title: Antitumor Effect of KX-01 through Inhibiting Src Family Kinases and Mitosis.
abstract: OBJECTIVE
  KX-01 is a novel dual inhibitor of Src and tubulin. Unlike previous Src inhibitors that failed to show clinical benefit during treatment of breast cancer, KX-01 can potentially overcome the therapeutic limitations of current Src inhibitors through inhibition of both Src and tubulin. The present study further evaluates the activity and mechanism of KX-01in vitroandin vivo.
  
  
  METHODS
  The antitumor effect of KX-01 in triple negative breast cancer (TNBC) cell lines was determined by MTT assay. Wound healing and immunofluorescence assays were performed to evaluate the action mechanisms of KX-01. Changes in the cell cycle and molecular changes induced by KX-01 were also evaluated. A MDA-MB-231 mouse xenograft model was used to demonstrate thein vivoeffects.
  
  
  RESULTS
  KX-01 effectively inhibited the growth of breast cancer cell lines. The expression of phospho-Src and proliferative-signaling molecules were down-regulated in KX-01-sensitive TNBC cell lines. In addition, migration inhibition was observed by wound healing assay. KX-01-induced G2/M cell cycle arrest and increased the aneuploid cell population in KX-01-sensitive cell lines. Multi-nucleated cells were significantly increased after KX-01 treatment. Furthermore, KX-01 effectively delayed tumor growth in a MDA-MB-231 mouse xenograft model.
  
  
  CONCLUSIONS
  KX-01 effectively inhibited cell growth and migration of TNBC cells. Moreover, this study demonstrated that KX-01 showed antitumor effects through the inhibition of Src signaling and the induction of mitotic catastrophe. The antitumor effects of KX-01 were also demonstratedin vivousing a mouse xenograft model.
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.
authors.forename: Seongyeong
authors.initials: S
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.|Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.
authors.forename: Ahrum
authors.initials: A
authors.lastname: Min
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.|Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Kyung-Hun
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.|Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Yaewon
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.|Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Tae-Yong
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.
authors.forename: Jee Min
authors.initials: JM
authors.lastname: Lim
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.
authors.forename: So Jung
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.
authors.forename: Hyun-Jin
authors.initials: HJ
authors.lastname: Nam
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.
authors.forename: Jung Eun
authors.initials: JE
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Song
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.|Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Han
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.|Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Do-Youn
authors.initials: DY
authors.lastname: Oh
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.|Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
authors.forename: Jee Hyun
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.|Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Tae-You
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Kinex Pharmaceutical Corporation, New York State Center of Excellence in Bioinformartics and Life Sciences, NY, USA.
authors.forename: David
authors.initials: D
authors.lastname: Hangauer
authors.affiliation: Kinex Pharmaceutical Corporation, New York State Center of Excellence in Bioinformartics and Life Sciences, NY, USA.
authors.forename: Johnson Yiu-Nam
authors.initials: JY
authors.lastname: Lau
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.
authors.forename: Kyongok
authors.initials: K
authors.lastname: Im
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Dong Soon
authors.initials: DS
authors.lastname: Lee
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.|Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
authors.affiliation: Cancer Research Institute, Seoul National University, Seoul, Korea.|Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea.|Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Seock-Ah
authors.initials: SA
authors.lastname: Im
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000782:Aneuploidy; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D008938:Mitosis / Q000187:drug effects*; D009025:Morpholines; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000081:Acetamides; D000970:Antineoplastic Agents; D009025:Morpholines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C000713668:tirbanibulin; D019061:src-Family Kinases
keywords: KX-01; Microtubules; Mitotic catastrophe; Src kinase inhibitor; Triple negative breast neoplasms