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Evaluating the Angiogenetic Properties of Ovarian Cancer Stem-Like Cells using the Three-Dimensional Co-Culture System, NICO-1
Published on: December 5, 2020
The Effects of Histone Deacetylase Inhibitor and Calpain Inhibitor Combination Therapies on Ovarian Cancer Cells
Karolina Lapinska1,2, Genevieve Housman3, Shannon Byler4
1Cancer Center, Department of Medicine, Boston University School of Medicine, Boston, MA, U.S.A.
Background:
Ovarian cancer is difficult to treat due to absence of selective drugs and tendency of platinum drugs to promote resistance. Combination therapy using epigenetic drugs is predicted to be a beneficial alternative.
Materials And Methods:
This study investigated the effects of combination therapies using two structurally different histone deacetylase (HDAC) inhibitors (HDACi), sodium butyrate and suberanilohydroxamic acid (SAHA), with the calpain inhibitor calpeptin on two characteristically different ovarian cancer cell lines, CAOV-3 and SKOV-3.
Results:
Suboptimal doses of HDACi and calpeptin produced several effects. Growth inhibition was enhanced and the epigenetically silenced tumor suppressor genes ARHI, p21 and RARβ2 were re-expressed. Methylation of specific CpG residues in ARHI were reduced. Cell-cycle progression was inhibited and apoptosis, as well as autophagy, were induced. The phosphorylation of ERK and Akt were differentially effected by these inhibitors.
Conclusion:
The re-expression of tumor suppressors may sensitize ovarian cancer cells, which then undergo apoptosis and autophagy for cell death.
Insights
Combination epigenetic and calpain inhibitor therapy shows promise for ovarian cancer treatment by re-expressing tumor suppressors and inducing cell death. This approach enhances growth inhibition and sensitizes cancer cells, offering a potential alternative to conventional drugs.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Ovarian cancer treatment is challenging due to a lack of targeted drugs and platinum drug resistance.
- Combination therapy with epigenetic drugs presents a promising alternative strategy.
Purpose of the Study:
- To investigate the synergistic effects of histone deacetylase inhibitors (HDACi) and a calpain inhibitor on ovarian cancer cell lines.
- To evaluate the impact of combination therapy on tumor suppressor gene re-expression, cell cycle, apoptosis, and autophagy.
Main Methods:
- Utilized two HDAC inhibitors (sodium butyrate, SAHA) and the calpain inhibitor calpeptin.
- Tested combination therapies on CAOV-3 and SKOV-3 ovarian cancer cell lines.
- Assessed gene re-expression, DNA methylation, cell cycle progression, apoptosis, and autophagy.
Main Results:
- Combination therapy enhanced growth inhibition and re-expressed epigenetically silenced tumor suppressor genes (ARHI, p21, RARβ2).
- Reduced methylation of CpG residues in the ARHI gene was observed.
- Inhibited cell-cycle progression and induced apoptosis and autophagy.
- Differential effects on ERK and Akt phosphorylation were noted.
Conclusions:
- Re-expression of tumor suppressors sensitizes ovarian cancer cells to therapy.
- Combination treatment with HDAC inhibitors and calpeptin promotes cancer cell death through apoptosis and autophagy.
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