1. Academic Validation
  2. Targeting Protein Translation by Rocaglamide and Didesmethylrocaglamide to Treat MPNST and Other Sarcomas

Targeting Protein Translation by Rocaglamide and Didesmethylrocaglamide to Treat MPNST and Other Sarcomas

  • Mol Cancer Ther. 2020 Mar;19(3):731-741. doi: 10.1158/1535-7163.MCT-19-0809.
Long-Sheng Chang 1 2 3 4 Janet L Oblinger 5 2 Sarah S Burns 5 2 Jie Huang 5 2 Larry W Anderson 6 Melinda G Hollingshead 6 Rulong Shen 4 Li Pan 7 Garima Agarwal 7 Yulin Ren 7 Ryan D Roberts 5 2 Barry R O'Keefe 6 8 A Douglas Kinghorn 7 Jerry M Collins 6
Affiliations

Affiliations

  • 1 Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio. lchang@chi.osu.edu.
  • 2 Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio.
  • 3 Department of Otolaryngology-Head and Neck Surgery, The Ohio State University College of Medicine, Columbus, Ohio.
  • 4 Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio.
  • 5 Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio.
  • 6 Division of Cancer Treatment and Diagnosis, Center for Cancer Research, National Cancer Institute, NIH, Frederick, Maryland.
  • 7 Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy, Columbus, Ohio.
  • 8 Molecular Targets Program, Center for Cancer Research, National Cancer Institute, NIH, Frederick, Maryland.
Abstract

Malignant peripheral nerve sheath tumors (MPNST) frequently overexpress eukaryotic initiation factor 4F components, and the eIF4A inhibitor silvestrol potently suppresses MPNST growth. However, silvestrol has suboptimal drug-like properties, including a bulky structure, poor oral bioavailability (<2%), sensitivity to MDR1 efflux, and pulmonary toxicity in dogs. We compared ten silvestrol-related rocaglates lacking the dioxanyl ring and found that didesmethylrocaglamide (DDR) and rocaglamide (Roc) had growth-inhibitory activity comparable with silvestrol. Structure-activity relationship analysis revealed that the dioxanyl ring present in silvestrol was dispensable for, but may enhance, cytotoxicity. Both DDR and Roc arrested MPNST cells at G2-M, increased the sub-G1 population, induced cleavage of caspases and PARP, and elevated the levels of the DNA-damage response marker γH2A.X, while decreasing the expression of Akt and ERK1/2, consistent with translation inhibition. Unlike silvestrol, DDR and Roc were not sensitive to MDR1 inhibition. Pharmacokinetic analysis confirmed that Roc had 50% oral bioavailability. Importantly, Roc, when administered intraperitoneally or orally, showed potent antitumor effects in an orthotopic MPNST mouse model and did not induce pulmonary toxicity in dogs as found with silvestrol. Treated tumors displayed degenerative changes and had more cleaved caspase-3-positive cells, indicative of increased Apoptosis. Furthermore, Roc effectively suppressed the growth of osteosarcoma, Ewing sarcoma, and rhabdomyosarcoma cells and patient-derived xenografts. Both Roc- and DDR-treated sarcoma cells showed decreased levels of multiple oncogenic kinases, including insulin-like growth factor-1 receptor. The more favorable drug-like properties of DDR and Roc and the potent antitumor activity of Roc suggest that these rocaglamides could become viable treatments for MPNST and other sarcomas.

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