title: Jasmonates induce nonapoptotic death in high-resistance mutant p53-expressing B-lymphoma cells.
abstract: Mutations in p53, a tumor suppressor gene, occur in more than half of human cancers. Therefore, we tested the hypothesis that jasmonates (novel anticancer agents) can induce death in mutated p53-expressing cells. Two clones of B-lymphoma cells were studied, one expressing wild-type (wt) p53 and the other expressing mutated p53. Jasmonic acid and methyl jasmonate (0.25-3 mM) were each equally cytotoxic to both clones, whereas mutant p53-expressing cells were resistant to treatment with the radiomimetic agent neocarzinostatin and the chemotherapeutic agent bleomycin. Neocarzinostatin and bleomycin induced an elevation in the p53 levels in wt p53-expressing cells, whereas methyl jasmonate did not. Methyl jasmonate induced mostly apoptotic death in the wt p53-expressing cells, while no signs of early apoptosis were detected in mutant p53-expressing cells. In contrast, neocarzinostatin and bleomycin induced death only in wt p53-expressing cells, in an apoptotic mode. Methyl jasmonate induced a rapid depletion of ATP in both clones. In both clones, oligomycin (a mitochondrial ATP synthase inhibitor) did not increase ATP depletion induced by methyl jasmonate, whereas inhibition of glycolysis with 2-deoxyglucose did. High glucose levels protected both clones from methyl jasmonate-induced ATP depletion (and reduced methyl jasmonate-induced cytotoxicity), whereas high levels of pyruvate did not. These results suggest that methyl jasmonate induces ATP depletion mostly by compromising oxidative phosphorylation in the mitochondria. In conclusion, jasmonates can circumvent the resistance of mutant p53-expressing cells towards chemotherapy by inducing a nonapoptotic cell death.
authors.affiliation: Department of Human Microbiology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Orit
authors.initials: O
authors.lastname: Fingrut
authors.forename: Dorit
authors.initials: D
authors.lastname: Reischer
authors.forename: Ronit
authors.initials: R
authors.lastname: Rotem
authors.forename: Natalia
authors.initials: N
authors.lastname: Goldin
authors.forename: Irit
authors.initials: I
authors.lastname: Altboum
authors.forename: Israel
authors.initials: I
authors.lastname: Zan-Bar
authors.forename: Eliezer
authors.initials: E
authors.lastname: Flescher
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000255:Adenosine Triphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001761:Bleomycin / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D002999:Clone Cells; D003517:Cyclopentanes / Q000494:pharmacology*; D003847:Deoxyglucose / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015151:Immunoblotting; D016393:Lymphoma, B-Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009840:Oligomycins / Q000494:pharmacology; D054883:Oxylipins; D010937:Plant Growth Regulators / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics* / Q000378:metabolism; D009353:Zinostatin / Q000494:pharmacology
chemical_list: D000085:Acetates; D000903:Antibiotics, Antineoplastic; D003517:Cyclopentanes; D009840:Oligomycins; D054883:Oxylipins; D010937:Plant Growth Regulators; D016159:Tumor Suppressor Protein p53; D001761:Bleomycin; C011006:jasmonic acid; D000255:Adenosine Triphosphate; C072239:methyl jasmonate; D009353:Zinostatin; D003847:Deoxyglucose