Abstract Title:

Inhibition of estrogen stimulated mitogenesis by 3-phenylacetylamino-2,6-piperidinedione and its para-hydroxy analog.

Abstract Source:

J Steroid Biochem Mol Biol. 1993 Oct ;46(4):451-62. PMID: 8217876

Abstract Author(s):

J A Copland, L B Hendry, C K Chu, J C Wood, R W Wrenn, C G Pantazis, V B Mahesh

Article Affiliation:

Department of Physiology, Medical College of Georgia, Augusta 30912-3000.


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.

Study Type : In Vitro Study
Additional Links
Pharmacological Actions : Antiproliferative : CK(6801) : AC(5032)

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