The Role Of The mTOR Pathway In Mediating The Biological Effects Of Arsenic TrioxidePublic Deposited
Arsenic trioxide (As<sub>2</sub>0<sub>3</sub>) is an arsenic-derivative that exhibits potent growth inhibitory effects against malignant cells. The remarkable antitumor effects of As<sub>2</sub>0<sub>3</sub> in vitro and in vivo have prompted the development of various clinical trials that established its activity in acute promyelocytic leukemia (APL). As<sub>2</sub>0<sub>3</sub> is part of the standard treatment for this leukemia, and is highly effective in cases that have developed resistance to retinoic acid (RA) treatment. As As<sub>2</sub>0<sub>3</sub> has potent effects in vitro and in vivo against a variety of neoplastic cells, it is also currently under clinical development for the treatment of other hematological malignancies as well, including chronic myelogenous leukemia (CML). There is evidence that As<sub>2</sub>0<sub>3</sub> 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. Because of the important antitumor properties of As<sub>2</sub>0<sub>3</sub>, extensive efforts have been made by several research groups to understand its mechanism of action in malignant cells. Several cascades appear to be engaged in the generation of arsenic-dependent growth inhibition and apoptosis of malignant cells. Previous studies have demonstrated the engagement of the PI3K/mTOR pathway in response to various biologically effecting agents such as interferons and retinoic acid; however, activation of mTOR by As<sub>2</sub>0<sub>3</sub> to regulate mRNA translation has not been elucidated. This dissertation provides evidence for a novel signaling cascade activated in response to As<sub>2</sub>0<sub>3</sub>, involving activation of the mammalian target of rapamycin (mTOR) and key upstream and downstream effector components of the mTOR pathway. In studies to determine the functional relevance of this pathway, inhibition of mTOR and downstream cascades utilizing rapamycin demonstrated enhanced induction of apoptosis by As<sub>2</sub>0<sub>3</sub>. Consistent with this, the mTOR inhibitor strongly potentiated As<sub>2</sub>0<sub>3</sub>-mediated suppression of primitive leukemic progenitors from the bone marrow of chronic myelogenous leukemia patients. Altogether, this dissertation provides evidence that the mTOR pathway is activated in a negative feedback regulatory manner in response to As<sub>2</sub>0<sub>3</sub> and plays a key regulatory role in the induction of anti-leukemic responses.