The Role Of The p38 MAP Kinase Pathway In Mediating The Biological Effects Of Arsenic Trioxide In Malignant Cells

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Arsenic trioxide exhibits potent antitumor effects in vitro and in vivo, and is widely used in the treatment of acute promyelocytic leukemia (APL) in humans. In addition to APL, arsenic is of potential therapeutic value for the treatment of other hematologic malignancies, including chronic myelogenous leukemia (CML). There is evidence that As2O3 can induce apoptosis of CML patient-derived cell lines and inhibit CML patient blast proliferation. These findings have suggested a potential role for this agent in the treatment of CML, but the precise mechanisms by which it induces its antileukemic effects remain to be defined. Mitogen-activated protein kinases (MAPKs) are a family of enzymes that transduce signals from the cell membrane to the nucleus in response to a wide range of stimuli, and modulate several important biological functions. Three major groups of Map kinases exist, the Erk, JNK, and p38 Map kinase families. The involvement of these kinases in the generation of stress responses, as well as in signaling for various cytokines and growth factors, has been extensively studied and documented in previous studies. However, little is known on the putative roles of Map kinases in leukemogenesis. Previous studies have demonstrated that arsenic trioxide induces activation of the p38 MAP kinase, suggesting a role for this pathway in the regulation of arsenic- mediated responses in malignant cells. This dissertation describes the functional relevance of activation of p38 by arsenic trioxide. Activation of p38alpha exhibits a negative regulatory role on the induction of apoptosis by As2O3, as evidenced by the enhanced induction of apoptosis during pharmacological inhibition of p38 or in cells with targeted disruption of the p38alpha gene. Furthermore, apoptosis and growth inhibition promoted by arsenic trioxide are augmented in cells lacking both upstream effectors of p38, Mkk3 and Mkk6, compared to their wild-type counterparts. Additionally, pharmacological inhibition of p38 promotes arsenic-mediated differentiation of APL blasts and enhances the suppressive properties of As2O3 on primitive leukemic CFU-GM progenitors from patients with CML. Altogether, these results suggest that the p38 MAP kinase signaling cascade acts as a negative feedback regulator for the generation of antileukemic responses by arsenic trioxide

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  • 05/09/2018
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