DNA as well as displace copper from metallothioneins.

Searching for strategies that can enhance the anti MPNST effects of dual PI3K/mTOR inhibitors, we sought to expand on our previous observation that these compounds mapk inhibitor induce the accumulation of autophagosomes in MPNST cells. The current study suggests that the PI3K/mTOR inhibitors induce productive autophagy in MPNST cells, in accord with effects previously observed in other tumor models in response to such compounds. mTOR is a master regulator of autophagy, and mTORC1 activation blocks this process through the phosphorylation of its downstream target ULK. Thus, it is not surprising that mTOR blockade leads to autophagy induction. While PI3K/AKT inhibition can result in autophagy through downregulation of mTORC1 activity, additional mTORindependent mechanisms have been suggested, including PI3K/AKT inhibition induced activation of FoxO proteins as well as increased mitochondrial superoxide and cellular ROS signals. Our data further supports these findings, demonstrating that while ULK knockdown is sufficient to abrogate rapamycin induced autophagy in MPNST cells, this genetic manipulation does not completely block XL765 Papillary thyroid cancer induced autophagy in these cells. Autophagy induced by the blockade of the PI3K/AKT axis has been identified in several studies as a mechanism of cell death, while others have provided data demonstrating the role of this process in therapeutic resistance. Recent examples of the former include the finding that PI3K/AKT inhibition increases radiosensitivity by augmenting autophagic response, and that combining the PI3K/mTOR inhibitor BEZ235 with the mTORC1 inhibitor temsirolimus in cell death secondary to massive autophagic response. Dovitinib Conversely, autophagy blockade has been identified as enhancing the proapoptotic effects of dual PI3K/mTOR inhibitors in preclinical models of lung and pancreatic cancer. Our data suggest that in MPNST, as in the latter examples discussed above, PI3K/mTOR blockade induced autophagy acts as a mechanism of apoptotic resistance and that combining PI3K/mTOR inhibitors with autophagy blockers can result in marked cytotoxicity in vitro and in vivo. These are similar to our recent findings using a different anti MPNST therapeutic strategy, HDAC inhibition, where autophagy blockade was found to augment anti tumor effects. Taken together, these findings possibly suggest that MPNST commonly utilizes autophagy to avoid the cytotoxic effects of therapeutic agents. The observation that the lysosomotropic agent chloroquine enhances the pro apoptotic effects of XL765 is of potential major translational relevance. Chloroquine is currently being evaluated in human clinical trials as a single agent or in combination with other therapies, initial studies already have confirmed its safety. The development of an MPNST clinical trial to test the effect PI3K/mTOR inhibitors in combination with chloroquine is supported by our study.