title: Downregulation of Sp1 by Minnelide leads to decrease in HSP70 and decrease in tumor burden of gastric cancer.
abstract: BACKGROUND
  Gastric cancer is the third leading cause of cancer related mortality worldwide with poor survival rates. Even though a number of chemotherapeutic compounds have been used against this disease, stomach cancer has not been particularly sensitive to these drugs. In this study we have evaluated the effect of triptolide, a naturally derived diterpene triepoxide and its water soluble pro-drug Minnelide on several gastric adenocarcinoma cell lines both as monotherapy and in combination with CPT-11.
  
  
  METHODS
  Gastric cancer cell lines MKN28 and MKN45 were treated with varying doses of triptolide in vitro. Cell viability was measured using MTT based assay kit. Apoptotic cell death was assayed by measuring caspase activity. Effect of the triptolide pro-drug, Minnelide, was evaluated by implanting the gastric cancer cells subcutaneously in athymic nude mice.
  
  
  RESULTS
  Gastric cancer cell lines MKN28 and MKN45 cells exhibited decreased cell viability and increased apoptosis when treated with varying doses of triptolide in vitro. When implanted in athymic nude mice, treatment with Minnelide reduced tumor burden in both MKN28 derived tumors as well as MKN45 derived tumors. Additionally, we also evaluated Minnelide as a single agent and in combination with CPT-11 in the NCI-N87 human gastric tumor xenograft model.
  
  
  CONCLUSIONS
  Our results indicated that the combination of Minnelide with CPT-11 resulted in significantly smaller tumors compared to control. These studies are extremely encouraging as Minnelide is currently undergoing phase 1 clinical trials for gastrointestinal cancers.
authors.affiliation: Div. of Basic and Translational Research Dept. of Surgery University of Minnesota, Minneapolis MN, United States of America.
authors.forename: Nivedita
authors.initials: N
authors.lastname: Arora
authors.affiliation: Div. of Basic and Translational Research Dept. of Surgery University of Minnesota, Minneapolis MN, United States of America.
authors.forename: Osama
authors.initials: O
authors.lastname: Alsaied
authors.affiliation: Div. of Basic and Translational Research Dept. of Surgery University of Minnesota, Minneapolis MN, United States of America.|Div. of Surgical Oncology Dept. of Surgery University of Miami, Miami, FL, United States of America.
authors.forename: Patricia
authors.initials: P
authors.lastname: Dauer
authors.affiliation: Div. of Basic and Translational Research Dept. of Surgery University of Minnesota, Minneapolis MN, United States of America.
authors.forename: Kaustav
authors.initials: K
authors.lastname: Majumder
authors.affiliation: Div. of Basic and Translational Research Dept. of Surgery University of Minnesota, Minneapolis MN, United States of America.|Div. of Surgical Oncology Dept. of Surgery University of Miami, Miami, FL, United States of America.
authors.forename: Shrey
authors.initials: S
authors.lastname: Modi
authors.affiliation: Div. of Basic and Translational Research Dept. of Surgery University of Minnesota, Minneapolis MN, United States of America.|Div. of Surgical Oncology Dept. of Surgery University of Miami, Miami, FL, United States of America.
authors.forename: Bhuwan
authors.initials: B
authors.lastname: Giri
authors.affiliation: Div. of Basic and Translational Research Dept. of Surgery University of Minnesota, Minneapolis MN, United States of America.|Div. of Surgical Oncology Dept. of Surgery University of Miami, Miami, FL, United States of America.
authors.forename: Vikas
authors.initials: V
authors.lastname: Dudeja
authors.affiliation: Div. of Basic and Translational Research Dept. of Surgery University of Minnesota, Minneapolis MN, United States of America.|Div. of Surgical Oncology Dept. of Surgery University of Miami, Miami, FL, United States of America.
authors.forename: Sulagna
authors.initials: S
authors.lastname: Banerjee
authors.affiliation: TGen/Virginia G. Piper Cancer Ctr, Suite 600, Phoenix, AZ United States of America.
authors.forename: Daniel
authors.initials: D
authors.lastname: Von Hoff
authors.affiliation: Div. of Basic and Translational Research Dept. of Surgery University of Minnesota, Minneapolis MN, United States of America.|Div. of Surgical Oncology Dept. of Surgery University of Miami, Miami, FL, United States of America.
authors.forename: Ashok
authors.initials: A
authors.lastname: Saluja
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015153:Blotting, Western; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004224:Diterpenes / Q000008:administration & dosage / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects*; D004852:Epoxy Compounds / Q000008:administration & dosage / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000077146:Irinotecan; D008819:Mice, Nude; D010755:Organophosphates / Q000008:administration & dosage / Q000494:pharmacology*; D010616:Phenanthrenes / Q000008:administration & dosage / Q000494:pharmacology*; D011355:Prodrugs / Q000008:administration & dosage / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D004224:Diterpenes; D004852:Epoxy Compounds; D018840:HSP70 Heat-Shock Proteins; D010755:Organophosphates; D010616:Phenanthrenes; D011355:Prodrugs; D016329:Sp1 Transcription Factor; C001899:triptolide; C579022:14-O-phosphonooxymethyltriptolide disodium salt; D000077146:Irinotecan; D002166:Camptothecin