The Akt inhibitor triciribine sensitizes prostate carcinoma cells to TRAIL‐induced apoptosis

Abstract

Aberrant PI3K/Akt signaling has been implicated in many human cancers, including prostate carcinomas. Currently different therapeutic strategies target the inhibition of this survival pathway. The nucleoside analog triciribine (TCN), which was initially described as a DNA synthesis inhibitor, has recently been shown to function as an inhibitor of Akt. Here, we demonstrate that TCN inhibits Akt phosphorylation at Thr308 and Ser473 and Akt activity in the human prostate cancer cell line PC‐3. In addition, TCN sensitized PC‐3 cells to TRAIL‐ and anti‐CD95‐induced apoptosis, whereas the cells remained resistant to DNA damaging chemotherapeutics. The observed sensitization essentially depended on the phosphorylation status of Akt. Thus, prostate cancer cell lines displaying constitutively active Akt, e.g. PC‐3 or LNCaP, were sensitized to death receptor‐induced apoptosis. Most importantly with respect to therapeutic application, derivatives of both TCN and TRAIL are already tested in current clinical trials. Therefore, this combinatorial treatment might open a promising therapeutic approach for the elimination of hormone‐refractory prostate cancers, which are largely resistant to conventional DNA damaging anticancer drugs or irradiation. © 2009 UICC

Ethanol promotes cytotoxic effects of tumor necrosis factor-related apoptosis-inducing ligand through induction of reactive oxygen species in prostate cancer cells

“…Pro-survival factors, particularly Akt is a constitutively active in PCa cells, promoting their survival and resistance to chemotherapy. [40][41][42][43][44]47,48 Thus, targeting Akt activity with a combination of agents is a promising approach to promote responsiveness to TRAIL as supported by our current results. Additionally, ethanol enhanced TRAIL's effects including caspase activation and PARP cleavage in LNCaP cells, which are inherently resistant to TRAIL.…”

Matricellular Signaling Molecule CCN1 Attenuates Experimental Autoimmune Myocarditis by Acting as a Novel Immune Cell Migration Modulator

“…mRNA expression levels of the ␥-subtype of phosphoinositide 3-kinase, the target of a new class of antiinflammatory drugs, 30 and of matrix metalloproteinases 2 and 9 were likewise unchanged (data not shown). Figure I in the online-only Data Supplement compares the chemotaxis-modulating effect of CCN1 preincubation with those of drugs that block all phosphoinositide 3-kinases, 31 the phosphoinositide 3-kinase-␥ subtype only, 30 AKT, 32 Rho kinase, 33 or MEK (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase). 31 CCN1 preincubation blocked the effect of all chemotactic stimuli (CCN1, SDF-1␣, MCP-1, and MIP-1␣), whereas the spectrum of action of the small-molecule drugs was more limited.…”

TCN, an AKT inhibitor, exhibits potent antitumor activity and enhances radiosensitivity in hypoxic esophageal squamous cell carcinoma in vitro and in vivo

“…It has been reported that TCN potently and selectively inhibits the activation, TCN, an AKT inhibitor, exhibits potent antitumor activity and enhances radiosensitivity in hypoxic esophageal squamous cell carcinoma in vitro and in vivo dimerization and nuclear translocation of AKT, resulting in an increase in the apoptosis of prostate carcinoma cells (19). Thus, we hypothesize that TCN inhibits AKT and HIF-1α expression, and improves tumor microenvironment in esophageal SCC (ESCC) cells.…”