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

Abstract

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 G 2 /M-phase arrest with a decreased S-and G 0 /G 1 -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 CK04 02 aga inst est rogen receptor-negative a nd HER2-overexpressing breast cancer cell lines, suggesting its future application for chemotherapy in breast cancer.

A systematic study of Girdin on cell proliferation, migration and angiogenesis in different breast cancer subtypes

“…To the best of our knowledge, the present study demonstrated for the first time the effect of Girdin silencing on different subtypes of breast cancer. Breast cancer has one of the highest incidences in females worldwide, and it is the primary cause of mortality in female patients with cancer (1). Breast cancer has long been a leading cause of mortality in women of both developed and developing countries (13).…”

“…Breast cancer has one of the highest incidences in females worldwide, and it is the primary cause of mortality in female patients with cancer (1). At present, various breast cancer treatment methods have limitations, for example; surgery does not preclude hematopoietic or lymphatic dissemination leading to distant metastasis (2).…”

A new look at 9‐substituted acridines with various biological activities

“…A summary of the most efficient 9-aminoacridines on cancer cell lines is given in Table 1. F I G U R E 2 7 Structure of sulfur-containing 9-amino-acridine derivatives 35a-b (Sun et al, 2016) F I G U R E 2 8 Structure of 9-phenoxyacridine derivative 36 (Bacherikov, 2014) 7 | CONCLUSION 9-Substituted acridines have been the focus of study since the early 20th century, and the need to develop novel derivatives with anticancer, antibacterial, antimalarial, or other biological activities is still as strong as ever. Together with other tricyclic aromatic heterocycles, 9-substituted acridines remain among the most intensely studied agents in this field.…”

“…Sun, Chen, Kwon, and Chen (2016) investigated two new sulfur‐containing 9‐anilinoacridine analogs of amsacrine 35a–b (Figure 27) against various breast cancer cell lines (MCF‐7, MDA‐MB‐231, BT474, and SKBR‐3) and the noncancerous MCF‐10A cell line using a sulforhodamine B assay. The results showed that derivative 35a displayed a more potent level of growth inhibition than derivative 35b in all of the breast cancer cell lines with the exception of MCF‐7.…”

“…The results showed that derivative 35a displayed a more potent level of growth inhibition than derivative 35b in all of the breast cancer cell lines with the exception of MCF‐7. The 9‐anilinoacridine compound 35a was found to possess the strongest anticancer activity against MDA‐MB‐231 cell lines, with an IC 50 value of 0.09 ± 0.02 μM (Sun, Chen, Kwon, & Chen, 2016).…”