CK0403, a 9-aminoacridine, is a potent anti-cancer agent in human breast cancer cells

Yuan Wan Sun, Kuen Yuan Chen, Chul Hoon Kwon, Kun Ming Chen

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

3-({4-[4-(Acridin-9-ylamino)phenylthio]phenyl}(3-hydroxypropyl)amino)propan-1-ol (CK0403) is a sulfur-containing 9-anilinoacridine analogue of amsacrine and was found to be more potent than its analogue 2-({4-[4-(acridin-9-ylamino)phenylthio]phenyl}(2-hydroxyethyl)amino)ethan-1-ol (CK0402) and amsacrine in the inhibition of the topoisomerase II-catalyzed decatenation reaction. A previous study by our group reported that CK0402 was effective against numerous breast cancer cell lines, and the combination of CK0402 with herceptin enhanced its activity in HER2(+) SKBR-3 cells. In order to identify novel chemotherapeutic agents with enhanced potency, the present study explored the potential of CK0403 in the treatment of breast cancer. First, the growth inhibitory activity of CK0403 in the breast cancer cell lines MCF-7, MDA-MB-231, BT474 and SKBR-3, as well as in the non-cancerous MCF-10A cell line, was examined using a sulforhodamine B assay. The results showed that CK0403 exerted more potent growth inhibitory activity than CK0402 in all of the breast cancer cell lines except MCF-7. SKBR-3 and MDA-MB-231 were the most sensitive cell lines tested, and the combination of CK0403 with herceptin in HER2(+) SKBR-3 cells enhanced the growth inhibitory activity of CK0403. Analysis of cell cycle alterations induced by CK0403 in SKBR-3 cells revealed that, similarly to CK0402, CK0403 induced G2/M-phase arrest with a decreased S- and G0/G1-phase ratio. In addition, it was shown that CK0403 induced apoptosis more effectively than CK0402 in SKBR-3 cells. Further analysis of autophagy protein 5 (Atg5) indicated that CK0403 induced more cleaved Atg5 than CK0402 and other chemotherapeutic agents tested. Of note, although still relatively potent, CK0403 exhibited reduced growth inhibitory activity under hypoxic conditions, which can induce autophagy. Collectively, the present results supported that CK0403 is highly potent and more effective than CK0402 against estrogen receptor-negative and HER2-overexpressing breast cancer cell lines, suggesting its future application for chemotherapy in breast cancer.

Original languageEnglish (US)
Pages (from-to)933-938
Number of pages6
JournalMolecular medicine reports
Volume13
Issue number1
DOIs
StatePublished - Jan 2016

Fingerprint

Aminacrine
Cells
Breast Neoplasms
Neoplasms
Cell Line
Amsacrine
Growth
lissamine rhodamine B
3-((4-(4-(acridin-9-ylamino)phenylthio)phenyl)(3-hydroxypropyl)amino)propan-1-ol
2-((4-(4-(acridin-9-ylamino)phenylthio)phenyl)(2-hydroxyethyl)amino)ethan-1-ol
Cell Cycle Resting Phase
Type II DNA Topoisomerase
Chemotherapy
G2 Phase
Autophagy
G1 Phase

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Oncology
  • Cancer Research

Cite this

@article{91f2df0dc1e34c6fa6dd9fe1eb2b445c,
title = "CK0403, a 9-aminoacridine, is a potent anti-cancer agent in human breast cancer cells",
abstract = "3-({4-[4-(Acridin-9-ylamino)phenylthio]phenyl}(3-hydroxypropyl)amino)propan-1-ol (CK0403) is a sulfur-containing 9-anilinoacridine analogue of amsacrine and was found to be more potent than its analogue 2-({4-[4-(acridin-9-ylamino)phenylthio]phenyl}(2-hydroxyethyl)amino)ethan-1-ol (CK0402) and amsacrine in the inhibition of the topoisomerase II-catalyzed decatenation reaction. A previous study by our group reported that CK0402 was effective against numerous breast cancer cell lines, and the combination of CK0402 with herceptin enhanced its activity in HER2(+) SKBR-3 cells. In order to identify novel chemotherapeutic agents with enhanced potency, the present study explored the potential of CK0403 in the treatment of breast cancer. First, the growth inhibitory activity of CK0403 in the breast cancer cell lines MCF-7, MDA-MB-231, BT474 and SKBR-3, as well as in the non-cancerous MCF-10A cell line, was examined using a sulforhodamine B assay. The results showed that CK0403 exerted more potent growth inhibitory activity than CK0402 in all of the breast cancer cell lines except MCF-7. SKBR-3 and MDA-MB-231 were the most sensitive cell lines tested, and the combination of CK0403 with herceptin in HER2(+) SKBR-3 cells enhanced the growth inhibitory activity of CK0403. Analysis of cell cycle alterations induced by CK0403 in SKBR-3 cells revealed that, similarly to CK0402, CK0403 induced G2/M-phase arrest with a decreased S- and G0/G1-phase ratio. In addition, it was shown that CK0403 induced apoptosis more effectively than CK0402 in SKBR-3 cells. Further analysis of autophagy protein 5 (Atg5) indicated that CK0403 induced more cleaved Atg5 than CK0402 and other chemotherapeutic agents tested. Of note, although still relatively potent, CK0403 exhibited reduced growth inhibitory activity under hypoxic conditions, which can induce autophagy. Collectively, the present results supported that CK0403 is highly potent and more effective than CK0402 against estrogen receptor-negative and HER2-overexpressing breast cancer cell lines, suggesting its future application for chemotherapy in breast cancer.",
author = "Sun, {Yuan Wan} and Chen, {Kuen Yuan} and Kwon, {Chul Hoon} and Chen, {Kun Ming}",
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CK0403, a 9-aminoacridine, is a potent anti-cancer agent in human breast cancer cells. / Sun, Yuan Wan; Chen, Kuen Yuan; Kwon, Chul Hoon; Chen, Kun Ming.

In: Molecular medicine reports, Vol. 13, No. 1, 01.2016, p. 933-938.

Research output: Contribution to journalArticle

TY - JOUR

T1 - CK0403, a 9-aminoacridine, is a potent anti-cancer agent in human breast cancer cells

AU - Sun, Yuan Wan

AU - Chen, Kuen Yuan

AU - Kwon, Chul Hoon

AU - Chen, Kun Ming

PY - 2016/1

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AB - 3-({4-[4-(Acridin-9-ylamino)phenylthio]phenyl}(3-hydroxypropyl)amino)propan-1-ol (CK0403) is a sulfur-containing 9-anilinoacridine analogue of amsacrine and was found to be more potent than its analogue 2-({4-[4-(acridin-9-ylamino)phenylthio]phenyl}(2-hydroxyethyl)amino)ethan-1-ol (CK0402) and amsacrine in the inhibition of the topoisomerase II-catalyzed decatenation reaction. A previous study by our group reported that CK0402 was effective against numerous breast cancer cell lines, and the combination of CK0402 with herceptin enhanced its activity in HER2(+) SKBR-3 cells. In order to identify novel chemotherapeutic agents with enhanced potency, the present study explored the potential of CK0403 in the treatment of breast cancer. First, the growth inhibitory activity of CK0403 in the breast cancer cell lines MCF-7, MDA-MB-231, BT474 and SKBR-3, as well as in the non-cancerous MCF-10A cell line, was examined using a sulforhodamine B assay. The results showed that CK0403 exerted more potent growth inhibitory activity than CK0402 in all of the breast cancer cell lines except MCF-7. SKBR-3 and MDA-MB-231 were the most sensitive cell lines tested, and the combination of CK0403 with herceptin in HER2(+) SKBR-3 cells enhanced the growth inhibitory activity of CK0403. Analysis of cell cycle alterations induced by CK0403 in SKBR-3 cells revealed that, similarly to CK0402, CK0403 induced G2/M-phase arrest with a decreased S- and G0/G1-phase ratio. In addition, it was shown that CK0403 induced apoptosis more effectively than CK0402 in SKBR-3 cells. Further analysis of autophagy protein 5 (Atg5) indicated that CK0403 induced more cleaved Atg5 than CK0402 and other chemotherapeutic agents tested. Of note, although still relatively potent, CK0403 exhibited reduced growth inhibitory activity under hypoxic conditions, which can induce autophagy. Collectively, the present results supported that CK0403 is highly potent and more effective than CK0402 against estrogen receptor-negative and HER2-overexpressing breast cancer cell lines, suggesting its future application for chemotherapy in breast cancer.

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