title: Effective killing of leukemia cells by the natural product OSW-1 through disruption of cellular calcium homeostasis.
abstract: 3β,16β,17α-Trihydroxycholest-5-en-22-one 16-O-(2-O-4-methoxybenzoyl-β-D-xylopyranosyl)-(1→3)-2-O-acetyl-α-L-arabinopyranoside (OSW-1) is a natural product with potent antitumor activity against various types of cancer cells, but the exact mechanisms of action remain to be defined. In this study, we showed that OSW-1 effectively killed leukemia cells at subnanomolar concentrations through a unique mechanism by causing a time-dependent elevation of cytosolic Ca(2+) prior to induction of apoptosis. A mechanistic study revealed that this compound inhibited the sodium-calcium exchanger 1 on the plasma membrane, leading to an increase in cytosolic Ca(2+) and a decrease in cytosolic Na(+). The elevated cytosolic Ca(2+) caused mitochondrial calcium overload and resulted in a loss of mitochondrial membrane potential, release of cytochrome c, and activation of caspase-3. Furthermore, OSW-1 also caused a Ca(2+)-dependent cleavage of the survival factor GRP78. Inhibition of Ca(2+) entry into the mitochondria by the uniporter inhibitor RU360 or by cyclosporin A significantly prevented the OSW-1-induced cell death, indicating the important role of mitochondria in mediating the cytotoxic activity. The extremely potent activity of OSW-1 against leukemia cells and its unique mechanism of action suggest that this compound may be potentially useful in the treatment of leukemia.
authors.affiliation: Department of Translational Molecular Pathology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: Celia
authors.initials: C
authors.lastname: Garcia-Prieto
authors.forename: Kausar Begam
authors.initials: KB
authors.lastname: Riaz Ahmed
authors.forename: Zhao
authors.initials: Z
authors.lastname: Chen
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhou
authors.forename: Naima
authors.initials: N
authors.lastname: Hammoudi
authors.forename: Ying
authors.initials: Y
authors.lastname: Kang
authors.forename: Changgang
authors.initials: C
authors.lastname: Lou
authors.forename: Yan
authors.initials: Y
authors.lastname: Mei
authors.forename: Zhendong
authors.initials: Z
authors.lastname: Jin
authors.forename: Peng
authors.initials: P
authors.lastname: Huang
mesh_terms: D001688:Biological Products / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000378:metabolism; D002154:Calpain / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D002783:Cholestenones / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology; D045304:Cytochromes c / Q000378:metabolism; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007938:Leukemia / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D008223:Lymphoma / Q000201:enzymology / Q000473:pathology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D012503:Saponins / Q000494:pharmacology*; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000378:metabolism; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors
chemical_list: D001688:Biological Products; D015220:Calcium Channels; D002783:Cholestenones; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; D012503:Saponins; D019831:Sodium-Calcium Exchanger; C034703:mitochondrial calcium uniporter; C110374:sodium-calcium exchanger 1; C106408:OSW 1; D019284:Thapsigargin; D016572:Cyclosporine; D045304:Cytochromes c; D002154:Calpain; D053148:Caspase 3; D002118:Calcium