title: Effect of lysosomotropic molecules on cellular homeostasis.
abstract: Weak bases that readily penetrate through the lipid bilayer and accumulate inside the acidic organelles are known as lysosomotropic molecules. Many lysosomotropic compounds exhibit therapeutic activity and are commonly used as antidepressant, antipsychotic, antihistamine, or antimalarial agents. Interestingly, studies also have shown increased sensitivity of cancer cells to certain lysosomotropic agents and suggested their mechanism of action as a promising approach for selective destruction of cancer cells. However, their chemotherapeutic utility may be limited due to various side effects. Hence, understanding the homeostatic alterations mediated by lysosomotropic compounds has significant importance for revealing their true therapeutic potential as well as toxicity. In this review, after briefly introducing the concept of lysosomotropism and classifying the lysosomotropic compounds into two major groups according to their cytotoxicity on cancer cells, we focused on the subcellular alterations mediated by class-II lysosomotropic compounds. Briefly, their effect on intracellular cholesterol homeostasis, autophagy and lysosomal sphingolipid metabolism was discussed. Accordingly, class-II lysosomotropic molecules inhibit intracellular cholesterol transport, leading to the accumulation of cholesterol inside the late endosomal-lysosomal cell compartments. However, the accumulated lysosomal cholesterol is invisible to the cellular homeostatic circuits, hence class-II lysosomotropic molecules also upregulate cholesterol synthesis pathway as a downstream event. Considering the fact that Niemann-Pick disease, a lysosomal cholesterol storage disorder, also triggers similar pathologic abnormalities, this review combines the knowledge obtained from the Niemann-Pick studies and lysosomotropic compounds. Taken together, this review is aimed at allowing readers a better understanding of subcellular alterations mediated by lysosomotropic drugs, as well as their potential therapeutic and/or toxic activities.
authors.affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Penn State Hershey Melanoma Center, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States.
authors.forename: Omer F
authors.initials: OF
authors.lastname: Kuzu
authors.affiliation: Department of Psychiatry, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States.
authors.forename: Mesut
authors.initials: M
authors.lastname: Toprak
authors.affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Penn State Hershey Melanoma Center, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States.
authors.forename: M Anwar
authors.initials: MA
authors.lastname: Noory
authors.affiliation: Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Department of Pathology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Department of Dermatology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Department of Surgery, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Penn State Hershey Melanoma Center, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; Penn State Melanoma Therapeutics Program, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States; The Foreman Foundation for Melanoma Research, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States. Electronic address: gprobertson@psu.edu.
authors.forename: Gavin P
authors.initials: GP
authors.lastname: Robertson
mesh_terms: D000818:Animals; D002784:Cholesterol / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D008247:Lysosomes / Q000187:drug effects* / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*
chemical_list: D004364:Pharmaceutical Preparations; D002784:Cholesterol
keywords: Antipsychotics; Butylamine (PubChem CID: 8007); Desipramine (PubChem CID: 2995); Dimethylamine (PubChem CID: 674); Fluphenazine (PubChem CID: 3372); Functional inhibitors of acid sphingomyelinase; Hexylamine (PubChem CID: 8102); Imidazole (PubChem CID: 795); Inhibition of intracellular cholesterol transport; Leelamine (PubChem CID: 118215); Lysosomotropic compounds; Lysosomotropism; Perphenazine (PubChem CID: 4748); Propylamine (PubChem CID: 7852); Tricyclic antidepressants; U18666A (PubChem CID: 9954082)