title: Identification of endoplasmic reticulum stress-inducing agents by antagonizing autophagy: a new potential strategy for identification of anti-cancer therapeutics in B-cell malignancies.
abstract: The endoplasmic reticulum (ER) plays a vital function in multiple cellular processes. There is a growing interest in developing therapeutic agents that can target the ER in cancer cells, inducing a stress response that leads to cell death. However, ER stress-inducing agents can also induce autophagy, a survival strategy of cancer cells. Therefore, by inhibiting autophagy we can increase the efficacy of the ER stress-inducing agents. Nelfinavir, a human immunodeficiency virus (HIV) protease inhibitor with anti-cancer properties, can induce ER stress. Nelfinavir's effects on chronic lymphocytic leukemia (CLL) are yet to be elucidated. Herein we demonstrate that nelfinavir induces ER morphological changes and stress response, along with an autophagic protective strategy. Our data reveal that chloroquine, an autophagy inhibitor, significantly increases nelfinavir cytotoxicity. These results identify a novel strategy potentially effective in CLL treatment, by repositioning two well-known drugs as a combinatorial therapy with anti-cancer properties.
authors.affiliation: Division of Hematology, Department of Internal Medicine, College of Medicine, The Ohio State University , Columbus, OH , USA.
authors.forename: Emilia
authors.initials: E
authors.lastname: Mahoney
authors.forename: Kami
authors.initials: K
authors.lastname: Maddocks
authors.forename: Joseph
authors.initials: J
authors.lastname: Flynn
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Jones
authors.forename: Sara L
authors.initials: SL
authors.lastname: Cole
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Zhang
authors.forename: John C
authors.initials: JC
authors.lastname: Byrd
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Johnson
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001343:Autophagy / Q000187:drug effects*; D015415:Biomarkers; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D015448:Leukemia, B-Cell / Q000188:drug therapy / Q000378:metabolism; D016393:Lymphoma, B-Cell / Q000188:drug therapy / Q000378:metabolism; D019888:Nelfinavir / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D002738:Chloroquine; D019888:Nelfinavir