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MicroRNAs and Glucocorticoid-Induced Apoptosis in Lymphoid Malignancies

DOI: 10.1155/2013/348212

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Abstract:

The initial response of lymphoid malignancies to glucocorticoids (GCs) is a critical parameter predicting successful treatment. Although being known as a strong inducer of apoptosis in lymphoid cells for almost a century, the signaling pathways regulating the susceptibility of the cells to GCs are only partly revealed. There is still a need to develop clinical tests that can predict the outcome of GC therapy. In this paper, I discuss important parameters modulating the pro-apoptotic effects of GCs, with a specific emphasis on the microRNA world comprised of small players with big impacts. The journey through the multifaceted complexity of GC-induced apoptosis brings forth explanations for the differential treatment response and raises potential strategies for overcoming drug resistance. 1. Introduction 1.1. Glucocorticoids in the Treatment of Lymphoid Malignancies Glucocorticoids (GCs) are among the most effective drugs used in the treatment of hematopoietic malignancies of the lymphoid lineage in virtue of their ability to induce apoptosis of these cancerous cells [1–3]. The main hematopoietic cancer types that respond well to GC therapy include T acute lymphoblastic leukemia (T-ALL), chronic B lymphocytic leukemia (CLL), multiple myeloma (MM), Hodgkin’s lymphoma (HL), and non-Hodgkin’s lymphoma (NHL). GCs appear, however, to have little value in the treatment of acute or chronic myeloid leukemia (AML/CML). A major drawback of GC therapy is the gradual development of resistance to GC during treatment that limits the clinical utility of this drug. Poor response to a 7-day monotherapy with the GC prednisone is one of the strongest predictors of adverse outcomes in the treatment of pediatric ALL [2, 4]. A great challenge today is to develop strategies that can overcome the drug resistant phenotype. For this purpose it is important to understand the underlying mechanisms of GC resistance and the signaling pathways regulating apoptosis induced by GCs. Besides inducing apoptosis of lymphoid cells, GCs are used in palliative care. GC treatment produces rapid symptomatic improvements, including relief of fever, sweats, lethargy, weakness, and other nonspecific effects of cancer. GCs decrease the severity of chemotherapy-induced emesis. GCs are also used in the clinics for other medical conditions such as autoimmune diseases, asthma, ulcerative colitis, chronic obstructive pulmonary disease, kidney diseases, and rheumatologic disorders due to their strong anti-inflammatory and immunosuppressive properties. GC therapy is hampered by a variety of metabolic and

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