The Role of NF-kappaB in Chemotherapy Resistance

NF-κB 在化疗耐药中的作用

• 批准号: 6871719
• 负责人: JAMES CAMPBELL CUSACK
• 金额: $ 35.88万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6871719
• 关键词: apoptosis; athymic mouse; cell line; chemosensitizing agent; clinical research; colon neoplasms; combination chemotherapy; disease /disorder model; drug resistance; gene expression; gene induction /repression; human tissue; multidrug resistance; neoplasm /cancer chemotherapy; neoplastic cell; nuclear factor kappa beta; p53 gene /protein; tissue /cell culture

DESCRIPTION (provided by applicant): Despite new cancer therapies, the majority of cancer patients with advanced disease still do not survive following diagnosis. A major reason for this is the ineffectiveness of cancer therapy due to chemotherapy resistance. Two types of chemotherapy resistance have been described: preexisting/acquired, where the constitutive expression of drug resistance genes or the loss of pro-apoptotic genes inhibits chemosensitivity; and inducible, whereby chemotherapy induces a transient resistance in the cancer cells blocking the cell death response. We have shown that the transcription factor NF-kappaB is activated in cancer cells in response to exposure to certain chemotherapies and radiation. The induction of NF-kappaB suppresses the ability of the cancer therapy to induce cell death in both cancer cell lines and in xenograft tumors. Inhibition of NF-kappaB by virally-delivered expression of a modified form of IkappaB or by an FDA-approved drug, PS-341, strongly potentiates the efficacy of the cancer therapy. Additionally, we and others have observed that NF-kappaB activity is elevated in tumors, raising the possibility that NF-kappaB contributes to pre-existing chemoresistance. Our hypothesis is that the activation of NF-kappaB in cancer, whether constitutive or inducible in response to cancer therapy, is the underlying major cause of chemotherapy resistance. In order to test our hypothesis, we propose the following set of goals: (1) determine which forms of chemotherapy activate NF-kappaB; (2) determine how chemotherapy activates NF-kappaB; (3) determine the mechanisms whereby NF-kappaB blocks apoptosis (focusing on NF-kappaB-regulated antiapoptotic genes); and determine if p53 is required or involved in the enhanced response to chemotherapy when NF-kappaB is inhibited. This proposal has the potential to completely alter chemotherapy strategies based on our understanding of the role of NF-kappaB in chemotherapy resistance.

描述（由申请人提供）：尽管新的癌症疗法，大多数患有晚期疾病的癌症患者在诊断后仍无法生存。造成这种情况的主要原因是由于抗化疗而导致的癌症治疗无效。已经描述了两种类型的化学疗法抗性：耐药性基因的本构表达或促凋亡基因的丧失抑制化学敏感性；和诱导，化学疗法在阻断细胞死亡反应的癌细胞中诱导瞬时抗性。我们已经表明，在暴露于某些化学疗法和辐射的情况下，转录因子NF-kappab在癌细胞中被激活。 NF-kappab的诱导抑制了癌症治疗在癌细胞系和异种移植肿瘤中诱导细胞死亡的能力。通过病毒传递的Ikappab或FDA批准的药物PS-341抑制NF-kappab，强烈增强了癌症治疗的功效。此外，我们和其他人观察到NF-kappab活性在肿瘤中升高，从而提高了NF-kappab有助于先前存在的化学耐药性的可能性。我们的假设是，癌症中NF-kappab在癌症治疗中的构成性或诱导性的激活是化学疗法耐药性的主要原因。为了检验我们的假设，我们提出以下一组目标：（1）确定哪种化学疗法激活NF-kappab； （2）确定化学疗法如何激活NF-kappab； （3）确定NF-kappab阻断细胞凋亡的机制（侧重于NF-kappab调节的抗凋亡基因）；并确定抑制NF-kappab时是否需要p53或参与化学疗法的增强反应。该提案有可能根据我们对NF-kappab在化学疗法抗性中的作用的理解，完全改变化学疗法策略。