title: Targeting cancer stem cells expressing an embryonic signature with anti-proteases to decrease their tumor potential.
abstract: Cancer stem cells (CSCs) are a specific subset of cancer cells that sustain tumor growth and dissemination. They might represent a significant treatment target to reduce malignant progression and prevent tumor recurrence. In solid tumors, several hierarchically organized CSC clones coexist, even within a single tumor. Among them, CSCs displaying an embryonic stem cell 'stemness' signature, based on the expression of Oct-4, Nanog and Sox2, are present in distinct high-grade tumor types associated with poor prognosis. We previously designed a model to isolate pure populations of these CSCs from distinct solid tumors and used it to screen for molecules showing selective toxicity for this type of CSC. Here we show that human immunodeficiency virus (HIV)-protease inhibitors (HIV-PIs) specifically target CSCs expressing an embryonic signature derived from tumors with distinct origins. They reduced proliferation in a dose-dependent manner with a higher specificity as compared with the total population of cancer cells and/or healthy stem cells, and they were efficient in inducing cell death. Lopinavir was the most effective HIV-PI among those tested. It reduced self-renewal and induced apoptosis of CSCs, subsequently impairing in vivo CSC-induced allograft formation. Two key pharmacophores in the LPV structure were also identified. They are responsible for the specificity of CSC targeting and also for the overall antitumoral activity. These results contribute to the identification of molecules presenting selective toxicity for CSCs expressing an embryonic stemness signature. This paves the way to promising therapeutic opportunities for patients suffering from solid cancer tumors of poor prognosis.
authors.affiliation: CNRS, iBV, 28 Avenue de Valombrose, F-06107 Nice, France.
authors.forename: C Y
authors.initials: CY
authors.lastname: Darini
authors.forename: P
authors.initials: P
authors.lastname: Martin
authors.forename: S
authors.initials: S
authors.lastname: Azoulay
authors.forename: M-D
authors.initials: MD
authors.lastname: Drici
authors.forename: P
authors.initials: P
authors.lastname: Hofman
authors.forename: S
authors.initials: S
authors.lastname: Obba
authors.forename: C
authors.initials: C
authors.lastname: Dani
authors.forename: A
authors.initials: A
authors.lastname: Ladoux
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018450:Disease Progression; D004354:Drug Screening Assays, Antitumor; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D007414:Intestinal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D061466:Lopinavir / Q000494:pharmacology; D059630:Mesenchymal Stem Cells / Q000187:drug effects; D051379:Mice; D016513:Mice, SCID; D019888:Nelfinavir / Q000494:pharmacology; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism; D011714:Pyrans / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured; D000095662:Polyether Polyketides
chemical_list: D000970:Antineoplastic Agents; D017320:HIV Protease Inhibitors; D061466:Lopinavir; D019888:Nelfinavir; D011714:Pyrans; C010327:salinomycin; D000095662:Polyether Polyketides