Mild hyperthermia predisposes tumor cells to undergo apoptosis upon treatment with onconase
H Dorota Halicka1, Barbara Ardelt, Kuslima Shogen
1Brander Cancer Research Institute and Department of Pathology, New York Medical College, Valhalla, NY 10595, USA.
Abstract:
Onconase (ONC), (ranpirnase) a cytotoxic ribonuclease isolated from amphibian oocytes and early embryos targeting tumor cells in vitro and in vivo, is currently in a confirmatory Phase IIIb clinical trial for unresectable malignant mesothelioma where it demonstrates antitumor activity with relatively minor overall toxicity to patients. Since hyperthermia has been shown to be synergistic with certain antitumor modalities, the aim of the present study was to explore whether the cytotoxic effects of ONC can be enhanced under conditions of mild hyperthermia. Treatment of human lymphoblastoid TK6 cells with 2 or 5 microg/ml of ONC at 40 degrees C for 24 or 48 h led to 64-200% enhancement in incidence of apoptosis assessed by frequency of cells showing the presence of activated (cleaved) caspase-3 or activated serine proteases, compared to treatment at 37.5 degrees C. The incidence of apoptosis at 40 degrees C in the absence of ONC was unchanged compared to 37.5 degrees C, for up to 48 h. Although at 41 degrees C in absence of ONC the incidence of apoptosis was elevated compared to 37 degrees C the cytotoxicity of ONC was further enhanced and the overall pro-apoptotic effect was above the level of additive effects of ONC plus that of 41 degrees C-hyperthermia. While the mechanism of the observed enhancement of ONC cytotoxicity is currently under investigation, the findings suggest that a combination of ONC and mild hyperthermia should be explored to increase effectiveness of ONC in cancer treatment.
Insights
Mild hyperthermia significantly enhances the cancer-fighting ability of Onconase (ONC), a cytotoxic ribonuclease. Combining ONC with mild heat boosts its effectiveness in killing tumor cells.
Area of Science:
- Oncology
- Biochemistry
Background:
- Onconase (ONC), also known as ranpirnase, is a cytotoxic ribonuclease derived from amphibian oocytes.
- ONC targets tumor cells both in vitro and in vivo, and is in a Phase IIIb trial for malignant mesothelioma.
- Hyperthermia is known to synergize with various antitumor treatments.
Purpose of the Study:
- To investigate if mild hyperthermia can enhance the cytotoxic effects of Onconase (ONC).
Main Methods:
- Human lymphoblastoid TK6 cells were treated with ONC (2 or 5 microg/ml) at 40 degrees C or 41 degrees C for 24-48 hours.
- Apoptosis incidence was assessed by measuring activated caspase-3 and activated serine proteases.
- Comparisons were made to treatment at 37.5 degrees C and to hyperthermia alone.
Main Results:
- Treatment with ONC at 40 degrees C resulted in a 64-200% increase in apoptosis compared to 37.5 degrees C.
- Mild hyperthermia (40 degrees C or 41 degrees C) alone did not significantly increase apoptosis in TK6 cells within 48 hours.
- The combination of ONC and 41 degrees C hyperthermia showed a synergistic pro-apoptotic effect, exceeding additive effects.
Conclusions:
- Mild hyperthermia significantly potentiates the cytotoxic activity of Onconase (ONC).
- The combination of ONC and mild hyperthermia presents a promising strategy for enhancing cancer treatment efficacy.
- Further investigation into the mechanism of this synergistic effect is warranted.
