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

John A III Copland, Lawrence B. Hendry, Chung K. Chu, Joseph C. Wood, Robert W. Wrenn, Cooley G. Pantazis, Virendra B. Mahesh

Research output: Contribution to journalArticle

13 Citations (Scopus)

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 × 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 × 10-6 M which was comparable to that of the antiestrogen, tamoxifen (IC50 1 × 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.

Original languageEnglish (US)
Pages (from-to)451-462
Number of pages12
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume46
Issue number4
DOIs
StatePublished - 1993
Externally publishedYes

Fingerprint

antineoplaston A10
Protein Kinases
Estradiol
Estrogens
Toxicity
Analog computers
Estrogen Receptor Modulators
Cell proliferation
Cell growth
Progesterone Receptors
Tamoxifen
Estrogen Receptors
Antineoplastic Agents
Inhibitory Concentration 50
Tumors
Hydrolysis
MCF-7 Cells
Cells
glutarimide
Growth

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology

Cite this

Inhibition of estrogen stimulated mitogenesis by 3-phenylacetylamino-2,6-piperidinedione and its Para-hydroxy analog. / Copland, John A III; Hendry, Lawrence B.; Chu, Chung K.; Wood, Joseph C.; Wrenn, Robert W.; Pantazis, Cooley G.; Mahesh, Virendra B.

In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 46, No. 4, 1993, p. 451-462.

Research output: Contribution to journalArticle

Copland, John A III ; Hendry, Lawrence B. ; Chu, Chung K. ; Wood, Joseph C. ; Wrenn, Robert W. ; Pantazis, Cooley G. ; Mahesh, Virendra B. / Inhibition of estrogen stimulated mitogenesis by 3-phenylacetylamino-2,6-piperidinedione and its Para-hydroxy analog. In: Journal of Steroid Biochemistry and Molecular Biology. 1993 ; Vol. 46, No. 4. pp. 451-462.
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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 × 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 × 10-6 M which was comparable to that of the antiestrogen, tamoxifen (IC50 1 × 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.",
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