title: Synergistically Anti-metastatic Effect of 5-Flourouracil on Colorectal Cancer Cells via Calcium-mediated Focal Adhesion Kinase Proteolysis.
abstract: To investigate the possibility of enhancing an anti-metastatic effect of 5-fluorouracil (5-FU) on colorectal cancer (CRC) cells by combining it with continuous calcium supplementation.
  
  
  
  Optimal doses of 5-FU with/without lactate salt (CaLa) were determined via clonogenicity and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays using human CRC cells cultured on normal or low-attachment plates. Invasion and migration assays confirmed the enhanced anti-metastatic effect of combining 5-FU and CaLa. Western blot analysis for elements of the focal adhesion kinase (FAK) signaling cascade and epithelial-mesenchymal transition (EMT) markers was used to investigate the underlying mechanism.
  
  
  
  5-FU (2.5 μM) had no antitumor activity against unanchored CRC cells, while it significantly suppressed anchorage-dependent cell proliferation. In contrast, treatment with CaLa (2.5 mM), alone and in combination with 5-FU, exerted antitumor activity against both anchored and unanchored CRC cells via calcium-mediated FAK proteolysis and inhibition of EMT markers, such as vimentin and SNAIL.
  
  
  
  Calcium supplementation represents a method of enhancing the potency of existing antitumor agents such as 5-FU, augmenting their clinical effectiveness.
authors.affiliation: Gachon Institute of Pharmaceutical Science, Gachon University, Incheon, Republic of Korea.
authors.forename: Minhee
authors.initials: M
authors.lastname: Park
authors.affiliation: Gachon Institute of Pharmaceutical Science, Gachon University, Incheon, Republic of Korea.
authors.forename: Pasupathi
authors.initials: P
authors.lastname: Sundaramoorthy
authors.affiliation: Gachon Institute of Pharmaceutical Science, Gachon University, Incheon, Republic of Korea.
authors.forename: Jae Jun
authors.initials: JJ
authors.lastname: Sim
authors.affiliation: Oncometplus Pharmaceuticals Co., R&D division, Incheon, Republic of Korea hwanmook@gachon.ac.kr alvirus@naver.com.
authors.forename: Keun-Yeong
authors.initials: KY
authors.lastname: Jeong
authors.affiliation: Gachon Institute of Pharmaceutical Science, Gachon University, Incheon, Republic of Korea hwanmook@gachon.ac.kr alvirus@naver.com.
authors.forename: Hwan Mook
authors.initials: HM
authors.lastname: Kim
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D017610:Calcium Compounds / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D005472:Fluorouracil / Q000494:pharmacology*; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D007773:Lactates / Q000494:pharmacology*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D059748:Proteolysis; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D014408:Biomarkers, Tumor; D017610:Calcium Compounds; D007773:Lactates; C110051:calcium lactate; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D005472:Fluorouracil
keywords: 5-FU; Colorectal cancer; combination treatment; epithelial–mesenchymal transition; focal adhesion kinase; lactate calcium salt; metastasis