Protective role of Honokiol in preventing c-Met-induced post-transplantation cancer

和厚朴酚在预防 c-Met 诱导的移植后癌症中的保护作用

• 批准号: 9924489
• 负责人: Soumitro Pal
• 金额: $ 40.49万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9924489
• 关键词: Allografting; Anti-Inflammatory Agents; Apoptosis; Apoptotic; Binding; CUL3 gene; Cancer cell line; Cell Cycle Progression; Cell Proliferation; Cell Survival; Chemopreventive Agent; Combined Modality Therapy; Complex; Development; Dose; Drug Metabolic Detoxication; Endothelial Cells; Event; FRAP1 gene; Goals; Growth; HGF gene; Human; Immune; Immunocompromised Host; Immunosuppression; Immunosuppressive Agents; In Vitro; Inbred BALB C Mice; Kidney; Kidney Neoplasms; Lead; Lesion; Ligands; Magnolia; Malignant Neoplasms; Mediating; Metabolic Pathway; Mitochondria; Modeling; Mus; Organ; Organ Transplantation; Oxidation-Reduction; Oxidative Stress; Pathway interactions; Patients; Pharmaceutical Preparations; Play; Pre-Clinical Model; Prevention; Property; RBX1 gene; Reactive Oxygen Species; Receptor Protein-Tyrosine Kinases; Regulation; Renal Cell Carcinoma; Renal carcinoma; Resistance development; Role; SCID Beige Mouse; Signal Transduction; Sirolimus; Solid; Testing; Therapeutic Agents; Therapeutic immunosuppression; Transcriptional Activation; Transplant Recipients; Xenograft Model; angiogenesis; cancer cell; cancer transplantation; heme oxygenase-1; honokiol; immunosuppressed; inhibitor/antagonist; mTOR Inhibitor; migration; mitochondrial metabolism; mouse model; neoplastic cell; novel; novel therapeutic intervention; novel therapeutics; overexpression; post-transplant; prevent; promoter; response; transcription factor; tumor; tumor growth; tumor xenograft; tumorigenesis; tumorigenic

PROJECT SUMMARY Cancer is a critical problem in immunosuppressed patients, particularly, who receive organ transplants; and kidney/renal cancer is one of the major cancers in these patients. Direct tumorigenic pathways (independent of immune escape mechanism) can play crucial roles in the development of post-transplantation cancer. c-Met is a receptor tyrosine kinase, which is significantly over-expressed in renal cancer. It can induce tumor growth by modulating the redox pathway, angiogenesis and apoptotic events, through the regulation of cytoprotective molecules Nrf2 and heme oxygenase-1 (HO-1). Nrf2/HO-1 has been shown to modulate the redox state of cancer cells (by detoxification of reactive oxygen species, ROS), and to protect them from chemotherapeutic drug-induced apoptosis. Interestingly, the c-Met-Nrf2-HO-1 pathway is also activated during the post- transplantation period. The mTOR inhibitor RAPA is used in transplant patients to prevent organ rejection; and interestingly, it also has anti-angiogenic potential, and is used for the treatment of renal cancer. However, the RAPA responses are short lived, and most of the patients finally develop resistance. Prolonged RAPA treatment cannot prevent post-transplantation cancer due to the activation of Akt by relieving the inhibitory loop. Thus, new therapeutic approach needs to be developed for kidney cancer. Honokiol (C18H18O2), a novel agent (isolated from Magnolia obovata), is being tested in pre-clinical models for its anti-tumorigenic potential. In addition, Honokiol also has anti-inflammatory property, which can be utilized for the treatment of transplant patients to sustain their immune suppression. In preliminary studies, we have observed that Honokiol treatment can down-regulate c-Met-induced Ras activation (having cross-talk with Akt-mTOR) and inhibit Nrf2/HO-1 in renal cancer cells. Together, Honokiol appears to be a promising therapeutic agent for c-Met-induced post- transplantation renal cancer. We hypothesize that a combination therapy using Honokiol and the mTOR inhibitor RAPA will not only prolong allograft survival, but also prevent c-Met-induced and Nrf2/HO-1-mediated post-transplantation renal cancer. In the specific aims, we will: 1) study the mechanism(s) by which Honokiol inhibits c-Met-induced tumorigenic signals in renal cancer cells through destabilization/inactivation of Nrf2/HO- 1 and regulation of the redox pathway (Aim-1), 2) examine how Honokiol treatment in the presence of mTOR inhibitor RAPA can down-regulate c-Met-induced pathways for renal cancer growth and progression in vitro, and in a tumor xenograft model (Aim-2), and 3) test the effect of Honokiol and RAPA combination therapy in preventing early renal tumorigenesis and c-Met-induced post-transplantation renal cancer using novel murine models (Aim-3). Our studies should lead to a paradigm shift to identify a novel combination therapy with Honokiol to prolong allograft survival as well as to prevent c-Met-induced post-transplantation cancer.

项目摘要 癌症是免疫抑制患者的一个严重问题，特别是接受器官移植的患者; 肾/肾癌是这些患者的主要癌症之一。直接致瘤途径（独立于 免疫逃逸机制）可以在移植后癌症的发展中起关键作用。c-Met是 一种受体酪氨酸激酶，在肾癌中显著过表达。它可以通过以下方式诱导肿瘤生长： 调节氧化还原途径，血管生成和凋亡事件，通过调节细胞保护作用， 分子Nrf 2和血红素加氧酶-1（HO-1）。Nrf 2/HO-1已被证明可以调节 癌细胞（通过活性氧，ROS的解毒），并保护它们免受化疗 药物诱导的细胞凋亡。有趣的是，c-Met-Nrf 2-HO-1通路也在细胞凋亡后被激活。 移植期。mTOR抑制剂RAPA用于移植患者，以防止器官排斥反应; 有趣的是，它还具有抗血管生成的潜力，并用于治疗肾癌。但 RAPA反应是短暂的，大多数患者最终产生耐药性。延长RAPA 治疗不能预防移植后癌症，因为Akt的激活通过解除抑制性肿瘤的发生而实现。 循环.因此，需要为肾癌开发新的治疗方法。Honokaline（C18H18O2），a novel 药剂（分离自Magnolia obovata），正在临床前模型中测试其抗肿瘤潜力。 此外，和厚朴还具有抗炎作用，可用于移植治疗 患者维持免疫抑制。在初步研究中，我们观察到和厚朴治疗 可下调c-Met诱导的Ras激活（与Akt-mTOR有交叉作用），并抑制Nrf 2/HO-1， 肾癌细胞总之，和诺平似乎是一种有前途的治疗药物，用于c-Met诱导的后 移植性肾癌我们假设使用和诺伐他汀和mTOR的联合治疗 抑制剂RAPA不仅可以延长移植物存活，而且可以防止c-Met诱导和Nrf 2/HO-1介导的 移植后肾癌在具体目标上，我们将：1）研究Honoketry的机制（S） 通过Nrf 2/HO-1的不稳定/失活抑制肾癌细胞中c-Met诱导的致瘤信号。 1和氧化还原途径的调节（Aim-1），2）检查在mTOR存在下和诺平治疗如何 抑制剂RAPA可以在体外下调c-Met诱导肾癌生长和进展的途径， 和在肿瘤异种移植物模型（Aim-2）中，和3）测试和厚朴酚和RAPA组合疗法在肿瘤异种移植物模型（Aim-2）中的作用。 使用新的小鼠预防早期肾肿瘤发生和c-Met诱导的移植后肾癌 模型（Aim-3）。我们的研究应该导致范式转变，以确定一种新的联合治疗， 和厚朴用于延长同种异体移植物存活以及预防c-Met诱导的移植后癌症。