title: Combination of metformin and 5-aminosalicylic acid cooperates to decrease proliferation and induce apoptosis in colorectal cancer cell lines.
abstract: BACKGROUND
  The link between inflammation and cancer has been confirmed by the use of anti-inflammatory therapies in cancer prevention and treatment. 5-aminosalicylic acid (5-ASA) was shown to decrease the growth and survival of colorectal cancer (CRC) cells. Studies also revealed that metformin induced apoptosis in several cancer cell lines.
  
  
  METHODS
  We investigated the combinatory effect of 5-ASA and metformin on HCT-116 and Caco-2 CRC cell lines. Apoptotic markers were determined using western blotting. Expression of pro-inflammatory cytokines was determined by RT-PCR. Inflammatory transcription factors and metastatic markers were measured by ELISA.
  
  
  RESULTS
  Metformin enhanced CRC cell death induced by 5-ASA through significant increase in oxidative stress and activation of apoptotic machinery. Moreover, metformin enhanced the anti-inflammatory effect of 5-ASA by decreasing the gene expression of IL-1β, IL-6, COX-2 and TNF-α and its receptors; TNF-R1 and TNF-R2. Significant inhibition of activation of NF-κB and STAT3 transcription factors, and their downstream targets was also observed. Metformin also enhanced the inhibitory effect of 5-ASA on MMP-2 and MMP-9 enzyme activity, indicating a decrease in metastasis.
  
  
  CONCLUSIONS
  The current data demonstrate that metformin potentiates the antitumor effect of 5-ASA on CRC cells suggesting their potential use as an adjuvant treatment in CRC.
authors.affiliation: Pharmacology and Toxicolgy Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt. mona.magdy@pharma.cu.edu.eg.
authors.forename: Mona M
authors.initials: MM
authors.lastname: Saber
authors.affiliation: Pharmacology and Toxicolgy Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt. mayouya2010@yahoo.com.
authors.forename: May A
authors.initials: MA
authors.lastname: Galal
authors.affiliation: Pharmacology and Toxicolgy Department, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt. drafafainshoka@yahoo.com.
authors.forename: Afaf A
authors.initials: AA
authors.lastname: Ain-Shoka
authors.affiliation: Parmacology Unit,Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, 11796, Egypt. samia.shouman@nci.cu.edu.eg.
authors.forename: Samia A
authors.initials: SA
authors.lastname: Shouman
mesh_terms: D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D017209:Apoptosis; D018938:Caco-2 Cells; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006801:Humans; D019804:Mesalamine / Q000494:pharmacology*; D008687:Metformin / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D019804:Mesalamine; D008687:Metformin