title: 2-(8-Hydroxy-6-methoxy-1-oxo-1H-2-benzopyran-3-yl)propionic acid, a small molecule isocoumarin, potentiates dexamethasone-induced apoptosis of human multiple myeloma cells.
abstract: 2-(8-Hydroxy-6-methoxy-1-oxo-1Eta-2-benzopyran-3-yl)propionic acid (NM-3) is a small molecule isocoumarin derivative that has recently entered clinical trials as an orally bioavailable anticancer agent. NM-3 induces lethality of human carcinoma cells by both apoptotic and nonapoptotic mechanisms and potentiates the effects of cytotoxic chemotherapeutic agents. The present studies have evaluated the effects of NM-3 on human multiple myeloma (MM) cells. The results demonstrate that NM-3 potentiates dexamethasone-induced killing of both dexamethasone-sensitive MM1.S and dexamethasone-resistant RPMI8226 and U266 MM cells. We show that NM-3 enhances dexamethasone-induced release of the mitochondrial apoptogenic factors cytochrome c and Smac/DIABLO. The results also demonstrate that NM-3 enhances dexamethasone-induced activation of the intrinsic caspase-9->caspase-3 apoptotic pathway. In concert with these results, NM-3 potentiates dexamethasone-induced apoptosis of MM1.S cells. Moreover, NM-3 acts synergistically with dexamethasone in inducing apoptosis of the dexamethasone-resistant RPMI8226 and U266 MM cells. These findings indicate that NM-3 may be effective in combination with dexamethasone in the treatment of MM.
authors.affiliation: ILEX Products, Inc., Boston, Massachusetts 02115, USA.
authors.forename: Naoki
authors.initials: N
authors.lastname: Agata
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nogi
authors.forename: Michael
authors.initials: M
authors.lastname: Milhollen
authors.forename: Surender
authors.initials: S
authors.lastname: Kharbanda
authors.forename: Donald
authors.initials: D
authors.lastname: Kufe
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins / Q000378:metabolism; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003374:Coumarins / Q000008:administration & dosage / Q000494:pharmacology*; D045304:Cytochromes c / Q000378:metabolism; D003907:Dexamethasone / Q000008:administration & dosage / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D049934:Isocoumarins; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D002352:Carrier Proteins; D003374:Coumarins; C412403:DIABLO protein, human; D047908:Intracellular Signaling Peptides and Proteins; D049934:Isocoumarins; D024101:Mitochondrial Proteins; D017382:Reactive Oxygen Species; C453300:isocoumarin NM-3; D003907:Dexamethasone; D045304:Cytochromes c; C505407:CASP3 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053453:Caspase 9; D020169:Caspases