Targeting Protein Translation by Rocaglamide and Didesmethylrocaglamide to Treat MPNST and Other Sarcomas
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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.
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A recent study showed potent antitumor effects of eIF4A inhibition in other sarcomas, including MPNST, Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma.
“A recent study also showed potent antitumor effects of eIF4A inhibition in other sarcomas, including malignant peripheral nerve sheath tumors (MPNST), Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma (39).”
From Targeting eIF4A-dependent translation in genetically complex sarcoma (2026) · cites this paper as [39]
The promising preclinical successes seen with CDK12 inhibitors and drugs that block protein elongation may not be surprising because osteosarcoma cells depend on massive levels of protein production.
“The promising preclinical successes seen with CDK12 inhibitors 92 and drugs that block protein elongation 93 may not be surprising as osteosarcoma cells depend on massive levels of protein production.”
From Osteosarcoma (2022) · cites this paper as [93]
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Zhang, Y., Liu, T., Li, P., Xing, Z., Mi, L., He, T., Wei, T., & Wu, W. (2025) · European Journal of Medicinal Chemistry · doi:10.1016/j.ejmech.2025.117638
BindingDB Entry 50016246: Discovery of Anticancer Agents of Diverse Natural Origin.
BindingDB (2023) · UC San Diego · doi:10.7270/q2j10752
- Authors
- Chang, L.-S., Oblinger, J. L., Burns, S. S., Huang, J., Anderson, L. W., Hollingshead, M. G., Shen, R., Pan, L., Agarwal, G., Ren, Y., Roberts, R. D., O'Keefe, B. R., Kinghorn, A. D., & Collins, J. M.
- Affiliations
- Nationwide Children's Hospital (US)
- National Institutes of Health (US)
- The Ohio State University (US)
- 6Division of Medicinal Chemistry and Pharmacognosy, The Ohio State University College of Pharmacy, Columbus, Ohio.
- 5Division of Cancer Treatment and Diagnosis, Center for Cancer Research, National Cancer Institute, NIH, Frederick, Maryland.
- Corresponding author
- Chang, Long-Sheng
- ORCID
- Venue
- Molecular Cancer Therapeutics
- Published
- 2020-03-01
- Volume
- 19
- Issue
- 3
- Pages
- 731-741
- ISSN
- 1535-7163 (ISSN-L)
- 1538-8514
- PMC
- PMC7056570
- OpenAlex
- W2995103867
- Cited by
- 22
- References
- 52
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 6 · 2023: 1 · 2022: 3 · 2021: 5 · 2020: 1
- FWCI
- 0.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Cancer Therapeutics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Department of Defense (W81XWH-16-1-0104, W81XWH-18-1-0547)
- National Cancer Institute (P01CA125066, P30CA16058)
- NCI (HHSN261200800001)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA and protein synthesis mechanisms
- Health Sciences › Medicine › Neurology › Neurofibromatosis and Schwannoma Cases
- Keywords
- rocaglamide, silvestrol, protein translation inhibition, malignant peripheral nerve sheath tumor, sarcoma, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, structure-activity relationship, oral bioavailability, apoptosis, caspase cleavage, PARP cleavage, γH2AX, Akt, ERK1/2, IGF-1 receptor, pulmonary toxicity, patient-derived xenografts
- MeSH terms
- Animals, Antineoplastic Agents, Phytogenic, Benzofurans, Cell Cycle, Humans, Protein Processing, Post-Translational, Tumor Cells, Cultured, Gene Expression Regulation, Neoplastic, Apoptosis, Neurofibrosarcoma, Xenograft Model Antitumor Assays, Aglaia, Cell Proliferation, Mice, Caspase 3
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