title: Methyljasmonate displays in vitro and in vivo activity against multiple myeloma cells.
abstract: Jasmonates, plant stress hormones, have been demonstrated to be effective in killing various types of cancer cells. We therefore tested if methyljasmonate (MJ) has activity against multiple myeloma (MM) in vitro and in vivo. MM cell lines and primary MM tumour cells responded to MJ in vitro at concentrations that did not significantly affect normal haematopoietic cells, without stroma-mediated resistance. Brief MJ exposures of MM cells caused release of Hexokinase 2 (HK2) from mitochondria, rapid ATP depletion, perturbation of major intracellular signalling pathways, and ensuing mainly apoptotic cell death. Sensitivity to MJ correlated with lower cellular glucose consumption and lactate production, as well as lower intracellular protein levels of HK2, phosphorylated Voltage-dependent anion channel 2/3 (pVDAC2/3) and Aldo-keto reductase family 1 member C1 (AKR1C1), which represent potential biomarkers of responsiveness to MJ treatment, especially as AKR1C1 transcript levels also correlate with clinical outcome in bortezomib- or dexamethasone-treated MM patients. Interestingly, MJ synergized with bortezomib in vitro and prolonged survival of immunocompromised mice harbouring diffuse lesions of MM.1S cells compared to vehicle-treated mice (P = 0·0046). These studies indicate that jasmonates represent a new, promising strategy to treat MM.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Steffen
authors.initials: S
authors.lastname: Klippel
authors.forename: Jana
authors.initials: J
authors.lastname: Jakubikova
authors.forename: Jake
authors.initials: J
authors.lastname: Delmore
authors.forename: Melissa
authors.initials: M
authors.lastname: Ooi
authors.forename: Douglas
authors.initials: D
authors.lastname: McMillin
authors.forename: Efstathios
authors.initials: E
authors.lastname: Kastritis
authors.forename: Jacob
authors.initials: J
authors.lastname: Laubach
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
mesh_terms: D000085:Acetates / Q000008:administration & dosage / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003517:Cyclopentanes / Q000008:administration & dosage / Q000494:pharmacology*; D004357:Drug Synergism; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D054883:Oxylipins / Q000008:administration & dosage / Q000494:pharmacology*; D010937:Plant Growth Regulators / Q000494:pharmacology*
chemical_list: D000085:Acetates; D000972:Antineoplastic Agents, Phytogenic; D003517:Cyclopentanes; D054883:Oxylipins; D010937:Plant Growth Regulators; D000255:Adenosine Triphosphate; C072239:methyl jasmonate