title: TMS, a chemically modified herbal derivative of resveratrol, induces cell death by targeting Bax.
abstract: Breast cancer recurrence after an initial favorable response to treatment is a major concern for patients who receive hormonal therapies. Additional therapies are necessary to extend the time of response, and ideally, these therapies should exhibit minimal toxicity. Our study described herein focuses on a non-toxic pro-apoptotic agent, TMS (2,4,3',5'-tetramethoxystilbene), which belongs to the Resveratrol family of stilbenes. Prior study demonstrated that TMS was more effective than Resveratrol for inducing apoptosis. Additionally, TMS was effective for invoking death of relapsing breast cancer cells. As TMS was effective for reducing tumor burden, we sought to determine the mechanism by which it achieved its effects. Microarray analysis demonstrated that TMS treatment increased tubulin genes as well as stress response and pro-apoptotic genes. Fractionation studies uncovered that TMS treatment causes cleavage of Bax from the p21 form to a truncated p18 form which is associated with the induction of potent apoptosis. Co-localization analysis of immunofluorescent studies showed that Bax moved from the cytosol to the mitochondria. In addition, the pro-apoptotic proteins Noxa and Bim (EL, L, and S) were increased upon TMS treatment. Cell lines reduced for Bax, Bim, and Noxa are compromised for TMS-mediated cell death. Electron microscopy revealed evidence of nuclear condensation, formation of apoptotic bodies and DAPI staining showed evidence of DNA fragmentation. TMS treatment was able to induce both caspase-independent and caspase-dependent death via the intrinsic death pathway.
authors.affiliation: Division of Endocrinology and Metabolism, University of Virginia Health System, PO Box 801416, Charlottesville, VA 22908, USA.
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Aiyar
authors.forename: Hoyong
authors.initials: H
authors.lastname: Park
authors.forename: Paulomi B
authors.initials: PB
authors.lastname: Aldo
authors.forename: Gil
authors.initials: G
authors.lastname: Mor
authors.forename: John J
authors.initials: JJ
authors.lastname: Gildea
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Miller
authors.forename: E Brad
authors.initials: EB
authors.lastname: Thompson
authors.forename: J David
authors.initials: JD
authors.lastname: Castle
authors.forename: Sanghee
authors.initials: S
authors.lastname: Kim
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Santen
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D053938:DNA Fragmentation; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D046529:Microscopy, Electron, Transmission; D020411:Oligonucleotide Array Sequence Analysis; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D013267:Stilbenes / Q000494:pharmacology*; D013997:Time Factors; D014404:Tubulin / Q000235:genetics / Q000378:metabolism; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C440850:2,4,3',5'-tetramethoxystilbene; D000972:Antineoplastic Agents, Phytogenic; D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D008565:Membrane Proteins; C498702:PMAIP1 protein, human; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D013267:Stilbenes; D014404:Tubulin; D051028:bcl-2-Associated X Protein; D020169:Caspases