Effects of tetramethoxystilbene on hormone-resistant breast cancer cells: biological and biochemical mechanisms of action.
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.
Park
Hoyong
H
Endocrinology and Metabolism, University of Virginia Health System, Charlottesville, Virginia 22908, USA.
Aiyar
Sarah E
SE
Fan
Ping
P
Wang
Jiping
J
Yue
Wei
W
Okouneva
Tatiana
T
Cox
Corey
C
Jordan
Mary Ann
MA
Demers
Laurence
L
Cho
Hyungjun
H
Kim
Sanghee
S
Song
Robert X-D
RX
Santen
Richard J
RJ
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
D000970:Antineoplastic Agents; D047072:Aromatase Inhibitors; D020847:Estrogen Receptor Modulators; D004967:Estrogens; D013267:Stilbenes; D013629:Tamoxifen