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.

Inhibition of 13-cis retinoic acid-induced gene expression of reactive-resistance genes by thalidomide in glioblastoma tumoursin vivo

“…Pathway analysis suggested that the Ribosome pathway was upregulated by RA or THAL as sole treatments although the effect was reduced after combined treatment. On the other hand, it has been reported that in multiple myeloma cells internal ribosome entry site (IRES) of bFGF was inhibited at low concentration of THAL [ 40 ].…”

Cap-Independent Translation in Hematological Malignancies

“…IRESes have the potential to impact upon MM drug response. For example, thalidomide may reduce the proliferative effects of MM cells in part by targeting the IRES of the b-FGF growth factor ( 72 ).…”