Pharmacologic inhibition of Akt in combination with chemotherapeutic agents effectively induces apoptosis in ovarian and endometrial cancer cell lines

• Published in: Molecular oncology Vol. 15; no. 8; pp. 2106 - 2119
• Main Authors: Fabi, François, Adam, Pascal, Parent, Sophie, Tardif, Laurence, Cadrin, Monique, Asselin, Eric
• Format: Journal Article
• Language: English
• Published: United States John Wiley & Sons, Inc 01.08.2021; John Wiley and Sons Inc; Wiley
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Apoptosis; Apoptosis - drug effects; AZD5363; Cancer; Cancer therapies; capivasertib; Cell Line, Tumor; chemoresistance; Chemotherapy; Cisplatin; Doxorubicin; Endometrial cancer; Endometrial Neoplasms - pathology; Endometrium; Female; FOXO1 protein; Gynecology; Health aspects; Humans; Kinases; Localization; Mutation; Ovarian cancer; Ovarian Neoplasms - pathology; p53 Protein; Phosphatase; Phosphorylation; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Proteins; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Ribosomal protein S6; Signal transduction; TOR protein; Tumor cell lines; Tumor proteins; Canada; United States > US; endometrial cancer; capivasertib; chemoresistance; doxorubicin; ovarian cancer; AZD5363
• ISSN: 1574-7891; 1878-0261
• DOI: 10.1002/1878-0261.12888

The PI3K/Akt signaling pathway, the most frequently altered signaling system in human cancer, is a crucial inducer of dysregulated proliferation and neoplastic processes; however, few therapeutic strategies using PI3K/Akt inhibitors singly have been shown to be effective. The purpose of this paper was to underline the potential benefit of pharmacological modulation of the PI3K/Akt pathway when combined with specific chemotherapeutic regimens. We have studied the ability of NVP‐BEZ235 (PI3K/mTOR inhibitor) and AZD5363 (Akt inhibitor) in the sensitization of cancer cells to cisplatin and doxorubicin. Our results show that NVP‐BEZ235 sensitizes cells preferentially to cisplatin while AZD5363 sensitizes cells to doxorubicin. At equal concentrations (5 μm), both inhibitors reduce ribosomal protein S6 phosphorylation, but AZD5363 is more effective in reducing GSK3β phosphorylation as well as S6 phosphorylation. Additionally, AZD5363 is capable of inducing FOXO1 and p53 nuclear localization and reduces BAD phosphorylation, which is generally increased by cisplatin and doxorubicin. Finally, the combination of AZD5363 and doxorubicin induces apoptosis in cells and robustly reduces cell ability to clonally replicate, which underlines a potential cooperative effect of the studied compounds. The use of Akt inhibitor AZD5363 sensitized ovarian and endometrial cancer cells to the chemotherapeutic drug doxorubicin. A combination of AZD5363 and doxorubicin activated pro‐apoptotic pathways, namely through the inhibition of BAD phosphorylation as well as through the nuclear localization of FOXO1 and p53. This collaborative effect appears to be a potential tool to overcome chemoresistance in these neoplastic entities.