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Molecular Cancer Therapeutics
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Small Molecule Therapeutics

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

Long-Sheng Chang, Janet L. Oblinger, Sarah S. Burns, Jie Huang, Larry 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, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio.
2Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio.
3Department of Otolaryngology-Head and Neck Surgery, The Ohio State University College of Medicine, Columbus, Ohio.
4Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio.
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  • ORCID record for Long-Sheng Chang
  • For correspondence: lchang@chi.osu.edu
Janet L. Oblinger
1Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio.
2Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio.
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Sarah S. Burns
1Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio.
2Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio.
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Jie Huang
1Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio.
2Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio.
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Larry W. Anderson
5Division of Cancer Treatment and Diagnosis, Center for Cancer Research, National Cancer Institute, NIH, Frederick, Maryland.
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Melinda G. Hollingshead
5Division of Cancer Treatment and Diagnosis, Center for Cancer Research, National Cancer Institute, NIH, Frederick, Maryland.
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  • ORCID record for Melinda G. Hollingshead
Rulong Shen
4Department of Pathology, The Ohio State University College of Medicine, Columbus, Ohio.
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Li Pan
6Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy, Columbus, Ohio.
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Garima Agarwal
6Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy, Columbus, Ohio.
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Yulin Ren
6Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy, Columbus, Ohio.
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Ryan D. Roberts
1Center for Childhood Cancer and Blood Diseases, Abigail Wexner Research Institute, Nationwide Children's Hospital, Columbus, Ohio.
2Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio.
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Barry R. O'Keefe
5Division of Cancer Treatment and Diagnosis, Center for Cancer Research, National Cancer Institute, NIH, Frederick, Maryland.
7Molecular Targets Program, Center for Cancer Research, National Cancer Institute, NIH, Frederick, Maryland.
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A. Douglas Kinghorn
6Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy, Columbus, Ohio.
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Jerry M. Collins
5Division of Cancer Treatment and Diagnosis, Center for Cancer Research, National Cancer Institute, NIH, Frederick, Maryland.
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DOI: 10.1158/1535-7163.MCT-19-0809 Published March 2020
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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.

This article is featured in Highlights of This Issue, p. 729

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2020;19:731–41

  • Received August 19, 2019.
  • Revision received December 2, 2019.
  • Accepted December 13, 2019.
  • Published first December 17, 2019.
  • ©2019 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 19 (3)
March 2020
Volume 19, Issue 3
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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, Larry 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 March 1 2020 (19) (3) 731-741; 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, Larry 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 March 1 2020 (19) (3) 731-741; DOI: 10.1158/1535-7163.MCT-19-0809
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