Novel acridine-based agents with topoisomerase II inhibitor activity suppress mesothelioma cell proliferation and induce apoptosis

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

Human topoisomerase II (hTopoII) inhibitors are important chemotherapeutic agents in many different settings including treatment of malignant mesothelioma. Topoisomerase poisons, such as etoposide and doxorubicin, function by trapping the DNA-enzyme covalent complex producing DNA strand breaks which can ultimately lead to cancer cell death, as well as development of secondary malignancies. While these compounds have been used successfully in treating a wide variety of cancers, their use against mesothelioma has been limited. This study evaluates the antiproliferative activity of series of acridine-based catalytic inhibitors of hTopoII using four mesothelioma cell lines (H513, H2372, H2461, and H2596). The results indicate these compounds inhibit malignant cell proliferation with EC50 values ranging from 6.9 to 32 μM. Experiments are also performed that show that combination therapies may be used to increase potency. Based on the results of PARP cleavage and Guava Nexin assay, it is concluded that the primary mode of cell death is by apoptosis. The results are consistent with prior work involving pancreatic cancer and hTopoII catalytic inhibitors and suggest substituted acridines may hold promise in treating malignant mesothelioma.

Original languageEnglish (US)
Pages (from-to)1443-1448
Number of pages6
JournalInvestigational New Drugs
Volume30
Issue number4
DOIs
StatePublished - Aug 1 2012

Fingerprint

Topoisomerase II Inhibitors
Acridines
Mesothelioma
Cell Proliferation
Apoptosis
Cell Death
Psidium
Neoplasms
DNA Breaks
Poisons
Etoposide
Pancreatic Neoplasms
Doxorubicin
Cell Line
DNA
Enzymes
Malignant Mesothelioma
Therapeutics

Keywords

  • 9-aminoacridine derivatives
  • Human topoisomerase II
  • Mesothelioma

Cite this

@article{c52ac481b7cc4ad7bc559ca074d7224e,
title = "Novel acridine-based agents with topoisomerase II inhibitor activity suppress mesothelioma cell proliferation and induce apoptosis",
abstract = "Human topoisomerase II (hTopoII) inhibitors are important chemotherapeutic agents in many different settings including treatment of malignant mesothelioma. Topoisomerase poisons, such as etoposide and doxorubicin, function by trapping the DNA-enzyme covalent complex producing DNA strand breaks which can ultimately lead to cancer cell death, as well as development of secondary malignancies. While these compounds have been used successfully in treating a wide variety of cancers, their use against mesothelioma has been limited. This study evaluates the antiproliferative activity of series of acridine-based catalytic inhibitors of hTopoII using four mesothelioma cell lines (H513, H2372, H2461, and H2596). The results indicate these compounds inhibit malignant cell proliferation with EC50 values ranging from 6.9 to 32 μM. Experiments are also performed that show that combination therapies may be used to increase potency. Based on the results of PARP cleavage and Guava Nexin assay, it is concluded that the primary mode of cell death is by apoptosis. The results are consistent with prior work involving pancreatic cancer and hTopoII catalytic inhibitors and suggest substituted acridines may hold promise in treating malignant mesothelioma.",
keywords = "9-aminoacridine derivatives, Human topoisomerase II, Mesothelioma",
author = "Ahmad Raza and Jacobson, {Blake A} and Adam Benoit and Patel, {Manish R} and Joe Jay-Dixon and Hiroshi Hiasa and Ferguson, {David M} and Kratzke, {Robert A}",
year = "2012",
month = "8",
day = "1",
doi = "10.1007/s10637-011-9720-7",
language = "English (US)",
volume = "30",
pages = "1443--1448",
journal = "Investigational New Drugs",
issn = "0167-6997",
publisher = "Kluwer Academic Publishers",
number = "4",

}

TY - JOUR

T1 - Novel acridine-based agents with topoisomerase II inhibitor activity suppress mesothelioma cell proliferation and induce apoptosis

AU - Raza, Ahmad

AU - Jacobson, Blake A

AU - Benoit, Adam

AU - Patel, Manish R

AU - Jay-Dixon, Joe

AU - Hiasa, Hiroshi

AU - Ferguson, David M

AU - Kratzke, Robert A

PY - 2012/8/1

Y1 - 2012/8/1

N2 - Human topoisomerase II (hTopoII) inhibitors are important chemotherapeutic agents in many different settings including treatment of malignant mesothelioma. Topoisomerase poisons, such as etoposide and doxorubicin, function by trapping the DNA-enzyme covalent complex producing DNA strand breaks which can ultimately lead to cancer cell death, as well as development of secondary malignancies. While these compounds have been used successfully in treating a wide variety of cancers, their use against mesothelioma has been limited. This study evaluates the antiproliferative activity of series of acridine-based catalytic inhibitors of hTopoII using four mesothelioma cell lines (H513, H2372, H2461, and H2596). The results indicate these compounds inhibit malignant cell proliferation with EC50 values ranging from 6.9 to 32 μM. Experiments are also performed that show that combination therapies may be used to increase potency. Based on the results of PARP cleavage and Guava Nexin assay, it is concluded that the primary mode of cell death is by apoptosis. The results are consistent with prior work involving pancreatic cancer and hTopoII catalytic inhibitors and suggest substituted acridines may hold promise in treating malignant mesothelioma.

AB - Human topoisomerase II (hTopoII) inhibitors are important chemotherapeutic agents in many different settings including treatment of malignant mesothelioma. Topoisomerase poisons, such as etoposide and doxorubicin, function by trapping the DNA-enzyme covalent complex producing DNA strand breaks which can ultimately lead to cancer cell death, as well as development of secondary malignancies. While these compounds have been used successfully in treating a wide variety of cancers, their use against mesothelioma has been limited. This study evaluates the antiproliferative activity of series of acridine-based catalytic inhibitors of hTopoII using four mesothelioma cell lines (H513, H2372, H2461, and H2596). The results indicate these compounds inhibit malignant cell proliferation with EC50 values ranging from 6.9 to 32 μM. Experiments are also performed that show that combination therapies may be used to increase potency. Based on the results of PARP cleavage and Guava Nexin assay, it is concluded that the primary mode of cell death is by apoptosis. The results are consistent with prior work involving pancreatic cancer and hTopoII catalytic inhibitors and suggest substituted acridines may hold promise in treating malignant mesothelioma.

KW - 9-aminoacridine derivatives

KW - Human topoisomerase II

KW - Mesothelioma

UR - http://www.scopus.com/inward/record.url?scp=84866728317&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84866728317&partnerID=8YFLogxK

U2 - 10.1007/s10637-011-9720-7

DO - 10.1007/s10637-011-9720-7

M3 - Article

C2 - 21789510

AN - SCOPUS:84866728317

VL - 30

SP - 1443

EP - 1448

JO - Investigational New Drugs

JF - Investigational New Drugs

SN - 0167-6997

IS - 4

ER -