222 Chapter 7 ABSTRACT Synthetic glucocorticoids such as dexamethasone and prednisone are cornerstone drugs in the treatment of pediatric acute lymphoblastic leukemia (ALL) because of their cytotoxic effect on leukemic cells. The effect of these steroids is mediated through activation of the glucocorticoid receptor (encoded by the NR3C1 gene). Besides the glucocorticoid receptor, leukemic cells are known to express the mineralocorticoid receptor (encoded by the NR3C2 gene). Currently, the role of the mineralocorticoid receptor in steroidinduced cytotoxicity is unclear. Furthermore, hydrocortisone, the synthetic equivalent of the natural occurring hormone cortisol, has never been considered as a potential cytotoxic steroid. In this preclinical study, we show that hydrocortisone can induce the expression of steroid-regulated genes through both steroid receptors, and effectively induces cell death in Reh cell lines that by doxycycline-induction express NR3C1 or NR3C2. Moreover, dexamethasone induces cell death in NR3C2-expressing Reh cells that lack an endogenous functional NR3C1 receptor gene. These results highlight that the mineralocorticoid receptor is a potent receptor to induce leukemic cell death after activation by steroid treatment, and that hydrocortisone treatment can induce cell death in leukemic cells. In PDX and patient samples, the role of the mineralocorticoid receptor in steroid-induced cytotoxicity seems less pronounced, possibly due to the (relative) low expression of NR3C2 in ALL patients.
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