Due to its cytotoxic effect in lymphoid cells, dexamethasone is widely used in the treatment of Multiple Myeloma. However, only a subset of myeloma patients responds to high-dose dexamethasone. Despite the undeniable anti-myeloma benefits of dexamethasone, significant adverse effects have been reported. The anti-tumor effect of dexamethasone was re-evaluated according to the molecular heterogeneity of Multiple Myeloma.
The pro-death effect of dexamethasone was demonstrated to be related to the genetic heterogeneity of Multiple Myeloma because sensitive cell lines were restricted to MAF and MMSET signature subgroups, whereas all CCND1 cell lines were resistant to dexamethasone.
The glucocorticoid receptor expression was found to be an important limiting factor for dexamethasone-induced cell death and a correlation was found between glucocorticoid receptor levels and the induction of glucocorticoid induced leucine zipper (GILZ) under dexamethasone treatment. By silencing GILZ, it was demonstrated that GILZ is necessary for dexamethasone induced apoptosis while triggering an imbalance between anti- and pro-apoptotic Bcl-2 proteins.
Finally, the heterogeneity of the dexamethasone response was further confirmed in vivo using myeloma xenograft (lien to in vivo page) models. Our findings suggested that the effect of dexamethasone should be re-evaluated within molecular subgroups of myeloma patients to improve its efficacy and reduce its adverse effects.