Abstract
Due to its cytotoxic effect in lymphoid cells, dexamethasone is widely used in the treatment of multiple myeloma (MM). 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. We re-evaluate the anti-tumor effect of dexamethasone according to the molecular heterogeneity of MM. We demonstrated that the pro-death effect of dexamethasone is related to the genetic heterogeneity of MM because sensitive cell lines were restricted to MAF and MMSET signature subgroups, whereas all CCND1 cell lines (n = 10) were resistant to dexamethasone. We demonstrated that the glucocorticoid receptor expression was an important limiting factor for dexamethasone-induced cell death and we found a correlation between glucocorticoid receptor levels and the induction of glucocorticoid-induced leucine zipper (GILZ) under dexamethasone treatment. By silencing GILZ, we next demonstrated that GILZ is necessary for Dex 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 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.
Highlights
Multiple myeloma (MM) is an incurable plasma cell malignancy despite considerable improvements to survival due to the introduction of new drugs, such as proteasome inhibitors and immunomodulatory agents [1]
We demonstrated that the glucocorticoid receptor expression was an important limiting factor for dexamethasone-induced cell death and we found a correlation between glucocorticoid receptor levels and the induction of glucocorticoidinduced leucine zipper (GILZ) under dexamethasone treatment
We first determined whether cell death was associated with caspase activation and PARP1 cleavage in a selected panel of cell lines, including Dexsensitive (>15% cell death) and Dex-resistant human myeloma cell lines (HMCLs), which were representative of the molecular diversity of MM (Figure 1B)
Summary
Multiple myeloma (MM) is an incurable plasma cell malignancy despite considerable improvements to survival due to the introduction of new drugs, such as proteasome inhibitors and immunomodulatory agents [1]. Glucocorticoids (GCs) are widely used in the treatment of MM, mainly in combination regimens. Among GCs, dexamethasone (Dex) is used in all phases of treatment, including induction, consolidation and maintenance. In 1992, Alexanian et al showed that high doses of Dex were effective in about half of untreated MM patients and that the efficacy of the combination of vincristine, doxorubicin and dexamethasone was mainly due to the high doses of Dex [2]. Following the introduction of thalidomide, Dex has mainly been used in combination regimens because the combination of Dex with thalidomide demonstrates significantly superior response rates in newly diagnosed MM patients compared with Dex alone [3]. Dex associated with bortezomib and lenalidomide has appeared as the most promising drug association recommended for high-risk patients [4]
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