CK0403, a 9-aminoacridine, is a potent anti-cancer agent in human breast cancer cells
Journal
Molecular Medicine Reports
Journal Volume
13
Journal Issue
1
Pages
933-938
Date Issued
2016
Author(s)
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.
SDGs
Other Subjects
2 [[4 [4 (acridin 9 ylamino)phenylthio]phenyl](2 hydroxyethyl)amino]ethan 1 ol; 3 [[4 [4 (acridin 9 ylamino)phenylthio]phenyl](3 hydroxypropyl)amino]propan 1 ol; aminoacridine derivative; amsacrine; antineoplastic agent; autophagy protein 5; camptothecin; doxorubicin; epidermal growth factor receptor 2; estrogen receptor; progesterone receptor; sulforhodamine B; trastuzumab; unclassified drug; 3-((4-(4-(acridin-9-ylamino)phenylthio)phenyl)(3-hydroxypropyl)amino)propan-1-ol; acridine derivative; ATG5 protein, human; autophagy related protein 5; epidermal growth factor receptor 2; microtubule associated protein; sulfide; apoptosis; Article; autophagy; breast cancer; breast cancer cell line; cancer inhibition; cell cycle G1 phase; cell cycle S phase; cell survival; cytotoxicity; human; human cell; LC50; M phase cell cycle checkpoint; MCF 7 cell line; oxidative stress; protein cleavage; signal transduction; biosynthesis; Breast Neoplasms; cell proliferation; drug effects; female; gene expression regulation; genetics; MCF-7 cell line; pathology; Acridines; Apoptosis; Autophagy-Related Protein 5; Breast Neoplasms; Cell Proliferation; Female; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Microtubule-Associated Proteins; Receptor, ErbB-2; Sulfides
Publisher
Spandidos Publications
Type
journal article