Targeting the phosphatidylinositol-3 kinase/Akt pathway for the treatment of cancer.
Phosphatidylinositol-3 kinase (PI3K)/Akt is overactivated in a wide range of tumor types, and this triggers a cascade of responses, from cell growth and proliferation to survival, motility, epithelial-mesenchymal transition and angiogenesis. Therefore, this pathway presents an exciting target for molecular therapeutics. In addition, ectopic expression of PI3K or Akt, especially constitutively activated PI3K (p110alpha) or Akt, is sufficient to induce the oncogenic transformation of cells and tumor formation in transgenic mice, as well as the development of chemoresistance. Inhibition of PI3K/Akt signaling induces apoptosis and inhibits the growth of tumor cells that have elevated Akt levels. The dependence of certain tumors on PI3K/Akt signaling for survival and growth has wide implications for cancer therapy, offering the potential for preferential tumor cell killing. In the past few years, a number of inhibitors of the Akt pathway have been identified by combinatorial chemistry, high-throughput and virtual screening, or traditional medicinal chemistry. This review focuses on ongoing translational efforts to therapeutically target the PI3K/Akt pathway.
Kim
Donghwa
D
University of South Florida College of Medicine, Departments of Pathology and Interdisciplinary Oncology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
Cheng
George Z
GZ
Lindsley
Craig W
CW
Yang
Hua
H
Cheng
Jin Q
JQ
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016503:Drug Delivery Systems; D006801:Humans; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D012263:Ribonucleosides / Q000008:administration & dosage / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects*
D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D012263:Ribonucleosides; C023764:triciribine