title: Enhanced efficacy of 5-fluorouracil in combination with a dual histone deacetylase and phosphatidylinositide 3-kinase inhibitor (CUDC-907) in colorectal cancer cells.
abstract: OBJECTIVE
  5-Fluorouracil (5-FU) is widely used in the treatment of patients with colorectal cancer (CRC). However, the efficacy of 5-FU as a single agent is limited, with multiple undesired side effects. Therefore, the aim of the current study was to assess the efficacy of CUDC-907 (a dual inhibitor of histone deacetylase and phosphatidylinositide 3-kinase) in combination with 5-FU against CRC cells.
  
  
  METHODS
  Cell viability was determined using AlamarBlue and colony formation assays. Acridine orange/ethidium bromide staining and flow cytometry were used to measure apoptotic and necrotic events, as well as cell cycle progression. Immunoblotting was used to assess acetylation of histone H3 and phosphorylation of AKT.
  
  
  RESULTS
  Our data revealed enhanced toxicity of CUDC-907 against HCT116, RKO, COLO-205, and HT-29 CRC cells when combined with 5-FU. Similarly, the colony formation capability of HCT116 cells was suppressed by the combination treatment. Cells treated with CUDC-907 and 5-FU underwent apoptosis and necrosis, and exhibited increased polyploidy. Furthermore, CRC cells treated with CUDC-907 exhibited a higher degree of histone H3 lysine 9 acetylation (H3K9ac) and reduced AKT phosphorylation (Ser473).
  
  
  CONCLUSIONS
  Our data revealed, for the first time, the enhanced inhibitory effect of CUDC-907 against CRC cells when combined with 5-FU, supporting the application of this combination as a potential therapeutic strategy in CRC treatment.
authors.affiliation: Department of Anatomy, Stem Cell Unit, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia.
authors.forename: Rimi
authors.initials: R
authors.lastname: Hamam
authors.affiliation: Department of Anatomy, Stem Cell Unit, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia.
authors.forename: Dalia
authors.initials: D
authors.lastname: Ali
authors.affiliation: Department of Anatomy, Stem Cell Unit, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia.
authors.forename: Radhakrishnan
authors.initials: R
authors.lastname: Vishnubalaji
authors.affiliation: Department of Anatomy, Stem Cell Unit, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia.
authors.forename: Zaid F
authors.initials: ZF
authors.lastname: Alsaaran
authors.affiliation: Department of Orthodontics, College of Dentistry, King Saud University, Riyadh, Kingdom of Saudi Arabia.
authors.forename: Elna Paul
authors.initials: EP
authors.lastname: Chalisserry
authors.affiliation: Department of Anatomy, Stem Cell Unit, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia.
authors.forename: Musaad
authors.initials: M
authors.lastname: Alfayez
authors.affiliation: Department of Anatomy, Stem Cell Unit, College of Medicine; Prince Naif Health Research Center, King Saud University, Riyadh, Kingdom of Saudi Arabia.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Aldahmash
authors.affiliation: Department of Anatomy, Stem Cell Unit, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia.
authors.forename: Nehad M
authors.initials: NM
authors.lastname: Alajez
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D005472:Fluorouracil / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D019073:HT29 Cells; D006657:Histones / Q000378:metabolism*; D006801:Humans; D009025:Morpholines / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011123:Polyploidy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*
chemical_list: C576940:CUDC-907; D006657:Histones; D009025:Morpholines; D011743:Pyrimidines; D051057:Proto-Oncogene Proteins c-akt; D005472:Fluorouracil