title: Combination of AKT inhibition with autophagy blockade effectively reduces ascites-derived ovarian cancer cell viability.
abstract: Recent genomics analysis of the high-grade serous subtype of epithelial ovarian cancer (EOC) show aberrations in the phosphatidylinositol 3-kinase (PI3K)/AKT pathway that result in upregulated signaling activity. Thus, the PI3K/AKT pathway represents a potential therapeutic target for aggressive high-grade EOC. We previously demonstrated that treatment of malignant ascites-derived primary human EOC cells and ovarian cancer cell lines with the allosteric AKT inhibitor Akti-1/2 induces a dormancy-like cytostatic response but does not reduce cell viability. In this report, we show that allosteric AKT inhibition in these cells induces cytoprotective autophagy. Inhibition of autophagy using chloroquine (CQ) alone or in combination with Akti-1/2 leads to a significant decrease in viable cell number. In fact, Akti-1/2 sensitizes EOC cells to CQ-induced cell death by exhibiting markedly reduced EC50 values in combination-treated cells compared with CQ alone. In addition, we evaluated the effects of the novel specific and potent autophagy inhibitor-1 (Spautin-1) and demonstrate that Spautin-1 inhibits autophagy in a Beclin-1-independent manner in primary EOC cells and cell lines. Multicellular EOC spheroids are highly sensitive to Akti-1/2 and CQ/Spautin-1 cotreatments, but resistant to each agent alone. Indeed, combination index analysis revealed strong synergy between Akti-1/2 and Spautin-1 when both agents were used to affect cell viability; Akti-1/2 and CQ cotreatment also displayed synergy in most samples. Taken together, we propose that combination AKT inhibition and autophagy blockade would prove efficacious to reduce residual EOC cells for supplying ovarian cancer recurrence.
authors.affiliation: Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, N6A 4L6, Canada, Department of Biochemistry and.
authors.forename: Rohann J M
authors.initials: RJ
authors.lastname: Correa
authors.affiliation: Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, N6A 4L6, Canada.
authors.forename: Yudith Ramos
authors.initials: YR
authors.lastname: Valdes
authors.affiliation: Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, N6A 4L6, Canada, Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, N6A 5C1, Canada.
authors.forename: Teresa M
authors.initials: TM
authors.lastname: Peart
authors.affiliation: Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, N6A 4L6, Canada.
authors.forename: Elena N
authors.initials: EN
authors.lastname: Fazio
authors.affiliation: Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, N6A 4L6, Canada, Department of Obstetrics and Gynaecology, University of Western Ontario, London, Ontario, N6A 5W9, Canada and.
authors.forename: Monique
authors.initials: M
authors.lastname: Bertrand
authors.affiliation: Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, N6A 4L6, Canada, Department of Obstetrics and Gynaecology, University of Western Ontario, London, Ontario, N6A 5W9, Canada and.
authors.forename: Jacob
authors.initials: J
authors.lastname: McGee
authors.affiliation: Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, N6A 4L6, Canada, Department of Obstetrics and Gynaecology, University of Western Ontario, London, Ontario, N6A 5W9, Canada and.
authors.forename: Michel
authors.initials: M
authors.lastname: Préfontaine
authors.affiliation: Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, N6A 4L6, Canada, Department of Obstetrics and Gynaecology, University of Western Ontario, London, Ontario, N6A 5W9, Canada and.
authors.forename: Akira
authors.initials: A
authors.lastname: Sugimoto
authors.affiliation: Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, N6A 4L6, Canada, Department of Biochemistry and Department of Obstetrics and Gynaecology, University of Western Ontario, London, Ontario, N6A 5W9, Canada and Department of Oncology, University of Western Ontario, London, Ontario, N6A 4L6, Canada.
authors.forename: Gabriel E
authors.initials: GE
authors.lastname: DiMattia
authors.affiliation: Translational Ovarian Cancer Research Program, London Regional Cancer Program, London, Ontario, N6A 4L6, Canada, Department of Anatomy and Cell Biology, University of Western Ontario, London, Ontario, N6A 5C1, Canada, Department of Obstetrics and Gynaecology, University of Western Ontario, London, Ontario, N6A 5W9, Canada and Department of Oncology, University of Western Ontario, London, Ontario, N6A 4L6, Canada tshephe6@uwo.ca.
authors.forename: Trevor G
authors.initials: TG
authors.lastname: Shepherd
mesh_terms: D000494:Allosteric Regulation; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001201:Ascites / Q000473:pathology; D001343:Autophagy / Q000187:drug effects*; D001596:Benzylamines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects*; D002738:Chloroquine / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology*; D018874:Spheroids, Cellular / Q000187:drug effects
chemical_list: C501521:Akt-I-1,2 compound; D000970:Antineoplastic Agents; D001596:Benzylamines; D011799:Quinazolines; D011810:Quinoxalines; C000591235:spautin-1; D002738:Chloroquine; D051057:Proto-Oncogene Proteins c-akt