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

Seiko Kato, Ken Shirato, Kazuhiko Imaizumi, Hiroko Toyota, Junichiro Mizuguchi, Masato Odawara, Xiao Fang Che, Shinichi Akiyama, Akihisa Abe, Akio Tomoda

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    29 Citations (Scopus)

    Abstract

    The aim of this study was to investigate the anticancer effects of the phenoxazine derivatives, 2-amino-4,4α-dihydro-4α,7-dimethyl-3H- phenoxazine-3-one (Phx-1), 3-amino-1,4α-dihydro-4α,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.

    Original languageEnglish
    Pages (from-to)843-848
    Number of pages6
    JournalOncology Reports
    Volume15
    Issue number4
    Publication statusPublished - 2006 Apr

    Keywords

    • Apoptosis
    • Pancreatic cancer cells
    • Phenoxazine
    • Proliferation inhibition
    • Tumor necrosis factor-related apoptosis-inducing ligand

    ASJC Scopus subject areas

    • Cancer Research
    • Oncology

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