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: 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
• 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

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.

项目总结

项目成果

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
• 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。

• DOI: 10.1016/j.cll.2018.10.006
• 发表时间: 2019
• 期刊: Clinics in laboratory medicine
• 影响因子: 1.7
• 作者: Balan,Murugabaskar;Chakraborty,Samik;Pal,Soumitro
• 通讯作者: Pal,Soumitro