PT  - JOURNAL ARTICLE
AU  - Chang, Long-Sheng
AU  - Oblinger, Janet L.
AU  - Burns, Sarah S.
AU  - Huang, Jie
AU  - Anderson, Lawrence W.
AU  - Hollingshead, Melinda G.
AU  - Shen, Rulong
AU  - Pan, Li
AU  - Agarwal, Garima
AU  - Ren, Yulin
AU  - Roberts, Ryan D.
AU  - O'Keefe, Barry R
AU  - Kinghorn, A. Douglas
AU  - Collins, Jerry M.
TI  - Targeting protein translation by rocaglamide and didesmethylrocaglamide to treat MPNST and other sarcomas
AID  - 10.1158/1535-7163.MCT-19-0809
DP  - 2019 Jan 01
TA  - Molecular Cancer Therapeutics
PG  - molcanther.0809.2019
4099  - http://mct.aacrjournals.org/content/early/2019/12/17/1535-7163.MCT-19-0809.short
4100  - http://mct.aacrjournals.org/content/early/2019/12/17/1535-7163.MCT-19-0809.full
AB  - 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.