title: Effects of tetramethoxystilbene on hormone-resistant breast cancer cells: biological and biochemical mechanisms of action.
abstract: Secondary resistance to hormonal therapy for breast cancer commonly develops after an initial response to tamoxifen or aromatase inhibitors. Agents to abrogate these adaptive changes would substantially enhance the long-term benefits of hormonal therapy. Our studies with a stilbene derivative called TMS (2,3',4,5'-tetramethoxystilbene) identified unexpected effects with potential utility for treatment of breast tumors secondarily resistant to hormonal therapy. TMS was originally developed as an inhibitor of cytochrome P450 1B1 to block the conversion of estradiol to 4-OH-estradiol. While studying this agent in three models of hormone resistance, we detected direct antitumor effects not related to its role as an inhibitor of catecholestrogens. During examination of the mechanisms involved, we showed that treatment with 3 micromol/L TMS for 24 h inhibited tubulin polymerization and microtubule formation, caused a cell cycle block at the G2-M phase, and induced apoptosis. TMS also inhibited activated focal adhesion kinase (FAK), Akt, and mammalian target of rapamycin (mTOR) and stimulated c-jun-NH2-kinase and p38 mitogen-activated protein kinase activity. With respect to antitumor effects, TMS at a concentrations of 0.2 to 0.3 micromol/L inhibited the growth of long-term tamoxifen-treated MCF-7 cells by 80% and fulvestrant-treated MCF-7 cells by 70%. In vivo studies, involving 8 weeks of treatment with TMS via a 30-mg s.c. implant, reduced tumor volume of tamoxifen-resistant MCF-7 breast cancer xenografts by 53%. Our data suggest that TMS is a promising therapeutic agent because of its unique ability to block several pathways involved in the development of hormone resistance.
authors.affiliation: Endocrinology and Metabolism, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
authors.forename: Hoyong
authors.initials: H
authors.lastname: Park
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Aiyar
authors.forename: Ping
authors.initials: P
authors.lastname: Fan
authors.forename: Jiping
authors.initials: J
authors.lastname: Wang
authors.forename: Wei
authors.initials: W
authors.lastname: Yue
authors.forename: Tatiana
authors.initials: T
authors.lastname: Okouneva
authors.forename: Corey
authors.initials: C
authors.lastname: Cox
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Jordan
authors.forename: Laurence
authors.initials: L
authors.lastname: Demers
authors.forename: Hyungjun
authors.initials: H
authors.lastname: Cho
authors.forename: Sanghee
authors.initials: S
authors.lastname: Kim
authors.forename: Robert X-D
authors.initials: RX
authors.lastname: Song
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Santen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D047072:Aromatase Inhibitors / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D004797:Enzyme-Linked Immunosorbent Assay; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D004967:Estrogens / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D013267:Stilbenes / Q000494:pharmacology*; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D013267:Stilbenes; D013629:Tamoxifen