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Effect of anticancer agents on Fas-mediated cytotoxicity against bladder cancer cells
1Department of Urology, Faculty of Medicine, Kyoto University, 54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan.
Abstract:
Fas and Fas ligand play an important role in cytotoxic T lymphocyte-mediated cytotoxicity. Like Fas ligand, anti-Fas monoclonal antibody (mAb) induces apoptosis of cells expressing Fas and mimics tumor necrosis factor-alpha (TNF-alpha) in its cytotoxic activity, but not in regard to other TNF-alpha-mediated activities. Since combination treatment with TNF-alpha and some anticancer chemotherapeutic agents results in synergistic cytotoxicity against various cancer cells, anti-Fas mAb may also synergize with anticancer agents in exerting cytotoxicity. The present study examined this hypothesis using bladder cancer cells. Cytotoxicity was examined by a 1-day microculture tetrazolium dye assay. Treatment of T24 cells with anti-Fas mAb in combination with mitomycin C, methotrexate, or 5-fluorouracil did not overcome their resistance to these agents. However, combination treatment with anti-Fas mAb and adriamycin (ADR) resulted in a synergistic cytotoxic effect on T24 cells, three other bladder cancer lines, and fresh bladder cancer cells derived from four patients. Treatment with ADR enhanced the expression of Fas on T24 cells. The expression of P-glycoprotein was not affected by the antibody-mediated sensitization. This study showed that combination treatment of bladder cancer cells with anti-Fas mAb and ADR can overcome their resistance and that the upregulation of Fas expression by ADR may play a role in the enhanced cytotoxicity.
Insights
Anti-Fas monoclonal antibody combined with adriamycin synergistically kills bladder cancer cells. This combination overcomes resistance by enhancing Fas expression, offering a potential new cancer therapy.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Fas and Fas ligand are crucial for cytotoxic T lymphocyte-mediated cytotoxicity.
- Anti-Fas monoclonal antibody (mAb) induces apoptosis and mimics tumor necrosis factor-alpha (TNF-alpha) cytotoxic activity.
- Combination treatments with TNF-alpha and chemotherapeutic agents can synergize cytotoxicity in cancer cells.
Purpose of the Study:
- To investigate the synergistic cytotoxic potential of anti-Fas mAb combined with anticancer agents against bladder cancer cells.
- To determine if anti-Fas mAb can overcome resistance to conventional chemotherapeutic agents in bladder cancer.
Main Methods:
- Cytotoxicity was assessed using a 1-day microculture tetrazolium dye assay.
- Bladder cancer cell lines (T24 and others) and primary patient-derived cells were treated with anti-Fas mAb alone or in combination with various chemotherapeutic agents (mitomycin C, methotrexate, 5-fluorouracil, adriamycin [ADR]).
- Fas and P-glycoprotein expression levels were analyzed after treatment.
Main Results:
- Combination of anti-Fas mAb with mitomycin C, methotrexate, or 5-fluorouracil did not overcome resistance in T24 bladder cancer cells.
- A synergistic cytotoxic effect was observed when anti-Fas mAb was combined with adriamycin (ADR) against T24 cells, three other bladder cancer lines, and primary bladder cancer cells.
- Adriamycin treatment enhanced the expression of Fas on T24 cells, while P-glycoprotein expression remained unaffected.
Conclusions:
- Combination therapy of anti-Fas mAb and adriamycin demonstrates synergistic cytotoxicity against bladder cancer cells, overcoming existing resistance.
- Adriamycin-induced upregulation of Fas expression may be a key mechanism contributing to the enhanced efficacy of the combination treatment.
- This combination strategy holds promise for improving bladder cancer treatment outcomes.