Olga Frankfurt1, Steven T Rosen. 1. Northwestern Memorial Hospital, Robert H. Lurie Comprehensive Cancer Center, 303 E. Chicago Avenue, Chicago, IL 60611, USA.
Abstract
PURPOSE OF REVIEW: Glucocorticoids remain a central component of the therapeutic armamentarium for a broad spectrum of hematologic malignancies. There is an extensive body of evidence suggesting that the efficacy of glucocorticoids stems from their ability to mediate apoptosis in leukemia, lymphoma, and myeloma cells. RECENT FINDINGS: Traditionally, glucocorticoid-induced apoptosis is divided into three stages: an initiation stage, which involves glucocorticoid receptor activation and glucocorticoid receptor-mediated gene regulation; a decision stage, which engages the prosurvival and proapoptotic factors at the mitochondrial level; and an execution stage, which implicates caspases and endonuclease activation. Recent discoveries have clarified many aspects of the apoptotic pathway, including activation of the caspases cascade and multicatalytic proteasome, suppression of prosurvival transcription factors such as AP-1, c-myc, nuclear factor-kappaB, as well as cross-talk between the T-cell receptor and cytokine signaling pathways. SUMMARY: This review focuses primarily on insights gained during recent years into the mechanism of the signaling pathways responsible for mediating glucocorticoid-induced apoptosis in hematologic malignancies. This information provides a scientific basis to explore synergistic approaches that may enhance glucocorticoid-induced apoptosis and may bypass mechanism of resistance.
PURPOSE OF REVIEW: Glucocorticoids remain a central component of the therapeutic armamentarium for a broad spectrum of hematologic malignancies. There is an extensive body of evidence suggesting that the efficacy of glucocorticoids stems from their ability to mediate apoptosis in leukemia, lymphoma, and myeloma cells. RECENT FINDINGS: Traditionally, glucocorticoid-induced apoptosis is divided into three stages: an initiation stage, which involves glucocorticoid receptor activation and glucocorticoid receptor-mediated gene regulation; a decision stage, which engages the prosurvival and proapoptotic factors at the mitochondrial level; and an execution stage, which implicates caspases and endonuclease activation. Recent discoveries have clarified many aspects of the apoptotic pathway, including activation of the caspases cascade and multicatalytic proteasome, suppression of prosurvival transcription factors such as AP-1, c-myc, nuclear factor-kappaB, as well as cross-talk between the T-cell receptor and cytokine signaling pathways. SUMMARY: This review focuses primarily on insights gained during recent years into the mechanism of the signaling pathways responsible for mediating glucocorticoid-induced apoptosis in hematologic malignancies. This information provides a scientific basis to explore synergistic approaches that may enhance glucocorticoid-induced apoptosis and may bypass mechanism of resistance.