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Targeting histone deacetylases (HDACs) and Wee1 for treating high-risk neuroblastoma
Santosh S Hanmod1, Guan Wang, Holly Edwards
1Division of Pediatric Hematology/Oncology, Children's Hospital of Michigan, Detroit, Michigan.
Background:
Despite advances in treatment regimens, patients with high-risk neuroblastoma have long-term survival rates of < 40%. Wee1 inhibition in combination with CHK1 inhibition has shown promising results in neuroblastoma cells. In addition, it has been demonstrated that panobinostat can downregulate CHK1. Therefore, combination of panobinostat and MK-1775 may result in synergistic cytotoxicity against neuroblastoma cell lines.
Procedure:
In vitro cytotoxicities of panobinostat and MK-1775 at clinically achievable concentrations, either alone or in combination, were evaluated in SK-N-AS, SK-N-DZ, and SK-N-BE(2) high-risk neuroblastoma cell lines using MTT assays. The mechanism of antitumor interaction was investigated using propidium iodide (PI) staining and flow cytometry analysis to determine apoptosis, as well as Western blotting to assess expression of phosphorylated CDK1/2, CHK1, and H2AX.
Results:
Treatment of neuroblastoma cell lines with 500 nM MK-1775 caused growth arrest and apoptosis in SK-N-DZ and SK-N-AS, while it had minimal effect on the SK-N-BE(2) cell line. The combination of panobinostat and MK-1775 resulted in synergistic antitumor interactions in all three of the cell lines tested. MK-1775 treatment in SK-N-BE(2) cells induced increased levels of p-CHK1(S345) , which could be decreased by the addition of panobinostat. This was accompanied by increased DNA damage and apoptosis.
Conclusions:
The combination of panobinostat and MK-1775 has synergistic antitumor activity against neuroblastoma cell lines and holds promise as a potential treatment strategy for the management of high-risk neuroblastoma patients.
Insights
Combining panobinostat and MK-1775 shows synergistic antitumor effects against high-risk neuroblastoma cells. This combination therapy offers a promising new strategy for treating neuroblastoma patients.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- High-risk neuroblastoma has poor long-term survival rates despite treatment advances.
- Wee1 and CHK1 inhibition show promise in neuroblastoma.
- Panobinostat downregulates CHK1, suggesting combined therapy potential.
Purpose of the Study:
- To evaluate the synergistic cytotoxicity of panobinostat and MK-1775 against high-risk neuroblastoma cell lines.
- To investigate the underlying mechanisms of their combined antitumor effects.
Main Methods:
- In vitro cytotoxicity assays (MTT) were performed on neuroblastoma cell lines (SK-N-AS, SK-N-DZ, SK-N-BE(2)).
- Apoptosis was assessed via propidium iodide staining and flow cytometry.
- Western blotting analyzed key protein expressions (p-CDK1/2, CHK1, H2AX).
Main Results:
- MK-1775 alone induced growth arrest and apoptosis in some cell lines but not others.
- The combination of panobinostat and MK-1775 demonstrated synergistic antitumor activity across all tested cell lines.
- Combined treatment increased DNA damage and apoptosis, particularly in MK-1775-resistant cells.
Conclusions:
- Panobinostat and MK-1775 exhibit synergistic antitumor activity against neuroblastoma.
- This combination represents a promising therapeutic strategy for high-risk neuroblastoma.
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