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: 8764690
• 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/8764690
• 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; Health; 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; 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）： 肺癌是世界上癌症死亡的主要原因之一。早期非小细胞肺癌（NSCLC）的治疗是手术，而化学疗法是小细胞肺癌（SCLC）治疗的支柱。大多数退伍军人作为局部晚期或转移性疾病，这使得切除不可能。对于这些患者，顺铂或其肾毒性类似型卡铂是NSCLC和SCLC使用的主要化学治疗药物。大多数肺癌患者最初将对顺铂治疗做出反应。但是，不可避免的耐药性发展导致疾病进展。因此，制定一种治疗顺铂抗性肺癌的新策略无疑将对这些患者的治疗产生重大影响。 尽管在过去的十年中，关于顺铂的耐药性有压倒性的出版物，但迄今为止，尚无药物可以逆转顺铂的耐药性或选择性地杀死这些抗性细胞。我们已经发现了抗顺铂抗性细胞的新生化变化，可以用作选择性地消除它们的靶标。首先，我们发现与正常细胞或其亲本细胞相比，所有抗异铂耐药细胞系（包括来自患者的原发性培养物）具有更高的活性氧（ROS）水平。因此，增加ROS（例如Elesclomol）的代理可以将其推向其公差极限，最终导致细胞死亡。其次，由于体外和体内条件下的分泌增加，这些抗铂耐药细胞已降低了细胞内硫蛋白-1（TRX1）水平，这可能是对更高ROS水平的主要因素。第三，顺铂耐药细胞不再依赖于糖酵解代谢，而是依赖于氨基酸和/或脂肪酸（氧化代谢）作为其碳骨架来源。值得注意的是，脂肪酸合成途径中的谷氨酰胺剥夺或抑制关键酶可以选择性地杀死顺铂耐药细胞。综上所述，我们假设减少细胞内TRX1（导致ROS累积）可能导致抗顺铂耐药性肿瘤的代谢重编程。 在此应用中，我们计划通过（i）确定抗顺铂的肺癌细胞从糖酵解代谢转换为氧化代谢作为其主要碳来源和生物合成的主要碳来源，（ii）研究TRX1是一个关键，我们计划进一步确认和利用这些发现。 ROS积累，顺铂敏感性和肿瘤代谢改变的因素，（III）确定ROS产生剂或代谢抑制剂可以选择性地杀死在 体内也发生了体外，（iv）确定ROS，TRX1和肿瘤代谢变化之间的可能关系，也可以在从未经顺铂治疗的患者中获得的肿瘤样本中发现。为了进一步评估我们发现的临床相关性，我们将确认产生ROS或代谢抑制剂对来自患者的新鲜分离的顺铂抗肺癌细胞也具有高度的细胞毒性。 总体而言，这项提出的工作将通过利用这些抗药性细胞生存的主要生化差异来克服顺铂耐药的新方法。因此，通过靶向这些差异，我们可以选择性地消除这些抗性细胞，并具有最小的正常组织毒性。此外，从该应用中获得的发现也可以用作一个平台，以研究从其他肿瘤类型中选择性杀死顺铂抗性细胞的可能方法。