title: Amino-functionalized nanoparticles as inhibitors of mTOR and inducers of cell cycle arrest in leukemia cells.
abstract: Activation of the mammalian target of rapamycin (mTOR) has been implicated in anticancer drug resistance, type 2 diabetes, and aging. Here, we show that surface functionalization of polystyrene nanoparticles with amino groups (PS-NH2), but not with carboxyl groups (PS-COOH), induces G2 cell-cycle arrest and inhibition of proliferation in three leukemia cell lines. Besides, PS-NH2 inhibit angiogenesis and proliferation of leukemia cells xenografted onto the chick chorioallantoic membrane. At the molecular level, PS-NH2 inhibit, whereas PS-COOH activate mTOR signaling in leukemia cells. Consistently, PS-NH2 block activation of the mTOR downstream targets, Akt and p70 ribosomal S6 kinase 1, and induce overexpression of the cell-cycle regulator p21(Cip1/Waf1) and degradation of cyclin B1. After addition, both types of particles rapidly induce autophagy in leukemia cells. Yet, only in PS-NH2-treated cells, acidic vesicular organelles show elevated pH and impaired processing of procathepsin B. Moreover, solely in PS-NH2-treated cells, autophagy is followed by permeabilization of acidic vesicular organelles and induction of apoptosis. By contrast, primary macrophages, which do not exhibit activated mTOR signaling, proved relatively resistant to PS-NH2-induced toxicity. These data indicate that functionalized nanoparticles can be used to control activation of mTOR signaling pathways, and to influence proliferation and viability of malignant cells.
authors: Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, D-89081 Ulm, Germany.
authors: Cornelia
authors: C
authors: Loos
authors: Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, D-89081 Ulm, Germany.
authors: Tatiana
authors: T
authors: Syrovets
authors: Max-Planck-Institute for Polymer Research, D-55128 Mainz, Germany.
authors: Anna
authors: A
authors: Musyanovych
authors: Max-Planck-Institute for Polymer Research, D-55128 Mainz, Germany; Department of Hematology, Medical Oncology, and Pneumology, University Medical Center Mainz, Langenbeckstr. 1, D-55131 Mainz, Germany.
authors: Volker
authors: V
authors: Mailänder
authors: Max-Planck-Institute for Polymer Research, D-55128 Mainz, Germany.
authors: Katharina
authors: K
authors: Landfester
authors: Institute of Pharmacology of Natural Products & Clinical Pharmacology, Ulm University, D-89081 Ulm, Germany. Electronic address: thomas.simmet@uni-ulm.de.
authors: Thomas
authors: T
authors: Simmet
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D006801:Humans; D007938:Leukemia / Q000188:drug therapy*; D053758:Nanoparticles / Q000737:chemistry* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Amino functionalization; Apoptosis; Carboxyl functionalization; Leukemia; Polystyrene nanoparticles; mTOR signaling