Farnesylthiosalicylic acid: inhibition of proliferation and enhancement of apoptosis of hormone-dependent breast cancer cells.
Farnesyltransferase inhibitors (FTIs) are being developed to block Ras-mediated actions, but current data suggest that the FTIs act through other non-Ras pathways. A new agent, farnesylthiosalicylic acid (FTS), blocks the binding of Ras to membrane acceptor sites and causes a marked reduction in Ras levels. Accordingly, FTS could be a useful new agent for the treatment of hormone-dependent breast cancer. We examined the dose-response effects of FTS on the growth of MCF-7 breast cancer cells in vitro and in vivo. Further, we dissected out its specific effects on cell proliferation and apoptosis by measuring BrdU incorporation into DNA and by using an ELISA assay to quantitate the magnitude of apoptosis. FTS and its solubilized conjoiner FTS-cyclodextrin markedly inhibited cell growth in MCF-7 breast cancer cells in culture and in xenografts. This agent exerted dual effects to reduce cell proliferation as assessed by BrdU incorporation and to enhance apoptosis as quantitated by ELISA assay. These data suggest that FTS is a promising agent to be developed for treatment of hormone-dependent breast cancer.
Santen
Richard J
RJ
Division of Endocrinology, University of Virginia Health Sciences Center, Charlottesville, Virginia 22908, USA. rjs5y@virginia.edu
Lynch
Amanda R
AR
Neal
Lindsey R
LR
McPherson
Robert A
RA
Yue
Wei
W
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D003505:Cyclodextrins / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004958:Estradiol / Q000494:pharmacology; D005204:Farnesol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy; D012459:Salicylates / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000037:antagonists & inhibitors
D000970:Antineoplastic Agents; D003505:Cyclodextrins; D012459:Salicylates; C093323:farnesylthiosalicylic acid; D005204:Farnesol; D004958:Estradiol; D018631:ras Proteins