title: Inhibition of IL-8 secretion on BxPC-3 and MIA PaCa-2 cells and induction of cytotoxicity in pancreatic cancer cells with marine natural products.
abstract: Pancreatic cancer presents one of the most negative prognosis of all cancers as it has usually metastasized by the time a patient is diagnosed. The American Cancer Society estimates that 93% of patients will die within 5 years of diagnosis, highlighting the need for new drugs to treat this disease. Interleukin 8 (IL-8) mediates the angiogenesis of tumors arising from Ras mutations, which are present in about 90% of pancreatic adenocarcinomas. Overexpression of IL-8 in pancreatic tumors is believed to promote tumor angiogenesis and to activate survival signaling pathways. A 96-well cell-based enzyme-linked immunosorbent assay was set up to screen the Harbor Branch Oceanographic Institute library of marine natural products to identify those with the ability to inhibit IL-8 production by BxPC-3 pancreatic cancer cells. Over 1000 fractions were screened, resulting in the identification of 10 known marine natural products with this ability. These compounds fall into four classes of compounds including the pyrroloiminoquinone alkaloids secobatzelline A and isobatzelline C; mycalamide A and B, onnamide A, discalamide A, and theopederin K from the mycalamide class of polyketides; the lipopeptide microcolin A; and the cyclic depsipeptides didemnin B and nordidemnin B. In addition, didemnin B, nordidemnin B, and theopederin K induce potent cytotoxicity against four pancreatic cancer cell lines tested. Many of these compounds have been previously reported to inhibit protein synthesis and the decrease in IL-8 production may be nonspecific. Nevertheless, this is a new activity for these compounds and inhibition of IL-8 secretion by pancreatic cancer cells can now be added to the previously reported antiangiogenic activities of the didemnins.
authors.affiliation: Marine Biomedical and Biotechnology Research, Harbor Branch Oceanographic Institute, Florida Atlantic University, Fort Pierce, Florida, USA.
authors.forename: Esther A
authors.initials: EA
authors.lastname: Guzmán
authors.forename: Dedra
authors.initials: D
authors.lastname: Harmody
authors.forename: Tara P
authors.initials: TP
authors.lastname: Pitts
authors.forename: Brunilda
authors.initials: B
authors.lastname: Vera-Diaz
authors.forename: Priscilla L
authors.initials: PL
authors.lastname: Winder
authors.forename: Yichao
authors.initials: Y
authors.lastname: Yu
authors.forename: Amy E
authors.initials: AE
authors.lastname: Wright
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001688:Biological Products / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D016209:Interleukin-8 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011161:Porifera / Q000737:chemistry; D014561:Urochordata / Q000737:chemistry; D014709:Vero Cells
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; D016209:Interleukin-8