title: Designing and developing S100P inhibitor 5-methyl cromolyn for pancreatic cancer therapy.
abstract: We have previously shown that the antiallergic drug cromolyn blocks S100P interaction with its receptor receptor for advanced glycation end product (RAGE) and improves gemcitabine effectiveness in pancreatic ductal adenocarcinoma (PDAC). However, the concentration required to achieve its effectiveness was high (100 μmol/L). In this study, we designed and synthesized analogs of cromolyn and analyzed their effectiveness compared with the parent molecule. An ELISA was used to confirm the binding of S100P with RAGE and to test the effectiveness of the different analogs. Analog 5-methyl cromolyn (C5OH) blocked S100P binding as well as the increases in NF-κB activity, cell growth, and apoptosis normally caused by S100P. In vivo C5OH systemic delivery reduced NF-κB activity to a greater extent than cromolyn and at 10 times lesser dose (50 mg vs. 5 mg). Treatment of mice-bearing syngeneic PDAC tumors showed that C5OH treatment reduced both tumor growth and metastasis. C5OH treatment of nude mice bearing orthotopic highly aggressive pancreatic Mpanc96 cells increased the overall animal survival. Therefore, the cromolyn analog, C5OH, was found to be more efficient and potent than cromolyn as a therapeutic for PDAC.
authors.affiliation: Department of Cancer Biology, UT MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Thiruvengadam
authors.initials: T
authors.lastname: Arumugam
authors.forename: Vijaya
authors.initials: V
authors.lastname: Ramachandran
authors.forename: Duoli
authors.initials: D
authors.lastname: Sun
authors.forename: Zhenghong
authors.initials: Z
authors.lastname: Peng
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Pal
authors.forename: David S
authors.initials: DS
authors.lastname: Maxwell
authors.forename: William G
authors.initials: WG
authors.lastname: Bornmann
authors.forename: Craig D
authors.initials: CD
authors.lastname: Logsdon
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004205:Cromolyn Sodium / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D016328:NF-kappa B / Q000378:metabolism; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; D016328:NF-kappa B; D009363:Neoplasm Proteins; D000067759:Receptor for Advanced Glycation End Products; C103003:S100P protein, human; D004205:Cromolyn Sodium