Briciclib (on 013105), an elF4E inhibitor, exhibits potent anti-cancer activity in various preclinical cancer models

Introduction: Eukaryotic translation initiation factor 4E (e1F4E) is a proto-oncogene that regulates protein synthesis by facilitating translation of mRNA in mammalian cells. eIF4E promotes translation of several potent oncogenic genes, including (Cyclin D1 and c-Myc) that further induce cellular growth and proliferation. Overexpression of eIF4E and its downstream targets (Cyclin D1 and c-Myc) has been associated with various human malignancies. Therefore, targeting of eIF4E with a selective inhibitor could aid in development of novel therapeutic regimen(s) for treatment of different types of cancer. Briciclib (ON 013105) is one such pre-clinical eIF4E inhibitor developed by Onconova Therapeutics Inc. In this study we investigated the anti-cancer activity of briciclib in various in vitro models of mantle cell lymphoma (MCL) breast cancer. In addition, we also determined the expression of eIF4E downstream targets (Cyclin DI and c-Myc) and apoptotic markers (P53, Cleaved Caspase 3 and Cleaved PARP) after treatment with briciclib.;Methods: MTT cell viability assay was performed to evaluate cellular viability after treatment with briciclib. Expression for the downstream targets of eIF4E (Cyclin D1 and c-Myc) was analyzed using western blot analysis and confirmed quantitatively with ELISA. Long term inhibitory effect of briciclib in MCL and breast cancer cell lines was examined with washout experiments and cell survival assays respectively. DNA fragmentation assay was performed to evaluate late stage apoptosis. Furthermore, cell cycle analyses were done to analyze the effect of briciclib on cell cycle progression in both MCL and breast cancer cells.;Results: The cell viability assay data indicate that briciclib treatment significantly reduced proliferation of MCL (JeKo-1 and M1NO) and breast (MCF7 and MDA-MB-231) cancer cell lines. The protein expression data showed that treatment with briciclib suppressed the expression of both Cyclin Dl and c-Myc in breast and MCL cancer cell lines. These observations were further supported by quantitative analysis of Cyclin Dl and c-Myc protein levels with ELISA. Moreover, treatment with briciclib enhanced the expression of pro-apoptotic proteins in MCL and breast cancer cell lines. Results from cell cycle analyses confirmed that briciclib showed significant increase in GO phase (accounts for cell death) for JeKo-1 cells and G2/M phase (accounts for mitotic arrest) for MCF7 cells.;Conclusion: Overall results emphasize the potential of briciclib, an oral eIF4 inhibitor, in treating hematopoietic and solid cancers. Briciclib is a promising anti-cancer agent that showed potent inhibitory effect in various MCL and breast cancer models, in vitro. Further characterization of various briciclib oral formulations in in vivo models of MCL and breast cancer is essential to bring this pre-clinical eIF4E inhibitor from bench-side to bed-side.