title: Anticancer effects of phenoxazine derivatives combined with tumor necrosis factor-related apoptosis-inducing ligand on pancreatic cancer cell lines, KLM-1 and MIA-PaCa-2.
abstract: The aim of this study was to investigate the anticancer effects of the phenoxazine derivatives, 2-amino-4,4alpha-dihydro-4alpha,7-dimethyl-3H-phenoxazine-3-one (Phx-1), 3-amino-1,4alpha-dihydro-4alpha,8-dimethyl-2H-phenoxazine-2-one (Phx-2), and 2-aminophenoxazine-3-one (Phx-3) on human pancreatic cancer cell lines, KLM-1 and MIA-PaCa-2, in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor superfamily of cytokines. Of these three phenoxazines, Phx-1 and Phx-3 inhibited proliferation of KLM-1 dose-dependently, but Phx-2 did not. Phx-3 caused both apoptosis and necrosis in KLM-1 cells, as evidenced by the phosphatidylserine externalization and propidium iodide permeable cells detected by a flow cytometric method using annexin-V and propidium iodide. Down-regulation of Bcl-2 expression appeared to be involved in the Phx-3-induced cell death. TRAIL did not affect proliferation of KLM-1, and the inhibitory effects of Phx-1 and Phx-3 on the KLM-1 cell line were not augmented by the combination with TRAIL. On the other hand, proliferation of the MIA-PaCa-2 cell line was not affected by Phx-1, Phx-2 and Phx-3, although it was significantly inhibited by TRAIL in a dose-dependent manner. Inhibitory effects of TRAIL on MIA-PaCa-2 were synergistically augmented by the addition of Phx-1 and Phx-3, but not by Phx-2. These results suggest that both Phx-1 and Phx-3 exert anticancer effects against human pancreatic cancer cells, KLM-1 and MIA-PaCa-2, through distinct action modes. Phx-1 and Phx-3 may be effective for the treatment of pancreatic cancer.
authors.affiliation: Third Department of Internal Medicine, Tokyo Medical University, Tokyo 160-0023, Japan.
authors.forename: Seiko
authors.initials: S
authors.lastname: Kato
authors.forename: Ken
authors.initials: K
authors.lastname: Shirato
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Imaizumi
authors.forename: Hiroko
authors.initials: H
authors.lastname: Toyota
authors.forename: Junichiro
authors.initials: J
authors.lastname: Mizuguchi
authors.forename: Masato
authors.initials: M
authors.lastname: Odawara
authors.forename: Xiao-Fang
authors.initials: XF
authors.lastname: Che
authors.forename: Shinichi
authors.initials: S
authors.lastname: Akiyama
authors.forename: Akihisa
authors.initials: A
authors.lastname: Abe
authors.forename: Akio
authors.initials: A
authors.lastname: Tomoda
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D015394:Molecular Structure; D010078:Oxazines / Q000737:chemistry / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: C104202:2-amino-4,4alpha-dihydro-4alpha,7-dimethyl-3H-phenoxazine-3-one; C470370:3-amino-1,4a-dihydro-4a,8-dimethyl-2H-phenoxazine-2-one; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C494826:BAX protein, human; C494811:BCL2L1 protein, human; D008562:Membrane Glycoproteins; D010078:Oxazines; D019253:Proto-Oncogene Proteins c-bcl-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C005512:3-aminophenoxazone; C039203:phenoxazine