On the role of topoisomerase I in mediating the cytotoxicity of 9-aminoacridine-based anticancer agents

Marina Gálvez-Peralta, Jennifer S McDonald, Karen S. Flatten, Scott H Kaufmann, Hiroshi Hiasa, Chenguo Xing, David M. Ferguson

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The cytotoxicity and mechanism of action of a series of substituted 9-aminoacridines is evaluated using topoisomerase I and cancer cell growth inhibition assays. In previous work, compounds of this type were shown to catalytically inhibit topoisomerase II, leading to a G1-S phase arrest of the cell cycle and apoptosis in pancreatic cancer cells in vitro and in vivo. The present study expands the potential utility of these compounds in the development of cancer therapeutics by showing that these compounds inhibit proliferation of cell lines derived from the nine most common human cancers. Further results show that at least one of the compounds effectively stabilizes topoisomerase I-DNA adduct formation in intact cells. RNA interference experiments, however, indicate that this interaction does not contribute to the drug-induced killing of cancer cells indicating the compounds may be non-lethal poisons of topoisomerase I.

Original languageEnglish (US)
Pages (from-to)4459-4462
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume19
Issue number15
DOIs
StatePublished - Aug 1 2009

Fingerprint

Aminacrine
Type I DNA Topoisomerase
Cytotoxicity
Antineoplastic Agents
Cells
Neoplasms
Type II DNA Topoisomerase
DNA Adducts
Poisons
G1 Phase
Cell growth
RNA Interference
Cell Cycle Checkpoints
Pancreatic Neoplasms
S Phase
Assays
RNA
Apoptosis
Cell Line
Growth

Keywords

  • Acridine
  • Anticancer agents
  • Catalytic inhibitor
  • Cleavable complex
  • Cytotoxicity
  • DNA
  • Doxorubicin
  • Etoposide
  • Mechanism of action
  • siRNA
  • Topoisomerase

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

On the role of topoisomerase I in mediating the cytotoxicity of 9-aminoacridine-based anticancer agents. / Gálvez-Peralta, Marina; McDonald, Jennifer S; Flatten, Karen S.; Kaufmann, Scott H; Hiasa, Hiroshi; Xing, Chenguo; Ferguson, David M.

In: Bioorganic and Medicinal Chemistry Letters, Vol. 19, No. 15, 01.08.2009, p. 4459-4462.

Research output: Contribution to journalArticle

Gálvez-Peralta, Marina ; McDonald, Jennifer S ; Flatten, Karen S. ; Kaufmann, Scott H ; Hiasa, Hiroshi ; Xing, Chenguo ; Ferguson, David M. / On the role of topoisomerase I in mediating the cytotoxicity of 9-aminoacridine-based anticancer agents. In: Bioorganic and Medicinal Chemistry Letters. 2009 ; Vol. 19, No. 15. pp. 4459-4462.
@article{361cb3280cd344b09346bebad25c64c9,
title = "On the role of topoisomerase I in mediating the cytotoxicity of 9-aminoacridine-based anticancer agents",
abstract = "The cytotoxicity and mechanism of action of a series of substituted 9-aminoacridines is evaluated using topoisomerase I and cancer cell growth inhibition assays. In previous work, compounds of this type were shown to catalytically inhibit topoisomerase II, leading to a G1-S phase arrest of the cell cycle and apoptosis in pancreatic cancer cells in vitro and in vivo. The present study expands the potential utility of these compounds in the development of cancer therapeutics by showing that these compounds inhibit proliferation of cell lines derived from the nine most common human cancers. Further results show that at least one of the compounds effectively stabilizes topoisomerase I-DNA adduct formation in intact cells. RNA interference experiments, however, indicate that this interaction does not contribute to the drug-induced killing of cancer cells indicating the compounds may be non-lethal poisons of topoisomerase I.",
keywords = "Acridine, Anticancer agents, Catalytic inhibitor, Cleavable complex, Cytotoxicity, DNA, Doxorubicin, Etoposide, Mechanism of action, siRNA, Topoisomerase",
author = "Marina G{\'a}lvez-Peralta and McDonald, {Jennifer S} and Flatten, {Karen S.} and Kaufmann, {Scott H} and Hiroshi Hiasa and Chenguo Xing and Ferguson, {David M.}",
year = "2009",
month = "8",
day = "1",
doi = "10.1016/j.bmcl.2009.05.037",
language = "English (US)",
volume = "19",
pages = "4459--4462",
journal = "Bioorganic and Medicinal Chemistry Letters",
issn = "0960-894X",
publisher = "Elsevier Limited",
number = "15",

}

TY - JOUR

T1 - On the role of topoisomerase I in mediating the cytotoxicity of 9-aminoacridine-based anticancer agents

AU - Gálvez-Peralta, Marina

AU - McDonald, Jennifer S

AU - Flatten, Karen S.

AU - Kaufmann, Scott H

AU - Hiasa, Hiroshi

AU - Xing, Chenguo

AU - Ferguson, David M.

PY - 2009/8/1

Y1 - 2009/8/1

N2 - The cytotoxicity and mechanism of action of a series of substituted 9-aminoacridines is evaluated using topoisomerase I and cancer cell growth inhibition assays. In previous work, compounds of this type were shown to catalytically inhibit topoisomerase II, leading to a G1-S phase arrest of the cell cycle and apoptosis in pancreatic cancer cells in vitro and in vivo. The present study expands the potential utility of these compounds in the development of cancer therapeutics by showing that these compounds inhibit proliferation of cell lines derived from the nine most common human cancers. Further results show that at least one of the compounds effectively stabilizes topoisomerase I-DNA adduct formation in intact cells. RNA interference experiments, however, indicate that this interaction does not contribute to the drug-induced killing of cancer cells indicating the compounds may be non-lethal poisons of topoisomerase I.

AB - The cytotoxicity and mechanism of action of a series of substituted 9-aminoacridines is evaluated using topoisomerase I and cancer cell growth inhibition assays. In previous work, compounds of this type were shown to catalytically inhibit topoisomerase II, leading to a G1-S phase arrest of the cell cycle and apoptosis in pancreatic cancer cells in vitro and in vivo. The present study expands the potential utility of these compounds in the development of cancer therapeutics by showing that these compounds inhibit proliferation of cell lines derived from the nine most common human cancers. Further results show that at least one of the compounds effectively stabilizes topoisomerase I-DNA adduct formation in intact cells. RNA interference experiments, however, indicate that this interaction does not contribute to the drug-induced killing of cancer cells indicating the compounds may be non-lethal poisons of topoisomerase I.

KW - Acridine

KW - Anticancer agents

KW - Catalytic inhibitor

KW - Cleavable complex

KW - Cytotoxicity

KW - DNA

KW - Doxorubicin

KW - Etoposide

KW - Mechanism of action

KW - siRNA

KW - Topoisomerase

UR - http://www.scopus.com/inward/record.url?scp=67649996706&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67649996706&partnerID=8YFLogxK

U2 - 10.1016/j.bmcl.2009.05.037

DO - 10.1016/j.bmcl.2009.05.037

M3 - Article

C2 - 19501511

AN - SCOPUS:67649996706

VL - 19

SP - 4459

EP - 4462

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

SN - 0960-894X

IS - 15

ER -