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Potentiation of tumor necrosis factor induced apoptosis by onconase
A Deptala1, H D Halicka, B Ardelt
1Brander Cancer Research Institute, New York Medical College, Valhalla, NY 10595, USA.
Abstract:
Onconase (ONC) a ribonuclease from amphibian oocytes is cytostatic and cytotoxic to many human tumor lines, shows in vivo antitumor activity in mouse tumor models and is in Phase III clinical trials. The mechanism of antitumor activity of ONC is presumed to be due to its internalization, degradation of intracellular RNA and suppression of protein synthesis. Since apoptosis triggered by TNF-alpha is known to be potentiated by inhibitors of protein synthesis, we have hypothesized that it also may be potentiated by ONC. Indeed, preincubation of U-937 or HL-60 leukemic cells with 0.17 microM ONC rendered them more sensitive to induction of apoptosis by TNF-alpha or antibody to CD95 (Fas). The mechanism by which ONC amplifies the effect of TNF-alpha may involve suppression of induction of the survival genes whose expression is triggered by activation of NFkB by this factor.
Insights
Onconase (ONC), an amphibian ribonuclease, enhances cancer cell sensitivity to apoptosis. This protein synthesis inhibitor may amplify TNF-alpha
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- Onconase (ONC), a ribonuclease from amphibian oocytes, exhibits cytostatic and cytotoxic effects on human tumor lines.
- ONC has demonstrated in vivo antitumor activity and is currently in Phase III clinical trials.
- The presumed mechanism of ONC's antitumor activity involves cellular internalization, RNA degradation, and protein synthesis suppression.
Purpose of the Study:
- To investigate whether ONC can potentiate apoptosis induced by Tumor Necrosis Factor-alpha (TNF-alpha).
- To determine if ONC enhances the sensitivity of leukemic cells to apoptosis triggered by TNF-alpha or anti-Fas antibody.
Main Methods:
- Preincubation of U-937 and HL-60 leukemic cells with 0.17 microM ONC.
- Exposure of preincubated cells to TNF-alpha or antibody to CD95 (Fas) to induce apoptosis.
Main Results:
- Preincubation with ONC significantly increased the sensitivity of U-937 and HL-60 cells to apoptosis induction by TNF-alpha or anti-Fas antibody.
- This potentiation suggests a synergistic effect between ONC and apoptosis-inducing agents.
Conclusions:
- Onconase (ONC) can amplify the apoptotic response to TNF-alpha and Fas signaling in leukemic cells.
- The mechanism may involve ONC's ability to suppress the induction of survival genes activated by NF-kappaB.
- ONC shows potential as an adjuvant therapy to enhance cancer treatment efficacy.