PI3K and Akt as molecular targets for cancer therapy: current clinical outcomes

Abstract

The PI3K-Akt pathway is a vital regulator of cell proliferation and survival. Alterations in the PIK3CA gene that lead to enhanced PI3K kinase activity have been reported in many human cancer types, including cancers of the colon, breast, brain, liver, stomach and lung. Deregulation of PI3K causes aberrant Akt activity. Therefore targeting this pathway could have implications for cancer treatment. The first generation PI3K-Akt inhibitors were proven to be highly effective with a low IC 50 , but later, they were shown to have toxic side effects and poor pharmacological properties and selectivity. Thus, these inhibitors were only effective in preclinical models. However, derivatives of these first generation inhibitors are much more selective and are quite effective in targeting the PI3K-Akt pathway, either alone or in combination. These second-generation inhibitors are essentially a specific chemical moiety that helps to form a strong hydrogen bond interaction with the PI3K/Akt molecule. The goal of this review is to delineate the current efforts that have been undertaken to inhibit the various components of the PI3K and Akt pathway in different types of cancer both in vitro and in vivo. Our focus here is on these novel therapies and their inhibitory effects that depend upon their chemical nature, as well as their development towards clinical trials.

The lipid-transfer protein Nir2 enhances epithelial-mesenchymal transition and facilitates breast cancer metastasis

“…Statistical analysis was performed by using x material Figs S1D, S2B). These pathways contribute to all aspects of breast cancer progression, including cell growth, survival, migration, invasion and metastasis (Whyte et al, 2009;Pal and Mandal, 2012). Furthermore, the PI3K/AKT pathway is abnormally activated in about 30% of breast cancer patients (Cancer Genome Atlas Network, 2012), and is required for EMT.…”

Wogonoside inhibits cell growth and induces mitochondrial-mediated autophagy-related apoptosis in human colon cancer cells through the PI3K/AKT/mTOR/p70S6K signaling pathway

“…Transcription factor forkhead box O1, a member of the forkhead family, performs numerous activities including the following: Inactivating Akt by translocating it from the nucleus to the cytoplasm; downregulating Fas ligand to induce apoptosis; phosphorylating proapoptotic protein BAD and caspase-9 to inhibit their activity; activating NF-κB to promote the transcription of apoptosis-inhibiting genes; suppressing the release of cytochrome C; and maintaining the integrity of mitochondria, thereby inhibiting cell death (26). Akt is also able to send survival signals by phosphorylating mTOR, and its downstream molecules, including P70S6K and eukaryotic translation initiation factor 4E-binding protein 1, thus inhibiting the apoptosis of cells that do not depend on p53 (22).…”

The roles of protein kinases in learning and memory

“…Protein kinases in learning and memory www.learnmem.org phosphatidylinositols, which activate 3-phosphoinositide-dependent kinase (PDK) and Akt (also called protein kinase B) (Pal and Mandal 2012). PI3K is regulated by receptor tyrosine kinases including trkB, the BDNF receptor.…”