title: Synergistic enhancement of TRAIL- and tumor necrosis factor alpha-induced cell death by a phenoxazine derivative.
abstract: 2-Amino-4,4alpha-dihydro-4alpha,7-dimethyl-3H-phenoxazine-3-one (Phx-1) has been developed as a novel phenoxazine derivative having an anticancer activity on a variety of cancer cell lines as well as transplanted tumors in mice with minimal toxicity to normal cells. We examined the effects of Phx-1 on Jurkat cells, a human T cell line. Phx-1 inhibited proliferation of the cells in a dose-dependent manner but hardly induced cell death, suggesting that Phx-1 acts primarily as an antiproliferative reagent but not as a cytocidal drug. Phx-1 enhanced tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptotic cell death about 100-fold. Tumor necrosis factor alpha, which alone does not induce cell death of Jurkat cells, caused apoptosis in combination with Phx-1. These enhancements of cell death were not due to up-regulation of the death receptors. Phx-1 decreased serum-induced phosphorylation of Akt, a kinase involved in cell proliferation and survival, and inhibited complex III of mitochondrial respiratory chain. Considering that both TRAIL and Phx-1 have only marginal cytotoxicity to most normal cells, Phx-1 may provide an ideal combination for cancer therapy with TRAIL.
authors: Department of Clinical Chemistry and Laboratory Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
authors: Keiichi
authors: K
authors: Hara
authors: Mayumi
authors: M
authors: Okamoto
authors: Toshihiko
authors: T
authors: Aki
authors: Hideo
authors: H
authors: Yagita
authors: Hirotoshi
authors: H
authors: Tanaka
authors: Yoichi
authors: Y
authors: Mizukami
authors: Hiroshi
authors: H
authors: Nakamura
authors: Akio
authors: A
authors: Tomoda
authors: Naotaka
authors: N
authors: Hamasaki
authors: Dongchon
authors: D
authors: Kang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D019069:Cell Respiration / Q000187:drug effects; D004357:Drug Synergism; D014450:Electron Transport Complex III / Q000037:antagonists & inhibitors; D006801:Humans; D019169:Jurkat Cells / Q000187:drug effects; D015458:Leukemia, T-Cell / Q000188:drug therapy / Q000473:pathology; D008562:Membrane Glycoproteins / Q000494:pharmacology*; D010078:Oxazines / Q000737:chemistry / Q000494:pharmacology*; D010766:Phosphorylation; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000187:drug effects / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology*
chemical_list: C104202:2-amino-4,4alpha-dihydro-4alpha,7-dimethyl-3H-phenoxazine-3-one; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D008562:Membrane Glycoproteins; D010078:Oxazines; D047888:Receptors, Tumor Necrosis Factor, Type I; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; C039203:phenoxazine; D014450:Electron Transport Complex III