title: A natural piper-amide-like compound NED-135 exhibits a potent inhibitory effect on the invasive breast cancer cells.
abstract: 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.
authors.affiliation: College of Pharmacy, Duksung Women's University, Samyang-ro, Dobong-gu, Seoul 132-714, Republic of Korea.
authors.forename: Eun-Sook
authors.initials: ES
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea.
authors.forename: Hyunkyung
authors.initials: H
authors.lastname: Cho
authors.affiliation: College of Pharmacy, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea.
authors.forename: Chaemin
authors.initials: C
authors.lastname: Lim
authors.affiliation: College of Pharmacy, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea.
authors.forename: Joo-Youn
authors.initials: JY
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Duksung Women's University, Samyang-ro, Dobong-gu, Seoul 132-714, Republic of Korea.
authors.forename: Da-In
authors.initials: DI
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Seoul National University, Gwanak-ro, Gwanak-gu, Seoul 151-742, Republic of Korea. Electronic address: pennkim@snu.ac.kr.
authors.forename: Sanghee
authors.initials: S
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Duksung Women's University, Samyang-ro, Dobong-gu, Seoul 132-714, Republic of Korea. Electronic address: armoon@duksung.ac.kr.
authors.forename: Aree
authors.initials: A
authors.lastname: Moon
mesh_terms: D000178:Acrylamides / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010627:Phenethylamines / Q000737:chemistry / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D049349:Receptors, Lysosphingolipid / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*
chemical_list: C000601831:3-(3,4-dimethoxyphenyl)-N-(4-hydroxyphenethyl)acrylamide; D000178:Acrylamides; D008246:Lysophospholipids; D010627:Phenethylamines; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D011494:Protein Kinases; D013110:Sphingosine
keywords: Cell invasion; MMP-9; NED-135