhibition of the putative mitochondrial pyruvate carrier (MPC), which would deplete the tumor cells of a key substrate for oxidative phosphorylation and induce an increase in glycolytic metabolism to compensate for decreased oxidative ATP production. We have recently validated a novel extension of isotopomer analysis called cumomer analysis and applied it to perfused DB1 melanoma cells. We believe that this is the first validated metabolic network model of tumor energy metabolism. We propose to test the hypotheses that 1) selective tumor acidification results from inhibition of MCT1, and 2) tumor de-energization is caused by inhibition of the MPC. In Aim 1 of this proposal, we propose to use 13C magnetic resonance spectroscopy (MRS) and liquid chromatography-mass spectrometry (LC-MS) in conjunction with bonded cumomer analysis to test these hypotheses in perfused DB1 and DB8 melanoma cells and in in vivo xenografts of these tumor lines. In Aim 2 we will directly measure the inhibitory effect of LND on MCT1 and MCT4 expressed in Xenopus laevis and will also evaluate the effect of LND on isolated liver and cardiac mitochondria and on permeabilized DB1 and DB8 cells. All of the criticisms of the previous review have been addressed including the critical issue of clinical translation for which we assembled a team of leading experts on melanoma who recommended: 1) define the mechanism of LND (the aim of this proposal), 2) first incorporate LND into hyperthermic isolated limb perfusion of melanoma with melphalan (a method already in clinical practice), and 3) then proceed to systemic therapy of cancers that are already treated with N-mustards or doxorubicin. This project will have a major impact on elucidating the mechanism of activity of a new class of drugs that like LND inhibit MCTs and other key transporters in tumor cells and thereby modify the tumor microenvironment to augment the activity of conventional anticancer agents. It will also develop novel metabolomic methods for the study of tumor metabolism and mechanisms of cancer drug activity.

描述（由申请人提供）：黑色素瘤仍然是最致命的人类癌症之一，没有治疗传播疾病的有效方法。尽管有针对性的疗法表现出一些功效，但迄今已证明它们是非生产的，这表明需要其他形式的全身疗法。该建议是开发黑色素瘤系统治疗方法的长期努力的一部分。我们最近表明，孤胺胺（LND，100 mg/kg）的施用显着增强了Melphalan的活性，现在将这一发现扩展到阿霉素治疗。作为最终临床翻译的关键一步，我们现在将研究LND活动的详细机制。我们和其他人已经表明，LND会产生肿瘤特异性细胞内酸化，并大大降低肿瘤能量状态（NTP/PI）。已经提出了许多机制的LND：1）抑制己糖激酶II，2）干扰线粒体电子转运，3）抑制细胞乳酸通过单核羧酸盐转运蛋白（MCT）的抑制。我们提出了一种解释LND处理后肿瘤的生物能下降的机制：4）抑制假定的线粒体丙酮酸载体（MPC），这会耗尽关键底物的肿瘤细胞，从而降低氧化磷酸化的肿瘤细胞，以增加氧化氧化的氧化氧化剂，以增加糖化氧化的氧化剂。我们最近验证了同位素分析的新型扩展，称为成为堆积物分析，并将其应用于灌注的DB1黑色素瘤细胞。我们认为，这是肿瘤能量代谢的第一个验证的代谢网络模型。我们建议测试以下假设，即1）选择性肿瘤酸化是由MCT1抑制而引起的，而2）肿瘤去耐药是由MPC抑制引起的。在该提案的目标1中，我们建议使用13C磁共振光谱（MRS）和液相色谱质量质谱法（LC-MS）与键合型兼职分析一起测试这些假设在灌注的DB1和DB8黑色素瘤细胞中以及这些肿瘤线的体内Xenogrofts In In In In In In In In In In In tumor tumor line。在AIM 2中，我们将直接测量LND对在Xenopus laevis中表达的MCT1和MCT4的抑制作用，还将评估LND对分离的肝脏和心脏线粒体以及透化DB1和DB8细胞的影响。已经解决了先前审查的所有批评，包括临床翻译的关键问题，我们组建了一支领先的专家黑色素瘤专家团队，建议：1）定义LND机制（本提议的目的）（目的），2）首先将LND纳入了超强型孤立的疾病中，因此已经与Melphalan的临床疗法进行了临床，并在临床上进行了临床疗法，并在3中进行了30次培训（3）用N-Mustards或阿霉素治疗。该项目将对阐明一类新药物的活性机理产生重大影响，这些药物像LND一样抑制MCT和其他关键转运蛋白在肿瘤细胞中，从而改变肿瘤微环境以增强常规抗癌剂的活性。它还将开发出新的代谢方法，以研究癌症药物活性的肿瘤代谢和机制。