Trichostatin A inhibits proliferation of triple negative breast cancer cells by inducing cell cycle arrest and apoptosis
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Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor outcome. Because of lacking therapeutic targets, chemotherapy is the main treatment option for patients with TNBC. Overexpression of HDACs correlates with tumorigenesis, highlighting the potential of HDACs as therapeutic targets for TNBC. Here we demonstrate that trichostatin A (TSA, a HDAC inhibitor) selectively inhibits the proliferation of TNBC cell lines HCC1806 and HCC38 rather than a normal breast cell line MCF10A. The inhibition of TNBC by TSA is via its roles in inducing cell cycle arrest and apoptosis. TSA treatment leads to decreased expression of CYCLIN D1, CDK4, CDK6 and BCL-XL, but increased P21 expression. Moreover, combination of TSA with doxorubicin has synergistic effects on inhibiting proliferation of HCC1806 and HCC38 cells. Our studies identified a promising epigenetic-based therapeutic strategy that may be implemented in the therapy of fatal human breast cancer.Keywords:
Triple-negative breast cancer
Trichostatin A
Cyclin-dependent kinase 6
Trichostatin A
Histone deacetylase inhibitor
Chromatin immunoprecipitation
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Abstract Histone deacetylase inhibitors (HDACI) are potential therapeutic agents that inhibit tumor cell growth and survival. Although there are several publications regarding the effects of HDACIs on prostate cancer cell growth, their mechanism(s) of action remains undefined. We treated several human prostate cancer cell lines with the HDACI trichostatin A and found that trichostatin A induced cell death in androgen receptor (AR)–positive cell lines to higher extent compared with AR-negative cell lines. We then discovered that trichostatin A and other HDACIs suppressed AR gene expression in prostate cancer cell lines as well as in AR-positive breast carcinoma cells and in mouse prostate. Trichostatin A also induced caspase activation, but trichostatin A–induced AR suppression and cell death were caspase independent. In addition, we found that doxorubicin inhibited AR expression, and p21 protein completely disappeared after simultaneous treatment with trichostatin A and doxorubicin. This effect may be attributed to the induction of protease activity under simultaneous treatment with these two agents. Further, simultaneous treatment with trichostatin A and doxorubicin increased cell death in AR-positive cells even after culturing in steroid-free conditions. The protease/proteasome inhibitor MG132 protected AR and p21 from the effects of trichostatin A and doxorubicin and inhibited trichostatin A–induced cell death in AR-positive prostate cells. Taken together, our data suggest that the main mechanism of trichostatin A–induced cell death in AR-positive prostate cancer is inhibition of AR gene expression. The synergistic effect of simultaneous treatment with trichostatin A and doxorubicin is mediated via inhibition of AR expression, induction of protease activity, increased expression of p53, and proteolysis of p21. (Mol Cancer Res 2006;4(2):113–23)
Trichostatin A
Histone deacetylase inhibitor
Vorinostat
Growth inhibition
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Trichostatin A
Histone deacetylase inhibitor
MCF-7
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Trichostatin A
Cyclin-dependent kinase 6
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Trichostatin A
G1 phase
Histone deacetylase inhibitor
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Objective:To investigate the influence of histone deacetylase inhibitor(Trichostatin A)to multiplication,invasion, cell cycle of breast cancer MDA-MB-231 cell line.Methods:After 6-48hours treatment with the concentration(100～400nmol/L)of Trichostatin,the growth activity of MDA-MB-231 cell line was detected by MTT.The expression of ERα,MMP-9 mRNA was detected by RT-PCR with different concentration(100～400nmal/L TSA)during 24 hours to MDA-MB-231 cell line.The expression of ERα,MMP-9 protein was examined by immunohistochemistry with different concentration(100～400nmol/L TSA)during 24 hours treatment to MDA-MB-231 cell line.With cell invasion experiment to detect the change of invasive power by using different concentration(100～400nmol/L TSA)during 24 hours to MDA-MB-231 cell line.Results: Trichostatin can inhibit the growth of MDA-MB-231 cell line,which was time and dose dependent.Trichostatin can delay the cell cycle G_2/M stage,stop the cell stage in G_2 stage.Trichostatin can up-regulate the expression of ERαmRNA, down-regulate the expression of MMP-9 mRNA in cells.The invasion experiment indicate that Trichostatin can conspicuous inhibit the invasion of MDA-MB-231 cell line.Conclusions:Trichostatin can inhibit the accrementition,invasion and metastasis of MDA-MB-231 cell line evidently,and one of the mechanism may be the up-regulation of ERαand the down-regulation of MMP-9.
Trichostatin A
Histone deacetylase inhibitor
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Introduction Albeit the advancement in breast cancer (BC) treatment, BC remains as the second leading cause of cancer death worldwide. Unlike the other BC subtypes, the lack of hormone receptor (HR) rendering the aggressive triple negative BC (TNBC) towards chemotherapy which is destructive to one’s quality of life. Tumour necrosis factor related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent due to its selective killing of malignant cells leaving the normal cells unharmed. Despite being TRAIL-sensitive, the TNBC MDA-MB-231 cells develop resistance to TRAIL after repeated treatment. The epigenetic drugs zebularine (Zeb) and trichostatin A (TSA) were reported to increase the TRAIL-induced apoptosis. Therefore, we aim to study the combinational anti-cancer effect of Zeb and TSA followed by TRAIL (TZT treatment) and compare its effect with the standard chemotherapy drug doxorubicin (DOX). Material and methods MDA-MB-231, MCF-7 (HR positive breast cancer cells) and MCF-10A (normal breast epithelial cells) were treated with TZT and DOX respectively and subjected to cell proliferation, cell cycle arrest and apoptosis analyses. Results and discussions Based on the results obtained, TZT treatment hampered the cell proliferation in MDA-MB-231 and MCF-7 as compared to TRAIL treatment alone but not in MCF-10A. Nevertheless, the cell proliferation of both breast cancer and normal cells treated with DOX was significant reduced. Subsequently, the cell cycle distribution was evaluated via flow cytometry analysis. Higher induction of G1 cell cycle arrest was observed in the MDA-MB-231 treated with TZT (57.5%) as compared to TRAIL alone (52.2%) at 24 hours. In MCF-7, there is the minimal induction of G1 arrest with TZT treatment (71.2%) as compared to TRAIL alone (69.7%) at 24 hours. However, DOX treatment induced G2/M arrest in breast cancer and normal cells. Furthermore, the morphological features of apoptosis were determined by haematoxylin and eosin staining. Intriguingly, the hallmark of apoptosis was clearly observed in breast cancer treated with TZT compared to MCF-10A. The results suggest the significance of Zeb and TSA to foster the TRAIL-induced apoptosis in TNBC but not in normal breast epithelial cells, despite further molecular analyses are requisite to validate the enhancement of apoptosis induction. Conclusion This research provides an insight of potential alternative of TZT in treating the TNBC to improve the patients’ prognosis in the near future.
Trichostatin A
Triple-negative breast cancer
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Trichostatin A
Histone deacetylase inhibitor
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5-Demethylnobiletin is the active ingredient in citrus polymethoxyflavones that could inhibit the proliferation of several tumor cells. However, the anti-tumor effect of 5-Demethylnobiletin on glioblastoma and the underlying molecular mechanisms are remains unknown. In our study, 5-Demethylnobiletin markedly inhibited the viability, migration and invasion of glioblastoma U87-MG, A172 and U251 cells. Further research revealed that 5-Demethylnobiletin induces cell cycle arrest at the G0/G1 phase in glioblastoma cells by downregulating Cyclin D1 and CDK6 expression levels. Furthermore, 5-Demethylnobiletin significantly induced glioblastoma cells apoptosis by upregulating the protein levels of Bax and downregulating the protein level of Bcl-2, subsequently increasing the expression of cleaved caspase-3 and cleaved caspase-9. Mechanically, 5-Demethylnobiletin trigged G0/G1 phase arrest and apoptosis by inhibiting the ERK1/2, AKT and STAT3 signaling pathway. Furthermore, 5-Demethylnobiletin inhibition of U87-MG cell growth was reproducible in vivo model. Therefore, 5-Demethylnobiletin is a promising bioactive agent that might be used as glioblastoma treatment drug.
Cyclin-dependent kinase 6
Viability assay
Cyclin B1
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Triple negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with poor outcome. Because of lacking therapeutic targets, chemotherapy is the main treatment option for patients with TNBC. Overexpression of HDACs correlates with tumorigenesis, highlighting the potential of HDACs as therapeutic targets for TNBC. Here we demonstrate that trichostatin A (TSA, a HDAC inhibitor) selectively inhibits the proliferation of TNBC cell lines HCC1806 and HCC38 rather than a normal breast cell line MCF10A. The inhibition of TNBC by TSA is via its roles in inducing cell cycle arrest and apoptosis. TSA treatment leads to decreased expression of CYCLIN D1, CDK4, CDK6 and BCL-XL, but increased P21 expression. Moreover, combination of TSA with doxorubicin has synergistic effects on inhibiting proliferation of HCC1806 and HCC38 cells. Our studies identified a promising epigenetic-based therapeutic strategy that may be implemented in the therapy of fatal human breast cancer.
Triple-negative breast cancer
Trichostatin A
Cyclin-dependent kinase 6
Cite
Citations (17)