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Synergistic Cytotoxicity and Apoptosis by Apo-2 Ligand and Adriamycin against Bladder Cancer Cells¹

Department of Urology, Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan [Y. M., O. Y.]; Department of Urology, Kyoto Prefectural University of Medicine, Kyoto 606-0841, Japan [T. M.]; and Department of Microbiology and Immunology, UCLA School of Medicine, University of California at Los Angeles, California 90095 [B. B.]

Resistance to conventional anticancer chemotherapeutic agents remains one of the major problems in the treatment of bladder cancer. Hence, new therapeutic modalities are necessary to treat the drug-resistant cancers. Apo-2 ligand (Apo-2L) is member of the tumor necrosis factor ligand family, and it induces apoptosis in cancer cells. Several cytotoxic anticancer drugs, including Adriamycin (ADR), also mediate apoptosis and may share the common intracellular pathways leading to cell death. We reasoned that combination treatment of the drug-resistant cancer cells with Apo-2L and drugs might overcome their resistance. Here, we examined whether bladder cancer cells are sensitive to Apo-2L-mediated cytotoxicity and whether Apo-2L can synergize with ADR in cytotoxicity and apoptosis against bladder cancer cells.

Recombinant human soluble Apo-2L (sApo-2L), which carries the extracellular domain of Apo-2L, was used as a ligand. Cytotoxicity was determined by a 1-day microculture tetrazolium dye assay. Synergy was assessed by isobolographic analysis.

Human T24 bladder cancer line was relatively resistant to sApo-2L. Treatment of T24 line with combination of sApo-2L and ADR resulted in a synergistic cytotoxic effect. Synergy was also achieved in the ADR-resistant T24 line (T24/ADR), two other bladder cancer lines, and three freshly derived human bladder cancer cell samples. In addition, T24 cells were sensitive to treatment with sApo-2L combined with epirubicin or pirarubicin. The synergy achieved in cytotoxicity with sApo-2L and ADR was also achieved in apoptosis. Intracellular accumulation of ADR was not affected by sApo-2L. Incubation of T24 cells with sApo-2L down-regulated the expression of glutathione S-transferase- mRNA.

This study demonstrates that combination treatment of bladder cancer cells with sApo-2L and ADR overcomes their resistance. The sensitization obtained with established ADR-resistant bladder cancer cells and freshly isolated bladder cancer cells required low subtoxic concentrations of ADR, thus supporting the in vivo potential application of combination of sApo-2L and ADR in the treatment of ADR-resistant bladder cancer.

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