The selective estrogen receptor modulator arzoxifene and the rexinoid LG100268 cooperate to promote transforming growth factor beta-dependent apoptosis in breast cancer.
We show that the selective estrogen receptor modulator arzoxifene (Arz) and the rexinoid LG100268 (268) synergize to promote apoptosis in a rat model of estrogen receptor-positive breast carcinoma and in estrogen receptor-positive human breast cancer cells in culture. We also show that it is not necessary to administer Arz and 268 continuously during tumor progression to prevent cancer in the rat model because dosing of these drugs in combination for relatively short periods, each followed by drug-free rests, is highly effective. This new approach to chemoprevention uses high doses of drugs that are too toxic for long-term administration. However, when given for short periods, the agents are nontoxic and still induce apoptosis in breast cancer cells. We also show that the ability of the two drugs to induce apoptosis is the combined result of induction of transforming growth factor beta by Arz, together with inhibition of the prosurvival nuclear factor kappaB and phosphatidylinositol 3' kinase signaling pathways by 268. The new protocol we have developed for chemoprevention allows the efficacious and safe administration of 268 and Arz, and these agents now should be considered for clinical use.
Rendi
Mara H
MH
Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Suh
Nanjoo
N
Lamph
William W
WW
Krajewski
Stan
S
Reed
John C
JC
Heyman
Richard A
RA
Berchuck
Andrew
A
Liby
Karen
K
Risingsong
Renee
R
Royce
Darlene B
DB
Williams
Charlotte R
CR
Sporn
Michael B
MB
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D004357:Drug Synergism; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology / Q000517:prevention & control; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009539:Nicotinic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage / Q000494:pharmacology*; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage / Q000494:pharmacology*; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D016328:NF-kappa B; D009539:Nicotinic Acids; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010880:Piperidines; D020845:Selective Estrogen Receptor Modulators; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; D016212:Transforming Growth Factor beta; C115121:LY 353381; C095104:LG 100268