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    The AKT inhibitor MK-2206 is cytotoxic in hepatocarcinoma cells displaying hyperphosphorylated AKT-1 and synergizes with conventional chemotherapy

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    Author
    Simioni, Carolina; Martelli, Alberto M.; Cani, Alice; Cetin-Atalay, Rengul; McCubrey, James A.; Capitani, Silvano; Neri, Luca M.
    Abstract
    Hepatocellular carcinoma (HCC) is one of the most common potentially lethal human malignancies worldwide. Advanced or recurrent HCC is frequently resistant to conventional chemotherapeutic agents and radiation. Therefore, targeted agents with tolerable toxicity are mandatory to improve HCC therapy and prognosis. In this neoplasia, the PI3K/Akt signaling network has been frequently shown to be aberrantly up-regulated. To evaluate whether Akt could represent a target for treatment of HCC, we studied the effects of the allosteric Akt inhibitor, MK-2206, on a panel of HCC cell lines characterized by different levels of Akt-1 activation. The inhibitor decreased cell viability and induced cell cycle arrest in the G0/G1 phase of the cell cycle, with a higher efficacy in cells with hyperphosphorylated Akt-1. Moreover, MK-2206 induced apoptosis, as documented by Annexin V labeling, and also caused autophagy, as evidenced by increased levels of the autophagy marker LC3A/B. Autophagy was shown to be a protective mechanism against MK-2206 cytotoxicity. MK-2206 down-regulated, in a concentration-dependent manner, the phosphorylation levels of Akt-1 synergizedand its downstream targets, GSK3 α/β and FOXO3A. MK-2206 synergized with doxorubicin, a chemotherapeutic drug widely used for HCC treatment. Our findings suggest that the use of Akt inhibitors, either alone or in combination with doxorubicin, may be considered as an attractive therapeutic regimen for the treatment of HCC.
    URI
    http://hdl.handle.net/10342/7794
    Subject
    Hepatocellular carcinoma, MK-2206, Akt-1, targeted therapy, apoptosis, autophagy
    Date
    2013-08-24
    Citation:
    APA:
    Simioni, Carolina, & Martelli, Alberto M., & Cani, Alice, & Cetin-Atalay, Rengul, & McCubrey, James A., & Capitani, Silvano, & Neri, Luca M.. (August 2013). The AKT inhibitor MK-2206 is cytotoxic in hepatocarcinoma cells displaying hyperphosphorylated AKT-1 and synergizes with conventional chemotherapy. , (), - . Retrieved from http://hdl.handle.net/10342/7794

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    MLA:
    Simioni, Carolina, and Martelli, Alberto M., and Cani, Alice, and Cetin-Atalay, Rengul, and McCubrey, James A., and Capitani, Silvano, and Neri, Luca M.. "The AKT inhibitor MK-2206 is cytotoxic in hepatocarcinoma cells displaying hyperphosphorylated AKT-1 and synergizes with conventional chemotherapy". . . (), August 2013. October 03, 2023. http://hdl.handle.net/10342/7794.
    Chicago:
    Simioni, Carolina and Martelli, Alberto M. and Cani, Alice and Cetin-Atalay, Rengul and McCubrey, James A. and Capitani, Silvano and Neri, Luca M., "The AKT inhibitor MK-2206 is cytotoxic in hepatocarcinoma cells displaying hyperphosphorylated AKT-1 and synergizes with conventional chemotherapy," , no. (August 2013), http://hdl.handle.net/10342/7794 (accessed October 03, 2023).
    AMA:
    Simioni, Carolina, Martelli, Alberto M., Cani, Alice, Cetin-Atalay, Rengul, McCubrey, James A., Capitani, Silvano, Neri, Luca M.. The AKT inhibitor MK-2206 is cytotoxic in hepatocarcinoma cells displaying hyperphosphorylated AKT-1 and synergizes with conventional chemotherapy. . August 2013; (): . http://hdl.handle.net/10342/7794. Accessed October 03, 2023.
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