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

基本信息

批准号：
10406240
负责人：
Soumitro Pal
金额：
$ 39.68万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10406240
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 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 mTOR Inhibitor migration mitochondrial metabolism mouse model neoplastic cell novel novel therapeutic intervention novel therapeutics organ transplant rejection overexpression post-transplant prevent promoter response transcription factor transplantation therapy tumor tumor growth tumor xenograft tumorigenesis tumorigenic

项目摘要

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，特别是接受器官移植的患者的关键问题。和肾脏/肾癌是这些患者的主要癌症之一。直接肿瘤途径（独立于免疫逃生机制）在移植后癌的发展中起着至关重要的作用。 C-Met是一种受体酪氨酸激酶，在肾癌中明显过表达。它可以通过通过细胞保护的调节调节氧化还原途径，血管生成和凋亡事件分子NRF2和血红素氧酶-1（HO-1）。已显示NRF2/HO-1可以调节癌细胞（通过活性氧的解毒，ROS），并保护它们免受化学治疗侵害药物诱导的凋亡。有趣的是，C-MET-NRF2-HO-1途径在后期也被激活移植期。 MTOR抑制剂RAPA用于移植患者以防止器官排斥。和有趣的是，它也具有抗血管生成潜力，用于治疗肾癌。但是， Rapa反应短暂寿命，大多数患者最终会产生抗药性。延长的拉帕治疗无法通过缓解AKT激活而导致移植后癌症环形。因此，需要为肾癌开发新的治疗方法。 Honokiol（C18H18O2），一部小说试剂（从木兰obovata中分离出来），正在临床前模型中测试其抗肿瘤潜能。此外，Honokiol还具有抗炎特性，可用于治疗移植维持免疫抑制的患者。在初步研究中，我们观察到Honokiol治疗可以下调C-MET诱导的RAS激活（与Akt-MTOR串扰），并抑制NRF2/HO-1 肾脏癌细胞。共同的Honokiol似乎是C-Met诱导的后的有前途的治疗剂移植肾癌。我们假设使用Honokiol和MTOR的组合疗法抑制剂RAPA不仅会延长同种异体移植存活，还可以防止C-MET诱导的NRF2/HO-1介导移植后肾癌。在具体目的中，我们将：1）研究Honokiol的机制通过不稳定/失活NRF2/HO-抑制C-MET诱导的肾脏癌细胞中的肿瘤信号 1和氧化还原途径的调节（AIM-1），2）检查在MTOR存在下如何处理Honokiol 抑制剂RAPA可以下调C-MET诱导的途径，用于体外肾脏癌的生长和进展，在肿瘤异种移植模型（AIM-2）中，3）测试Honokiol和Rapa组合疗法的影响防止早期肾脏肿瘤发生和C-MET诱导的移植后肾癌使用新型鼠模型（AIM-3）。我们的研究应导致范式转变，以确定与 Honokiol延长同种异体移植生存，并预防C-Met诱导的移植后癌。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Metabolic reprogramming in renal cancer: Events of a metabolic disease.

DOI：
10.1016/j.bbcan.2021.188559
发表时间：
2021-08
期刊：
Biochimica et biophysica acta. Reviews on cancer
影响因子：
0
作者：
Chakraborty S;Balan M;Sabarwal A;Choueiri TK;Pal S
通讯作者：
Pal S

A Novel Combination Treatment with Honokiol and Rapamycin Effectively Restricts c-Met-Induced Growth of Renal Cancer Cells, and also Inhibits the Expression of Tumor Cell PD-L1 Involved in Immune Escape.

和厚朴酚和雷帕霉素的新型联合治疗可有效限制 c-Met 诱导的肾癌细胞生长，并抑制参与免疫逃逸的肿瘤细胞 PD-L1 的表达。

DOI：
10.3390/cancers12071782
发表时间：
2020
期刊：
Cancers
影响因子：
5.2
作者：
Sabarwal,Akash;Chakraborty,Samik;Mahanta,Simran;Banerjee,Selina;Balan,Murugabaskar;Pal,Soumitro
通讯作者：
Pal,Soumitro

Signaling Molecules in Posttransplantation Cancer.

移植后癌症中的信号分子。