title: Antineoplastic activity of the thiazolo[5,4-b]quinoline derivative D3CLP in K-562 cells is mediated through effector caspases activation.
abstract: Thiazolo[5,4-b]quinolines are compounds structurally related to m-Amsacrine (m-Amsa), a potent antileukemic drug that intercalates to DNA and inhibits topoisomerase II in vitro inducing cell death. The clinical use of m-Amsa and other neoplastic drugs is limited due to side effects and drug resistance. In the present study we evaluated one thiazolo[5,4-b]quinoline derivate, 9-[(3-chloro)phenylamine]-2-[3-(diethylamine)propylamine]thiazolo[5,4-b]quinoline (D3CLP), considered isosteric with 9-anilinoacridines, in order to determine its relative cytotoxic activity in tumoral versus non-tumoral cells, as well as the cell death mechanism induced by D3CLP on K-562 human leukemia cells. D3CLP was found to be four times more cytotoxic to tumor cells than Peripheral Blood Monocyte Cells (PBMCs). On the other hand, D3CLP induces cell death without previous cell cycle arrest at any phase, as shown by flow cytometry after 12 h of exposure to this compound. Interestingly, we detected a subdiploid peak 24 h after treatment. Signs of apoptosis were evident, as detected by TUNEL positive cells, chromatin condensation and nuclear fragmentation. Effector caspases activation were assessed with peak activity at 24 h after treatment (as detected by fluorometry assays), at which time a subdiploid peak was found in flow cytometry histograms. All data are consistent with the induction of apoptotic cell death in K-562 cells via effector caspases activation. In conclusion, the significant cytotoxicity of D3CLP together with the cell death type it produces, justifies further experimental and preclinical evaluation of this compound in the effort to find new and highly specific anti-tumor agents against leukemia cells.
authors.affiliation: Departamento de Biología, Facultad de Química, Universidad Nacional Autónoma de México, Cd. Universitaria, Coyoacán, México 04510, Mexico.
authors.forename: Ignacio
authors.initials: I
authors.lastname: González-Sánchez
authors.forename: José D
authors.initials: JD
authors.lastname: Solano
authors.forename: Marco A
authors.initials: MA
authors.lastname: Loza-Mejía
authors.forename: Susana
authors.initials: S
authors.lastname: Olvera-Vázquez
authors.forename: Rogelio
authors.initials: R
authors.lastname: Rodríguez-Sotres
authors.forename: Julio
authors.initials: J
authors.lastname: Morán
authors.forename: Alfonso
authors.initials: A
authors.lastname: Lira-Rocha
authors.forename: Marco A
authors.initials: MA
authors.lastname: Cerbón
mesh_terms: D000634:Aminoquinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D061945:Caspase Inhibitors; D002453:Cell Cycle / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: C560931:9-((3-chloro)phenylamine)-2-(3-(diethylamine)propylamine)thiazolo(5,4-b)quinoline; D000634:Aminoquinolines; D000970:Antineoplastic Agents; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D013844:Thiazoles