title: Internal ribosome entry site of bFGF is the target of thalidomide for IMiDs development in multiple myeloma.
abstract: Although new analogues of immunomodulatory drugs (IMiDs) are being developed for MM, the molecular mechanism of these drugs remains unclear. In the current study, we used MM cell lines as a model to investigate the molecular mechanism of thalidomide and to compare its potency with IMiDs such as pomalidomide. We determined that thalidomide did not inhibit cell proliferation of RPMI8226 and U266 MM cells, whereas pomalidomide showed a significant inhibitory effect on these two MM cell lines. Interestingly, we further demonstrated that although thalidomide down-regulated bFGF translation through the inhibition of IRES even at 0.1 μg/ml, pomalidomide did not have a similar affect bFGF levels. A colony formation assay demonstrated that thalidomide and the bFGF knock-down clones caused a significant reduction in the clonogenic ability of MM cells, and treatment with exogenous bFGF can recover the clonogenic ability of thalidomide-treated cells and knock-down clones, but not that of pomalidomide-treated cells. This implies that thalidomide, but not pomalidomide, targets the IRES of FGF-2. In conclusion, our results highlight a non-cytotoxic anticancer drug target for thalidomide, the IRES of bFGF, and provide the mechanistic rationale for developing IMiDs as anti-cancer therapeutics in MM patients, with improved potency and fewer side effects.
authors: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, ROC (Taiwan).
authors: I-Chia
authors: IC
authors: Lien
authors: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, ROC (Taiwan) ; Research Centre for Drug Discovery, National Yang-Ming University, Taipei, ROC (Taiwan).
authors: Lin-Yea
authors: LY
authors: Horng
authors: Research Centre for Drug Discovery, National Yang-Ming University, Taipei, ROC (Taiwan).
authors: Pei-Lun
authors: PL
authors: Hsu
authors: Research Centre for Drug Discovery, National Yang-Ming University, Taipei, ROC (Taiwan).
authors: Chia-Ling
authors: CL
authors: Wu
authors: Research Centre for Drug Discovery, National Yang-Ming University, Taipei, ROC (Taiwan).
authors: Hui-Ching
authors: HC
authors: Sung
authors: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, ROC (Taiwan) ; Research Centre for Drug Discovery, National Yang-Ming University, Taipei, ROC (Taiwan).
authors: Rong-Tsun
authors: RT
authors: Wu
keywords: Internal ribosome entry site (IRES); Thalidomide; bFGF