Selection of a highly tumorigenic breast cancer cell line sensitive to estradiol to evidence in vivo the tumor-inhibitory effect of butyrate derivative Monobut-3.
To increase butyric acid mean residence time in vivo, we have produced a stable butyric acid derivative. Monobut-3. Recently, we have described that Monobut-3 is able to induce phenotypic changes in human mammary tumor cells in vitro. In this study, we explore the in vivo effect of Monobut-3. Human breast tumor cell-lines did not easily produce in vivo xenografts, thus, MCF-7 cells required exogenous 17 beta-estradiol to grow and to form in vivo xenografts. To evaluate in vivo and anti-tumor effects of monobut-3 without exogenous 17 beta-estradiol addition, we have established MCF-7 variant cells, highly tumorigenic MCF-7vht, in which transfection of ras oncogene induced a bypass of estrogen requirement but did not delete the presence of functional estrogen receptor (ER). Monobut-3 inhibited growth of this variant by about 90% at 4 mM and reduced 17 beta-estradiol cell growth stimulation. In vivo, in absence of 17 beta-estradiol, 2 mg per mouse monobut-3 decreased tumor take by about 25% and tumor growth by about 50% in nude mice. This is the first experimental demonstration of an in vivo antitumoral effect of a butyric acid derivative alone on a solid human tumor. These data suggest that this compound does not only act by reducing of 17 beta-estradiol stimulation but it also has an 17 beta-estradiol-independent effect. Absence of toxicity and its antiproliferative effects could suggest its use in clinical treatment of well differentiated carcinoma.
Planchon
P
P
Institut d'Oncologie Cellulaire et Moléculaire Humaine, Bobigny, France.
Magnien
V
V
Starzec
A
A
Prevost
G
G
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002087:Butyrates / Q000494:pharmacology / Q000627:therapeutic use*; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy*; D002455:Cell Division / Q000187:drug effects; D004958:Estradiol / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D011960:Receptors, Estrogen / Q000032:analysis; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002087:Butyrates; D011960:Receptors, Estrogen; C069135:esterbut-3; D004958:Estradiol; D005947:Glucose