Mode of action of the antitumor compound bruceantin, an inhibitor of protein synthesis

L. L. Liao, S. M. Kupchan, Susan Band Horwitz

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

The plant derivative bruceantin, an antitumor compound, irreversibly inhibits protein synthesis in HeLa cells, rabbit reticulocytes, and reticulocyte lysates. Bruceantin has a secondary effect on DNA synthesis, but little effect on the synthesis of RNA. After addition of bruceantin to a reticulocyte lysate, there is a delay of 2-3 min before inhibition of protein synthesis is observed. At a concentration of 0.1 mM, bruceantin induces sequential breakdown of polyribosomes to monosomes; concomitantly, nascent peptides are released from the ribosomes as completed chains of globin. These observations suggest that the principal inhibitory effect of the drug is on initiation of protein synthesis. Higher concentrations of bruceantin (1 mM) inhibit elongation of peptide chains; under these conditions, breakdown of polyribosomes is incomplete. Bruceantin does not prevent binding of radioactive poly U, poly C, or Escherichia coli tRNA to reticulocyte ribosomes, nor does it alter the conformation of ribosomal subunits. The structure activity relationships of bruceantin and its analogues, as determined by their effects on protein synthesis in HeLa cells, rabbit reticulocyte cells, and reticulocyte lysates, correlate well with their activity as antitumor agents in experimental animals. These studies demonstrate that the side chain of bruceantin is important for transport of the drug into intact cells and that partial unsaturation in ring A is required for inhibition of protein synthesis.

Original languageEnglish (US)
Pages (from-to)167-176
Number of pages10
JournalMolecular Pharmacology
Volume12
Issue number1
StatePublished - 1976

Fingerprint

Protein Synthesis Inhibitors
Reticulocytes
Polyribosomes
Proteins
Ribosomes
HeLa Cells
Rabbits
Poly C
Ribosome Subunits
Peptides
Globins
bruceantin
Structure-Activity Relationship
Transfer RNA
Pharmaceutical Preparations
Antineoplastic Agents
RNA
Escherichia coli
DNA

ASJC Scopus subject areas

  • Pharmacology

Cite this

Mode of action of the antitumor compound bruceantin, an inhibitor of protein synthesis. / Liao, L. L.; Kupchan, S. M.; Band Horwitz, Susan.

In: Molecular Pharmacology, Vol. 12, No. 1, 1976, p. 167-176.

Research output: Contribution to journalArticle

@article{70b170ff323749e7a5a648a0a1fe0d70,
title = "Mode of action of the antitumor compound bruceantin, an inhibitor of protein synthesis",
abstract = "The plant derivative bruceantin, an antitumor compound, irreversibly inhibits protein synthesis in HeLa cells, rabbit reticulocytes, and reticulocyte lysates. Bruceantin has a secondary effect on DNA synthesis, but little effect on the synthesis of RNA. After addition of bruceantin to a reticulocyte lysate, there is a delay of 2-3 min before inhibition of protein synthesis is observed. At a concentration of 0.1 mM, bruceantin induces sequential breakdown of polyribosomes to monosomes; concomitantly, nascent peptides are released from the ribosomes as completed chains of globin. These observations suggest that the principal inhibitory effect of the drug is on initiation of protein synthesis. Higher concentrations of bruceantin (1 mM) inhibit elongation of peptide chains; under these conditions, breakdown of polyribosomes is incomplete. Bruceantin does not prevent binding of radioactive poly U, poly C, or Escherichia coli tRNA to reticulocyte ribosomes, nor does it alter the conformation of ribosomal subunits. The structure activity relationships of bruceantin and its analogues, as determined by their effects on protein synthesis in HeLa cells, rabbit reticulocyte cells, and reticulocyte lysates, correlate well with their activity as antitumor agents in experimental animals. These studies demonstrate that the side chain of bruceantin is important for transport of the drug into intact cells and that partial unsaturation in ring A is required for inhibition of protein synthesis.",
author = "Liao, {L. L.} and Kupchan, {S. M.} and {Band Horwitz}, Susan",
year = "1976",
language = "English (US)",
volume = "12",
pages = "167--176",
journal = "Molecular Pharmacology",
issn = "0026-895X",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
number = "1",

}

TY - JOUR

T1 - Mode of action of the antitumor compound bruceantin, an inhibitor of protein synthesis

AU - Liao, L. L.

AU - Kupchan, S. M.

AU - Band Horwitz, Susan

PY - 1976

Y1 - 1976

N2 - The plant derivative bruceantin, an antitumor compound, irreversibly inhibits protein synthesis in HeLa cells, rabbit reticulocytes, and reticulocyte lysates. Bruceantin has a secondary effect on DNA synthesis, but little effect on the synthesis of RNA. After addition of bruceantin to a reticulocyte lysate, there is a delay of 2-3 min before inhibition of protein synthesis is observed. At a concentration of 0.1 mM, bruceantin induces sequential breakdown of polyribosomes to monosomes; concomitantly, nascent peptides are released from the ribosomes as completed chains of globin. These observations suggest that the principal inhibitory effect of the drug is on initiation of protein synthesis. Higher concentrations of bruceantin (1 mM) inhibit elongation of peptide chains; under these conditions, breakdown of polyribosomes is incomplete. Bruceantin does not prevent binding of radioactive poly U, poly C, or Escherichia coli tRNA to reticulocyte ribosomes, nor does it alter the conformation of ribosomal subunits. The structure activity relationships of bruceantin and its analogues, as determined by their effects on protein synthesis in HeLa cells, rabbit reticulocyte cells, and reticulocyte lysates, correlate well with their activity as antitumor agents in experimental animals. These studies demonstrate that the side chain of bruceantin is important for transport of the drug into intact cells and that partial unsaturation in ring A is required for inhibition of protein synthesis.

AB - The plant derivative bruceantin, an antitumor compound, irreversibly inhibits protein synthesis in HeLa cells, rabbit reticulocytes, and reticulocyte lysates. Bruceantin has a secondary effect on DNA synthesis, but little effect on the synthesis of RNA. After addition of bruceantin to a reticulocyte lysate, there is a delay of 2-3 min before inhibition of protein synthesis is observed. At a concentration of 0.1 mM, bruceantin induces sequential breakdown of polyribosomes to monosomes; concomitantly, nascent peptides are released from the ribosomes as completed chains of globin. These observations suggest that the principal inhibitory effect of the drug is on initiation of protein synthesis. Higher concentrations of bruceantin (1 mM) inhibit elongation of peptide chains; under these conditions, breakdown of polyribosomes is incomplete. Bruceantin does not prevent binding of radioactive poly U, poly C, or Escherichia coli tRNA to reticulocyte ribosomes, nor does it alter the conformation of ribosomal subunits. The structure activity relationships of bruceantin and its analogues, as determined by their effects on protein synthesis in HeLa cells, rabbit reticulocyte cells, and reticulocyte lysates, correlate well with their activity as antitumor agents in experimental animals. These studies demonstrate that the side chain of bruceantin is important for transport of the drug into intact cells and that partial unsaturation in ring A is required for inhibition of protein synthesis.

UR - http://www.scopus.com/inward/record.url?scp=0017281125&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0017281125&partnerID=8YFLogxK

M3 - Article

C2 - 1256442

AN - SCOPUS:0017281125

VL - 12

SP - 167

EP - 176

JO - Molecular Pharmacology

JF - Molecular Pharmacology

SN - 0026-895X

IS - 1

ER -