Induction of Akt Activity by Chemotherapy Confers Acquired Resistance

Resistance to chemotherapy is a major cause of treatment failure in human cancer. Accumulating evidence has indicated that the acquisition of resistance to chemotherapeutic drugs involves the activation of the PI3K/Akt pathway, modulating Akt activity ill response to chemotherapy has been observed often ill chemoresistant cancers. The potential molecular mechanisms by which chemotherapeutic agents activate the PI3K/Akt pathway arc emerging. Activation of this pathway evades the cytotoxic effects of chemotherpeutic agents via regulation of essential cellular functions such as protein synthesis, antiapoptosis, survival and proliferation in cancer flow chemotherapeutic agents induce Akt activation and how activated Akt confers chemoresistance through regulation of signaling networks are discussed in this review. Combining PI3K/Akt inhibitors with standard chemotherapy has been successful in increasing the efficacy of chemotherapeutic agents both in vivo and in vitro. Several small molecules have been developed to specifically target PI3K/Akt and other components of this pathway, which in combination with chemotherapy may be a valid approach mechanisms Of signaling networks for maintenance, of the Akt activity for cell survival. These regulatory mechanisms may limit the efficacy Of PI3K/Akt-targeted therapy; therefore, disruption of these mechanisms may be an effective strategy for development of novel anti-cancer therapies. [J Formos Med Assoc 2009; 108(3); 180-194]