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Published on: February 17, 2019
Targeting neuroblastoma stem cells with retinoic acid and proteasome inhibitor
Barbara Hämmerle1, Yania Yañez, Sarai Palanca
1Laboratory of Molecular Endocrinology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
Background:
Neuroblastma cell lines contain a side-population of cells which express stemness markers. These stem-like cells may represent the potential underlying mechanism for resistance to conventional therapy and recurrence of neuroblastoma in patients.
Methodology/Principal Findings:
To develop novel strategies for targeting the side-population of neurobastomas, we analyzed the effects of 13-cis-retinoic acid (RA) combined with the proteasome inhibitor MG132. The short-term action of the treatment was compared with effects after a 5-day recovery period during which both chemicals were withdrawn. RA induced growth arrest and differentiation of SH-SY5Y and SK-N-BE(2) neuroblastoma cell lines. Inhibition of the proteasome caused apoptosis in both cell lines, thus, revealing the critical role of this pathway in the regulated degradation of proteins involved in neuroblastoma proliferation and survival. The combination of RA with MG132 induced apoptosis in a dose-dependent manner, in addition to promoting G2/M arrest in treated cultures. Interestingly, expression of stem cell markers such as Nestin, Sox2, and Oct4 were reduced after the recovery period of combined treatment as compared with untreated cells or treated cells with either compound alone. Consistent with this, neurosphere formation was significantly impaired by the combined treatment of RA and MG132.
Conclusions:
Given that stem-like cells are associated with resistant to conventional therapy and are thought to be responsible for relapse, our results suggest that dual therapy of RA and proteasome inhibitor might be beneficial for targeting the side-population of cells associated residual disease in high-risk neuroblastoma.
Insights
Dual therapy with 13-cis-retinoic acid (RA) and proteasome inhibitor MG132 effectively targets neuroblastoma stem-like cells. This combination reduces stem cell marker expression and neurosphere formation, offering a potential strategy against therapy resistance and relapse in high-risk neuroblastoma.
Area of Science:
- Oncology
- Cancer Stem Cell Biology
- Pharmacology
Background:
- Neuroblastoma side-population cells express stemness markers, potentially driving therapy resistance and recurrence.
- Identifying therapeutic targets for these resistant stem-like cells is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the combined effects of 13-cis-retinoic acid (RA) and the proteasome inhibitor MG132 on neuroblastoma stem-like cells.
- To assess the potential of this dual therapy in targeting residual disease and preventing relapse.
Main Methods:
- Neuroblastoma cell lines (SH-SY5Y, SK-N-BE(2)) were treated with RA and/or MG132.
- Short-term and post-recovery effects were analyzed, including apoptosis, cell cycle arrest, and stem cell marker expression (Nestin, Sox2, Oct4).
- Neurosphere formation assays were conducted to evaluate stem cell self-renewal capacity.
Main Results:
- RA induced growth arrest and differentiation; MG132 induced apoptosis, highlighting the proteasome's role in neuroblastoma survival.
- The combination of RA and MG132 induced dose-dependent apoptosis and G2/M arrest.
- Combined treatment significantly reduced stem cell marker expression and impaired neurosphere formation after a recovery period.
Conclusions:
- Dual therapy with RA and MG132 demonstrates efficacy against neuroblastoma stem-like cells.
- This combination may offer a promising strategy for targeting the side-population of cells responsible for residual disease and relapse in high-risk neuroblastoma.
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