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Mitochondrial Damage and Apoptosis Induced by Adenosine Deaminase Inhibition and Deoxyadenosine in Human
Mercedes Garcia-Gil1, Maria Grazia Tozzi2, Francesco Balestri2
1Dipartimento di Biologia, Unità Fisiologia Generale, Via S. Zeno 31, Pisa, Italy.
Abstract:
The treatment with deoxycoformycin, a strong adenosine deaminase inhibitor, in combination with deoxyadenosine, causes apoptotic cell death of two human neuroblastoma cell lines, SH-SY5Y and LAN5. Herein we demonstrate that, in SH-SY5Y cells, this combination rapidly decreases mitochondrial reactive oxygen species and, in parallel, increases mitochondrial mass, while, later, induces nuclear fragmentation, and activation of caspase-8, -9, and -3. In previous papers we have shown that a human astrocytoma cell line, subjected to the same treatment, undergoes apoptotic death as well. Therefore, both astrocytoma and neuroblastoma cell lines undergo apoptotic death following the combined treatment with deoxycoformycin and deoxyadenosine, but several differences have been found in the mode of action, possibly reflecting a different functional and metabolic profile of the two cell lines. Overall this work indicates that the neuroblastoma cell lines, like the line of astrocytic origin, are very sensitive to purine metabolism perturbation thus suggesting new therapeutic approaches to nervous system tumors. J. Cell. Biochem. 117: 1671-1679, 2016. © 2015 Wiley Periodicals, Inc.
Insights
The combined treatment of deoxycoformycin and deoxyadenosine induces apoptotic cell death in neuroblastoma cells. This purine metabolism perturbation suggests novel therapeutic strategies for nervous system tumors.
Area of Science:
- Biochemistry
- Cell Biology
- Oncology
Background:
- Neuroblastoma is a pediatric cancer with limited treatment options.
- Adenosine deaminase (ADA) plays a role in purine metabolism.
- Perturbing purine metabolism can induce cancer cell death.
Purpose of the Study:
- To investigate the effects of deoxycoformycin and deoxyadenosine on human neuroblastoma cell lines.
- To elucidate the mechanisms of cell death induced by this combination treatment.
- To compare the response of neuroblastoma cells with astrocytoma cells to this treatment.
Main Methods:
- Treatment of SH-SY5Y and LAN5 neuroblastoma cell lines with deoxycoformycin and deoxyadenosine.
- Assessment of mitochondrial reactive oxygen species (ROS) and mitochondrial mass.
- Analysis of nuclear fragmentation and caspase activation (caspase-8, -9, and -3).
Main Results:
- The combination treatment rapidly decreased mitochondrial ROS and increased mitochondrial mass in SH-SY5Y cells.
- Later, nuclear fragmentation and activation of caspases -8, -9, and -3 were observed.
- Neuroblastoma cell lines exhibited apoptotic cell death, similar to astrocytoma cells, but with distinct mechanistic differences.
Conclusions:
- Neuroblastoma cells are sensitive to purine metabolism perturbation induced by deoxycoformycin and deoxyadenosine.
- The observed cell death mechanisms involve mitochondrial dysfunction and caspase activation.
- This study suggests potential new therapeutic approaches for nervous system tumors by targeting purine metabolism.
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