Novel flavagline‐like compounds with potent Fli‐1 inhibitory activity suppress diverse types of leukemia

• DOI: 10.1111/febs.14690
• Publication Date: 2018-11-02T09:29:48Z
• Authors: Jialei Song; Chunmao Yuan; Jue Yang; Tangjingjun Liu; Yao Yao; Xiao Xiao; Babu Gajendran; Dahai Xu; You‐Jun Li; Chunlin Wang; Wuling Liu; Min Wen; David Spaner; Jorge Filmus; Eldad Zacksenhaus; Yiguo Zhang; Xiaojiang Hao; Yaacov Ben‐David
• Keywords: 0301 basic medicine; Leukemia; Plants, Medicinal; Plant Extracts; Proto-Oncogene Protein c-fli-1; Cell Cycle; Apoptosis; Antineoplastic Agents, Phytogenic; High-Throughput Screening Assays; 3. Good health; Mice; 03 medical and health sciences; Tumor Cells, Cultured; Animals; Humans; Benzofurans; Cell Proliferation; Signal Transduction

E26 transformation‐specific ( ETS ) gene family contains a common DNA ‐binding domain, the responsible for sequence‐specific recognition on target promoters. The Fli‐1 oncogene, member of family, plays critical role in hematopoiesis and is overexpressed diverse hematological malignancies. This transcription factor regulates genes controlling several hallmarks cancer thus represents an excellent therapy. By screening compounds isolated from medicinal plant Dysoxylum binectariferum China, we identified two chemically related flavagline‐like including 4′‐demethoxy‐3′,4′‐methylenedioxyrocaglaol rocaglaol that strongly inhibited transactivation ability. These altered expression GATA 1, EKLF , SHIP BCL 2. Consequently, suppressed proliferation, induced apoptosis, promoted erythroid differentiation leukemic cells culture. also erythroleukemogenesis vivo Fli‐1‐driven mouse model. Mechanistically, blocked c‐Raf‐ MEK ‐ MAPK / ERK signaling, reduced phosphorylation eukaryotic translation initiation 4E (eIF4E), protein synthesis. Consistent with its high myelomas, B‐cell lymphoma, B chronic lymphocytic leukemia (B‐CLL), pharmacological inhibition by or genetic knock‐down via sh RNA significantly hindered proliferation corresponding cell lines patients’ samples. results uncover growth survival various malignancies point to agents as lead development anti‐Fli‐1 drugs treat leukemias/lymphomas overexpressing Fli‐1.