title: Arsenic sulfide combined with JQ1, chemotherapy agents, or celecoxib inhibit gastric and colon cancer cell growth.
abstract: BACKGROUND
  Arsenic compounds have modest cytotoxic activity in solid tumors. We investigated if arsenic sulfide (As4S4) in combination with other distinct agents could enhance its cytotoxic activity.
  
  
  METHODS
  We used gastric and colon cancer cell lines to study the synergistic effect of As4S4 in combination with BRD4 inhibitor JQ1, or with chemotherapy drug cisplatin and irinotecan or with COX2 inhibitor celecoxib. We investigated the mechanism of the cytotoxic effect of these novel combinations.
  
  
  RESULTS
  We found that when As4S4 was combined with JQ1, cisplatin, irinotecan or celecoxib, its cytotoxic activity was dramatically enhanced in both gastric and colon cancer cell lines. As4S4 and JQ1 inhibited BRD4 and c-Myc while activating p53 expression synergistically. As4S4 inhibited COX2 and cyclin D1 expression. When As4S4 was combined with chemotherapy drug cisplatin or COX2 inhibitor celecoxib, its inhibition of COX2, BCL2, and p38 expression was enhanced. As4S4 and cisplatin synergistically stimulated p53, phosphor-p38 (p-p38), and increased cleaved caspase 3 (c-caspase 3).
  
  
  CONCLUSIONS
  As4S4 in combination with JQ1, cisplatin, irinotecan or celecoxib showed enhanced cytotoxic effect on gastric and colon cancer cells, indicating the potential application of these novel drug combinations as part of treatment strategy that warrants further investigation. As4S4 and JQ1 demonstrate synergistic activation of p53 and inhibition of c-Myc. As4S4 and cisplatin and celecoxib activated multiple apoptosis pathways.
authors.affiliation: Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Lian
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Tong
authors.affiliation: Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Oncology and Hematology, Kaiser Permanente Medical Center, Santa Clara, USA ; Division of Research, Kaiser Permanente, Oakland, CA, USA.
authors.forename: Minggui
authors.initials: M
authors.lastname: Pan
authors.affiliation: Department of Oncology, Xin Hua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Siyu
authors.initials: S
authors.lastname: Chen
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001152:Arsenicals / Q000008:administration & dosage; D001381:Azepines / Q000008:administration & dosage; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068579:Celecoxib / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D000077146:Irinotecan; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000473:pathology; D013440:Sulfides / Q000008:administration & dosage; D014230:Triazoles / Q000008:administration & dosage; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics
chemical_list: C561695:(+)-JQ1 compound; D001152:Arsenicals; D001381:Azepines; D013440:Sulfides; D014230:Triazoles; D016159:Tumor Suppressor Protein p53; C045816:arsenic trisulfide; D000077146:Irinotecan; D048051:p38 Mitogen-Activated Protein Kinases; D000068579:Celecoxib; D002945:Cisplatin; D002166:Camptothecin
keywords: As4S4; JQ1; celecoxib; cisplatin; colon cancer; gastric cancer; irinotecan