Abstract
Breast cancer is a common malignancy among women worldwide. Gelatinases such as matrix metallopeptidase 2 (MMP2) and MMP9 play crucial roles in cancer cell migration, invasion, and metastasis. To develop a novel platform compound, we synthesized a flavonoid derivative, (E)-5-((4-oxo-4H-chromen-3-yl)methyleneamino)-1-phenyl-1H-pyrazole-4-carbonitrile (named DK4023) and characterized its inhibitory effects on the motility and MMP2 and MMP9 expression of highly metastatic MDA-MB-231 breast cancer cells. We found that DK4023 inhibited tumor necrosis factor alpha (TNFα)-induced motility and F-actin formation of MDA-MB-231 cells. DK4023 also suppressed the TNFα-induced mRNA expression of MMP9 through the downregulation of the TNFα-extracellular signal-regulated kinase (ERK)/early growth response 1 (EGR-1) signaling axis. These results suggest that DK4023 could serve as a potential platform compound for the development of novel chemopreventive/chemotherapeutic agents against invasive breast cancer.
Highlights
Breast cancer is a common malignancy among women worldwide [1]
matrix metallopeptidase 2 (MMP2) and MMP9 expression is known to be highly upregulated in almost every metastatic cancer cell type [5,6], and elevated MMP9 level is associated with the high potential of metastasis in several human carcinomas, including breast cancer [6,7,8]
We examined the inhibitory effects of DK4023 on TNFα-induced motility and invasive capability of the highly metastatic MDA-MB-231 breast cancer cells
Summary
Breast cancer is a common malignancy among women worldwide [1]. Metastasis, the spread of primary tumor cells to different organs through the blood or lymphatic vessels, is a typical hallmark of all malignant tumors and is responsible for high mortality among patients with cancer. Experimental metastasis studies have shown that the downregulation of MMP9 expression in cancer cells by ribozyme could reduce tumor foci in the lungs of mice [10], consistent with the results observed in Mmp2- [10] or Mmp9-deficient mice [11]. These observations suggest that a therapeutic strategy to manipulate MMP2 or MMP9 expression could be potentially advantageous for the development of anti-metastatic agents. Genistein and daidzein are known to inhibit TNFα-induced migration and invasion of human breast cancer cells by preventing the inhibition of NF-κB [17]. We determined the inhibitory effect of DK4023 on TNFα-induced MMP2 and MMP9 mRNA expression
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