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Synergistic antitumor effects of a selective proteasome inhibitor and TNF in mice
J Golab1, T Stoklosa, A Czajka
1Department of Immunology, Medical University of Warsaw, Poland. jgolab@ib.amwaw.edu.pl
Abstract:
The ubiquitin-proteasome pathway is becoming an attractive target in cancer therapy. The inhibitors of proteasomes have recently been shown to induce apoptosis of tumor cells in vitro and to exert significant antitumor effects in murine tumor models in vivo. Proteasome inhibitors, also prevent NF-kappa B activation. Since this transcription factor is responsible for counteracting apoptosis induced by numerous agents, and proteasome inhibitors have already proved efficacious in increasing the proapoptotic activity of TNF in vitro, we decided to evaluate the antitumor effects of the combined PSI and TNF treatment against a murine C-26 carcinoma. Both agents separately exerted moderate antitumor efficacy. However, their combination proved to exert dramatic antitumor activity with retardation of tumor growth and prolongation of mice survival time. Moreover, 50% of the mice were completely cured by this drug combination. Unexpectedly, there was no potentiation of the cytostatic/cytotoxic effects of these drugs in in vitro assays which argues against the direct influence on C-26 cells. Similarly, the influence of these drugs on tumor induced angiogenesis does not seem to explain the observed antitumor effects. Further studies are necessary to explain the striking antitumor effects of the PSI and TNF combination.
Insights
Combining proteasome inhibitors (PSI) and tumor necrosis factor (TNF) demonstrated significant antitumor effects against murine C-26 carcinoma. This combination therapy led to tumor growth retardation and prolonged survival, with a notable cure rate in mice.
Area of Science:
- Oncology
- Cancer Therapy
- Immunology
Background:
- The ubiquitin-proteasome pathway is a key target in cancer therapy.
- Proteasome inhibitors induce tumor cell apoptosis and inhibit NF-kappa B activation.
- NF-kappa B counteracts apoptosis, and proteasome inhibitors enhance TNF-induced apoptosis in vitro.
Purpose of the Study:
- To evaluate the combined antitumor effects of proteasome inhibitors (PSI) and tumor necrosis factor (TNF) against murine C-26 carcinoma.
- To investigate the efficacy of this combination therapy in vivo.
Main Methods:
- Treatment of C-26 carcinoma-bearing mice with PSI and TNF, both individually and in combination.
- Assessment of tumor growth, survival time, and in vitro cytotoxic effects.
- Evaluation of potential mechanisms including direct cellular effects and tumor angiogenesis.
Main Results:
- Both PSI and TNF showed moderate antitumor efficacy individually.
- The combination of PSI and TNF exhibited dramatic antitumor activity, significantly retarding tumor growth and prolonging survival.
- Remarkably, 50% of the treated mice achieved complete cure.
- No potentiation of direct cytostatic/cytotoxic effects was observed in vitro.
- The observed effects were not explained by direct influence on C-26 cells or tumor angiogenesis.
Conclusions:
- The combination of PSI and TNF demonstrates potent in vivo antitumor efficacy against C-26 carcinoma, exceeding the effects of individual agents.
- The mechanism behind this striking synergistic effect remains to be elucidated, as it does not appear to be mediated by direct cytotoxicity or anti-angiogenesis.