scholarly journals Additive Pharmacological Interaction between Cisplatin (CDDP) and Histone Deacetylase Inhibitors (HDIs) in MDA-MB-231 Triple Negative Breast Cancer (TNBC) Cells with Altered Notch1 Activity—An Isobolographic Analysis

2019 ◽  
Vol 20 (15) ◽  
pp. 3663 ◽  
Author(s):  
Anna Wawruszak ◽  
Jarogniew J. Luszczki ◽  
Joanna Kalafut ◽  
Karolina Okla ◽  
Marta Halasa ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Histone Deacetylase ◽  
Triple Negative Breast Cancer ◽  
Histone Deacetylase Inhibitors ◽  
Triple Negative ◽  
Activity Level ◽  
Additive Interaction ◽  
Pharmacological Interaction ◽  
Isobolographic Analysis

The aim of this study was to investigate the influence of the Notch1 activity level on the pharmacological interaction between cisplatin (CDDP) and two histone deacetylase inhibitors (HDIs)—valproic acid (VPA) and vorinostat (SAHA) in the triple negative breast cancer (TNBC) cells. Stable breast cancer (BC) cell lines with increased and decreased activity of Notch1 were generated using a transfection method. The type of interaction between CDDP and the HDIs was determined by isobolographic analysis of cell proliferation in MDA-MB-231 cells with differential levels of Notch1 activity in vitro. The combination of CDDP/SAHA and CDDP/VPA in the MDA-MB-231 triple negative breast cancer (TNBC) cells with increased activity of Notch1, as well as CDDP/VPA in the MDA-MB-231 cells with decreased activity of Notch1, yielded an additive interaction, whereas additivity with a tendency towards antagonism was observed for the combination of CDDP/SAHA in MDA-MB-231 cells with the decreased activity of Notch1. Our studies demonstrated that SAHA and VPA might be considered as potential therapeutic agents in combination therapy with CDDP against TNBC with altered Notch1 activity.

scholarly journals Multiple screening approaches reveal HDAC6 as a novel regulator of glycolytic metabolism in triple-negative breast cancer

2021 ◽  
Vol 7 (3) ◽  
pp. eabc4897
Author(s):  
Catríona M. Dowling ◽  
Kate E. R. Hollinshead ◽  
Alessandra Di Grande ◽  
Justin Pritchard ◽  
Hua Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Histone Deacetylase Inhibitors ◽  
Triple Negative ◽  
Mitochondrial Apoptosis ◽  
Glycolytic Metabolism ◽  
Set Up ◽  
Screening Approaches

Triple-negative breast cancer (TNBC) is a subtype of breast cancer without a targeted form of therapy. Unfortunately, up to 70% of patients with TNBC develop resistance to treatment. A known contributor to chemoresistance is dysfunctional mitochondrial apoptosis signaling. We set up a phenotypic small-molecule screen to reveal vulnerabilities in TNBC cells that were independent of mitochondrial apoptosis. Using a functional genetic approach, we identified that a “hit” compound, BAS-2, had a potentially similar mechanism of action to histone deacetylase inhibitors (HDAC). An in vitro HDAC inhibitor assay confirmed that the compound selectively inhibited HDAC6. Using state-of-the-art acetylome mass spectrometry, we identified glycolytic substrates of HDAC6 in TNBC cells. We confirmed that inhibition or knockout of HDAC6 reduced glycolytic metabolism both in vitro and in vivo. Through a series of unbiased screening approaches, we have identified a previously unidentified role for HDAC6 in regulating glycolytic metabolism.

scholarly journals A New Histone Deacetylase Inhibitor Enhances Radiation Sensitivity through the Induction of Misfolded Protein Aggregation and Autophagy in Triple-Negative Breast Cancer

Cancers ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 1703
Author(s):  
Hui-Wen Chiu ◽  
Ya-Ling Yeh ◽  
Sheng-Yow Ho ◽  
Yuan-Hua Wu ◽  
Bour-Jr Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Protein Aggregation ◽  
Er Stress ◽  
Histone Deacetylase ◽  
Triple Negative Breast Cancer ◽  
Combination Treatment ◽  
Histone Deacetylase Inhibitors ◽  
Triple Negative ◽  
Combined Treatment ◽  
Misfolded Protein

Radiation therapy (RT) is one of the main treatments for triple-negative breast cancer (TNBC). However, many patients experience RT failure due to the metastatic potential of RT and the radiation resistance of several cancers. Histone deacetylase inhibitors (HDACis) can serve as radiosensitizers. In this study, we investigated whether a novel HDACi, TMU-35435, could reinforce radiosensitivity through the induction of misfolded protein aggregation and autophagy in TNBC. Significantly enhanced toxicity was found for the combination treatment compared with TMU-35435 or irradiation (IR) treatment alone in TNBC cells. The combination treatment induced misfolded protein aggregation and TMU-35435 inhibited the interaction of HDAC6 with dynein. Furthermore, the combined treatment induced endoplasmic reticulum (ER) stress but did not trigger apoptosis. In addition, the combination treatment caused autophagic cell death. Tumor growth in the mouse of model orthotopic breast cancer was suppressed by the combination treatment through the induction of ER stress and autophagy. These findings support the future evaluation of the novel HDACi TMU-35435, as a potent radiosensitizer in TNBC.

scholarly journals Sensitization of MCF7 Cells with High Notch1 Activity by Cisplatin and Histone Deacetylase Inhibitors Applied Together

2021 ◽  
Vol 22 (10) ◽  
pp. 5184
Author(s):  
Anna Wawruszak ◽  
Jarogniew Luszczki ◽  
Marta Halasa ◽  
Estera Okon ◽  
Sebastian Landor ◽  
...  
Keyword(s):  
Histone Deacetylase ◽  
Histone Deacetylase Inhibitors ◽  
Combined Therapy ◽  
Fixed Ratio ◽  
Activity Level ◽  
Mcf7 Cells ◽  
Pharmacological Interaction ◽  
Isobolographic Analysis ◽  
Anti Cancer ◽  
Luminal Type

Histone deacetylase inhibitors (HDIs) are promising anti-cancer agents that inhibit proliferation of many types of cancer cells including breast carcinoma (BC) cells. In the present study, we investigated the influence of the Notch1 activity level on the pharmacological interaction between cisplatin (CDDP) and two HDIs, valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA, vorinostat), in luminal-like BC cells. The type of drug–drug interaction between CDDP and HDIs was determined by isobolographic analysis. MCF7 cells were genetically modified to express differential levels of Notch1 activity. The cytotoxic effect of SAHA or VPA was higher on cells with decreased Notch1 activity and lower for cells with increased Notch1 activity than native BC cells. The isobolographic analysis demonstrated that combinations of CDDP with SAHA or VPA at a fixed ratio of 1:1 exerted additive or additive with tendency toward synergism interactions. Therefore, treatment of CDDP with HDIs could be used to optimize a combined therapy based on CDDP against Notch1-altered luminal BC. In conclusion, the combined therapy of HDIs and CDDP may be a promising therapeutic tool in the treatment of luminal-type BC with altered Notch1 activity.

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