title: The triptolide derivative MRx102 inhibits Wnt pathway activation and has potent anti-tumor effects in lung cancer.
abstract: The natural compound triptolide has been shown to decrease cell proliferation and induce apoptosis and cellular senescence. We previously demonstrated that triptolide decreases tumor formation and metastasis of human non-small cell lung cancer cells (NSCLC). Due to the toxicity of triptolide, derivatives of the natural compound have been developed that show more favorable toxicity profiles and pharmacokinetics in animal models. The purpose of this study was to evaluate MRx102 as a novel therapeutic for lung cancer.
  
  
  
  Mice injected subcutaneously with H460 lung cancer cells were treated with MRx102 or carboplatin to determine the effect of MRx102 on tumor formation in comparison to standard treatment. Patient-derived xenografts (PDX) with different WIF1 expression levels were treated with MRx102 or cisplatin. We tested the effects of MRx102 treatment on migration and invasion of lung cancer cells using Transwell filters coated with fibronectin and Matrigel, respectively. Tail vein injections using H460 and A549 cells were performed.
  
  
  
  Here we report that the triptolide derivative MRx102 significantly decreases NSCLC proliferation and stimulates apoptosis. Further, MRx102 potently inhibits NSCLC haptotactic migration and invasion through Matrigel. In vivo, NSCLC tumor formation and metastasis were greatly decreased by MRx102 treatment. The decrease in tumor formation by MRx102 in the patient-derived xenograft model was WIF1-dependent, demonstrating that MRx102 is a potent inhibitor of the Wnt pathway in low WIF1 expressing NSCLC patient tumors.
  
  
  
  These results indicate that MRx102 has potent antitumor effects both in vitro and in vivo, and is a potential novel therapy for the treatment of NSCLC.
authors.affiliation: Division of Thoracic Surgery, City of Hope Medical Center, 1500 E. Duarte Rd., Duarte, CA, 91010, USA. treno@coh.org.
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Reno
authors.affiliation: Department of Pathology, City of Hope Medical Center, Duarte, CA, USA.
authors.forename: Sun-Wing
authors.initials: SW
authors.lastname: Tong
authors.affiliation: Division of Comparative Medicine, Beckman Research Institute, City of Hope Medical Center, Duarte, CA, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wu
authors.affiliation: MyeloRx LLC, Vallejo, CA, USA.
authors.forename: John M
authors.initials: JM
authors.lastname: Fidler
authors.affiliation: Department of Biostatistics, City of Hope Medical Center, Duarte, CA, USA.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Nelson
authors.affiliation: Division of Thoracic Surgery, City of Hope Medical Center, 1500 E. Duarte Rd., Duarte, CA, 91010, USA.
authors.forename: Jae Y
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Division of Thoracic Surgery, City of Hope Medical Center, 1500 E. Duarte Rd., Duarte, CA, 91010, USA.
authors.forename: Dan J
authors.initials: DJ
authors.lastname: Raz
mesh_terms: D000072283:A549 Cells; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D016190:Carboplatin / Q000008:administration & dosage / Q000627:therapeutic use; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004224:Diterpenes / Q000009:adverse effects / Q000627:therapeutic use; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D004852:Epoxy Compounds / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009361:Neoplasm Invasiveness; D010616:Phenanthrenes / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012097:Repressor Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D004224:Diterpenes; D004852:Epoxy Compounds; C571885:MRx102; D010616:Phenanthrenes; D012097:Repressor Proteins; C485569:WIF1 protein, human; C001899:triptolide; D016190:Carboplatin
keywords: Lung cancer; MRx102; Metastasis; Triptolide; Wnt