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Molecular Cancer Therapeutics
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Research Article

Targeting protein translation by rocaglamide and didesmethylrocaglamide to treat MPNST and other sarcomas

Long-Sheng Chang, Janet L. Oblinger, Sarah S. Burns, Jie Huang, Lawrence W. Anderson, Melinda G. Hollingshead, Rulong Shen, Li Pan, Garima Agarwal, Yulin Ren, Ryan D. Roberts, Barry R O'Keefe, A. Douglas Kinghorn and Jerry M. Collins
Long-Sheng Chang
1Center for Childhood Cancer and Blood Diseases and Departments of Pediatrics, Otolaryngology-Head & Neck Surgery, and Pathology, Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute, Nationwide Children's Hospital and The Ohio State University College of Medicine
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  • For correspondence: lchang@chi.osu.edu
Janet L. Oblinger
2Center for Childhood Cancer, The Research Institute at Nationwide Children's Hospital
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Sarah S. Burns
3Center for Childhood Cancer and Blood Diseases and Department of Pediatrics, Nationwide Children's Hospital and The Ohio State University College of Medicine
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Jie Huang
4Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital
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Lawrence W. Anderson
5NCI, National Institutes of Health
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Melinda G. Hollingshead
6Biological Testing Branch, National Cancer Institute
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Rulong Shen
7Department of Pathology, Ohio State University
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Li Pan
8Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy
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Garima Agarwal
8Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy
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Yulin Ren
8Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy
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Ryan D. Roberts
9Pediatric Hematology/Oncology/BMT, Nationwide Children's Hospital
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Barry R O'Keefe
10Molecular Targets Program, National Cancer Institute
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A. Douglas Kinghorn
11Medicinal Chemistry and Pharmacognosy, The Ohio State University
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Jerry M. Collins
5NCI, National Institutes of Health
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DOI: 10.1158/1535-7163.MCT-19-0809
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Abstract

Malignant peripheral nerve sheath tumors (MPNSTs) frequently overexpress eIF4F 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 10 silvestrol-related rocaglates lacking the dioxanyl ring and found that didesmethylrocaglamide (DDR) and rocaglamide (Roc) had growth-inhibitory activity comparable to 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 poly(ADP-ribose) polymerase, 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 anti-tumor 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 IGF-1R. The more favorable drug-like properties of DDR and Roc and the potent anti-tumor activity of Roc suggest that these rocaglamides could become viable treatments for MPNST and other sarcomas.

  • Received August 19, 2019.
  • Revision received December 2, 2019.
  • Accepted December 13, 2019.
  • Copyright ©2019, American Association for Cancer Research.
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This OnlineFirst version was published on December 17, 2019
doi: 10.1158/1535-7163.MCT-19-0809

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Targeting protein translation by rocaglamide and didesmethylrocaglamide to treat MPNST and other sarcomas
Long-Sheng Chang, Janet L. Oblinger, Sarah S. Burns, Jie Huang, Lawrence W. Anderson, Melinda G. Hollingshead, Rulong Shen, Li Pan, Garima Agarwal, Yulin Ren, Ryan D. Roberts, Barry R O'Keefe, A. Douglas Kinghorn and Jerry M. Collins
Mol Cancer Ther December 17 2019 DOI: 10.1158/1535-7163.MCT-19-0809

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Targeting protein translation by rocaglamide and didesmethylrocaglamide to treat MPNST and other sarcomas
Long-Sheng Chang, Janet L. Oblinger, Sarah S. Burns, Jie Huang, Lawrence W. Anderson, Melinda G. Hollingshead, Rulong Shen, Li Pan, Garima Agarwal, Yulin Ren, Ryan D. Roberts, Barry R O'Keefe, A. Douglas Kinghorn and Jerry M. Collins
Mol Cancer Ther December 17 2019 DOI: 10.1158/1535-7163.MCT-19-0809
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Molecular Cancer Therapeutics
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