Metabolic reprogramming: A new paradigm for targeting cisplatin resistant cells

代谢重编程：针对顺铂耐药细胞的新范例

• 批准号: 8332468
• 负责人: Medhi Wangpaichitr
• 金额: --
• 依托单位: MIAMI VA HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-10-01 至 2017-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8332468
• 关键词: Adopted; Affect; Amino Acids; Anabolism; Biochemical; Biological Assay; Cancer Etiology; Cancer Patient; Carbon; Carboplatin; Cause of Death; Cell Death; Cell Line; Cell Respiration; Cells; Cessation of life; Cisplatin; Complex; Development; Disease; Disease Progression; Disease remission; Drug resistance; Drug usage; Early treatment; Energy-Generating Resources; Enzymes; Excision; Fatty Acids; Future; Generations; Glutamine; Glycolysis; In Vitro; Knowledge; Lead; Malignant neoplasm of lung; Metabolic; Metabolic Pathway; Metabolism; Molecular; Mus; Nephrotoxic; Non-Small-Cell Lung Carcinoma; Normal Cell; Normal tissue morphology; Operative Surgical Procedures; Outcome; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Platinum; Production; Publications; Reactive Oxygen Species; Resistance; Sampling; Skeleton; Source; Staging; Testing; Thioredoxin; Toxic effect; Treatment outcome; Veterans; Warburg Effect; Work; Xenograft procedure; analog; cancer cell; chemotherapy; clinically relevant; cytotoxic; deprivation; design; fatty acid metabolism; improved; in vivo; inhibitor/antagonist; killings; lung Carcinoma; lung small cell carcinoma; novel; novel strategies; novel therapeutic intervention; oxidation; public health relevance; resistance mechanism; small hairpin RNA; tumor; tumor metabolism; uptake

DESCRIPTION (provided by applicant): Lung carcinoma is one of the leading causes of cancer deaths in the world. Treatment for early stage non small cell lung cancer (NSCLC) is surgery while chemotherapy is the mainstay of treatment in small cell lung cancer (SCLC). Most veterans present as locally advanced or metastatic disease which makes resection not possible. For these patients, cisplatin or its less nephrotoxic analog carboplatin is the main chemotherapeutic drug used for both NSCLC and SCLC. The majority of lung cancer patients will respond initially to cisplatin treatment; however, development of drug resistance is inevitable which results in disease progression. Thus, development of a new strategy to treat cisplatin resistant lung cancer will undoubtedly have a major impact for the treatment of these patients. Although there are overwhelming publications in the past decade on cisplatin resistance, but thus far no drugs are available which could reverse cisplatin resistance or selectively kill these resistant cells. We have discovered novel biochemical changes in cisplatin resistant cells which can be utilized as targets to selectively eradicate them. Firstly, we have found that all cisplatin resistant cells lines including primary culture from patients possess higher reactive oxygen species (ROS) levels when compared to normal cells or their parental cell counterparts. Consequently, agents which increase ROS such as elesclomol can push them beyond their tolerance limit which ultimately leads to cell death. Secondly, these cisplatin resistant cells have decreased intracellular thioredoxin-1 (TRX1) levels as a result of increasing secretion under in vitro and in vivo conditions which could be a primary contributory factor to higher ROS levels. Thirdly, cisplatin resistant cells are no longer dependent on glycolysis metabolism, but rely on amino acids and/or fatty acids (oxidative metabolism) as their carbon skeleton source. Significantly, glutamine deprivation or inhibition of key enzyme in fatty acid synthetic pathway can selectively kill cisplatin resistant cells. Taken together, we hypothesize that decreased intracellular TRX1, which results in higher ROS accumulation, could lead to metabolic reprogramming in cisplatin resistant tumors. In this application, we plan to further confirm and exploit these findings by (i) determine that cisplatin resistant lung cancer cells switch from glycolytic metabolism to oxidative metabolism as their main carbon source for energy and biosynthesis, (ii) investigate that TRX1 is a key factor in ROS accumulation, cisplatin sensitivity, and alteration in tumor metabolism, (iii) determine that ROS generation agent or metabolic inhibitor which can selectively kill cisplatin resistant cells in vitro also occurs in vivo, (iv) determine the possible relationships between ROS, TRX1, and changes in tumor metabolism are also found in tumor samples obtained from patients who have failed cisplatin treatment. To further evaluate the clinical relevance of our findings, we will confirm that a ROS producing agent or metabolic inhibitor is also highly cytotoxic to freshly isolated cisplatin resistant lung cancer cells from patients. Overall, this proposed work will sere as a novel approach to overcome cisplatin resistance by exploiting the primary biochemical differences which these resistant cells adopt to survive. Thus, by targeting these differences, we can selectively eradicate these resistant cells with minimal normal tissue toxicity. Furthermore, the findings obtained from this application can also be used as a platform to investigate possible ways to selectively kill cisplatin resistant cells from other tumor types.

描述（由申请人提供）：