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Actinomycin D Down-regulates SOX2 Expression and Induces Death in Breast Cancer Stem Cells
Tuhin Das1, Rajesh R Nair2,3, Ryan Green1,4
1Department of Molecular Medicine, University of South Florida, Tampa, FL, U.S.A.
Background/Aim:
One of the major hurdles in the treatment of breast cancers is the inability of anti-cancer drugs to eliminate the breast cancer stem cells (BCSCs) population, which leads to disease relapse. The dearth in anti-cancer drugs that target BCSCs can be attributed to the absence of in vitro screening models that can not only recapitulate the tumor microenvironment consisting of BCSCs but also preserve the 3-dimensional (3D) architecture of in vivo tumors.
Materials And Methods:
In our present study, we have developed a 3D cell culture system that shows: (i) enrichment of BCSCs, (ii) increased drug resistance, and (iii) generation of hypoxic conditions similar to tumors.
Results:
Using this model, we were able to screen a FDA-approved diversity set and identify as well as validate actinomycin D as a potential anti-breast cancer agent. Interestingly, we show that actinomycin D specifically targets and down-regulates the expression of the stem cell transcription factor, Sox-2. Additionally, down-regulation of Sox-2 leads to depletion of the stem-cell population resulting in the inability of breast cancer cells to initiate tumor progression.
Conclusion:
This study demonstrates the utility of an in vivo-like 3D cell culture system for the identification and validation of anti-cancer agents that will have a better probability of success in the clinic.
Insights
A novel 3D cell culture model effectively screens for breast cancer drugs. This system identified actinomycin D, which targets breast cancer stem cells (BCSCs) by down-regulating Sox-2, preventing tumor progression.
Area of Science:
- Oncology
- Biotechnology
- Drug Discovery
Background:
- Breast cancer treatment faces challenges due to drug resistance in breast cancer stem cells (BCSCs), leading to relapse.
- Current limitations in targeting BCSCs stem from a lack of in vitro models that mimic the tumor microenvironment and 3D architecture.
Purpose of the Study:
- To develop a 3D cell culture system that enriches BCSCs, enhances drug resistance, and replicates tumor hypoxia.
- To utilize this model for screening and identifying novel anti-breast cancer agents.
Main Methods:
- Developed a 3D cell culture system to enrich BCSCs and mimic tumor conditions.
- Screened a FDA-approved drug library using the developed 3D model.
- Validated potential drug candidates by assessing their effect on BCSCs and Sox-2 expression.
Main Results:
- The 3D model successfully enriched BCSCs, increased drug resistance, and generated hypoxic conditions.
- Actinomycin D was identified and validated as a potential anti-breast cancer agent.
- Actinomycin D specifically targets and down-regulates Sox-2, leading to BCSCs depletion and reduced tumor initiation.
Conclusions:
- The in vivo-like 3D cell culture system is effective for identifying and validating anti-cancer agents.
- This model improves the probability of clinical success for new breast cancer therapies.