title: Inhibition of estrogen stimulated mitogenesis by 3-phenylacetylamino-2,6-piperidinedione and its para-hydroxy analog.
abstract: 3-Phenylactetylamino-2,6-piperidinedione (A10) inhibited estradiol stimulated cell growth in the MCF-7 (E3) human breast tumor cell line in vivo and in vitro. While high concentrations of A10 were needed to inhibit cell proliferation (IC50 = 3 x 10(-3) M in vitro), the compound demonstrated little toxicity. The effect appeared specific since a hydrolysis product of A10, phenylacetylglutamine, demonstrated no growth inhibitory activity at similar concentrations in MCF-7 (E3) cells in vitro. A computer designed analog, p-hydroxy A10, was more potent than A10 in inhibiting activity in MCF-7 (E3) cells in vitro. The IC50 for p-hydroxy A10 was 7 x 10(-6) M which was comparable to that of the antiestrogen, tamoxifen (IC50 1 x 10(-7) M). All three compounds caused a decline in estrogen receptor levels in a dose-dependent fashion. A10 also inhibited estradiol induction of progesterone receptors. Examination of protein kinase activity following an acute exposure to a 10(-11) M growth stimulatory dose of estradiol revealed a 168% increase in protein kinase activity over that of untreated control cells. A10 in a dose-responsive fashion inhibited the estradiol stimulated increase in protein kinase activity. The protein kinase activity was also inhibited by p-hydroxy A10. These activities of A10 and p-hydroxy A10 coupled with the low toxicity and novelty of the basic A10 structure provide an exciting possibility of developing a new class of clinically useful antineoplastic drugs with minimal side effects.
authors.affiliation: Department of Physiology, Medical College of Georgia, Augusta 30912-3000.
authors.forename: J A
authors.initials: JA
authors.lastname: Copland
authors.forename: L B
authors.initials: LB
authors.lastname: Hendry
authors.forename: C K
authors.initials: CK
authors.lastname: Chu
authors.forename: J C
authors.initials: JC
authors.lastname: Wood
authors.forename: R W
authors.initials: RW
authors.lastname: Wrenn
authors.forename: C G
authors.initials: CG
authors.lastname: Pantazis
authors.forename: V B
authors.initials: VB
authors.lastname: Mahesh
mesh_terms: D000818:Animals; D044482:Benzeneacetamides; D001667:Binding, Competitive; D002455:Cell Division / Q000187:drug effects*; D002467:Cell Nucleus / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004965:Estrogen Antagonists / Q000494:pharmacology; D005260:Female; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000737:chemistry; D066298:In Vitro Techniques; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010881:Piperidones / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000187:drug effects; D011980:Receptors, Progesterone / Q000187:drug effects; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D044482:Benzeneacetamides; D004965:Estrogen Antagonists; D006131:Growth Inhibitors; D010881:Piperidones; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C052091:antineoplaston A10