title: OSW-1: a natural compound with potent anticancer activity and a novel mechanism of action.
abstract: The naturally occurring compound 3beta,16beta,17alpha-trihydroxycholest-5-en-22-one 16-O-(2-O-4-methoxybenzoyl-beta-D-xylopyranosyl)-(1-->3)-(2-O-acetyl-alpha-L-arabinopyranoside) (OSW-1) is found in the bulbs of Ornithogalum saudersiae and is highly cytotoxic against tumor cell lines. Using various human cancer and nonmalignant cell lines, we investigated the anticancer activity and selectivity of OSW-1 and its underlying mechanisms of action. OSW-1 exhibited extremely potent cytotoxic activity against cancer cells in vitro. Nonmalignant cells were statistically significantly less sensitive to OSW-1 than cancer cells, with concentrations that cause a 50% loss of cell viability 40-150-fold greater than those observed in malignant cells. Electron microscopy and biochemical analyses revealed that OSW-1 damaged the mitochondrial membrane and cristae in both human leukemia and pancreatic cancer cells, leading to the loss of transmembrane potential, increase of cytosolic calcium, and activation of calcium-dependent apoptosis. Clones of leukemia cells with mitochondrial DNA defects and respiration deficiency that had adapted the ability to survive in culture without mitochondrial respiration also were resistant to OSW-1. In vitro analysis revealed that OSW-1 effectively killed primary leukemia cells from chronic lymphocytic leukemia patients with disease refractory to fludarabine. The promising anticancer activity of OSW-1 and its unique mechanism of action make this compound worthy of further investigation for its potential to overcome drug resistance.
authors.affiliation: Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Celia
authors.initials: C
authors.lastname: Garcia-Prieto
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Carney
authors.forename: Rui-hua
authors.initials: RH
authors.lastname: Xu
authors.forename: Helene
authors.initials: H
authors.lastname: Pelicano
authors.forename: Ying
authors.initials: Y
authors.lastname: Kang
authors.forename: Wensheng
authors.initials: W
authors.lastname: Yu
authors.forename: Changgang
authors.initials: C
authors.lastname: Lou
authors.forename: Seiji
authors.initials: S
authors.lastname: Kondo
authors.forename: Jinsong
authors.initials: J
authors.lastname: Liu
authors.forename: David M
authors.initials: DM
authors.lastname: Harris
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Jin
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D015220:Calcium Channels / Q000378:metabolism; D045744:Cell Line, Tumor; D002783:Cholestenones / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020128:Inhibitory Concentration 50; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008854:Microscopy, Electron; D051336:Mitochondrial Membranes / Q000187:drug effects*; D012503:Saponins / Q000494:pharmacology*; D014740:Vidarabine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D015220:Calcium Channels; D002783:Cholestenones; D012503:Saponins; C106408:OSW 1; D014740:Vidarabine; C024352:fludarabine