A natural piper-amide-like compound NED-135 exhibits a potent inhibitory effect on the invasive breast cancer cells

Invasiveness and metastasis are the primary factors indicating poor prognosis in breast cancer patients. To identify a novel lead compound for the development of therapeutics for the treatment of breast cancer through inhibiting invasion, we screened the natural piper amide-like compounds library that we previously constructed. Among the compounds tested, (E)-3-(3,4-dimethoxyphenyl)-N-(4-hydroxyphenethyl)acrylamide (NED-135) showed potent inhibitory effects on matrix metalloproteinase (MMP)-9 and invasiveness of MCF10A human breast epithelial cells treated with an inflammatory lipid, sphingosine-1-phosphate (S1P). The invasive phenotypes of MDA-MB-231 and Hs578T triple-negative breast cancer cells were significantly inhibited by NED-135. NED-135 efficiently inhibited the S1P-induced MMP-9 expression at the transcriptional level with a comparable degree to FTY720, a known antagonist of S1P. We further showed that NED-135 significantly inhibited activation of S1P-induced signaling molecules, Akt, ERKs, and p38 MAPK. Computational similarity analysis led us to postulate that NED-135 and FTY720 may exert anti-invasive effects on breast cells possibly via different mechanisms. Due to its novel structural and functional features, we suggest that NED-135 can be used as a novel lead compound against breast cancer in an inflammatory microenvironment and highly invasive triple-negative breast cancer.