Abstract
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.
Highlights
Female breast cancer (BC) was the leading cause of cancer incidence globally in 2020.It accounted for 11.7% of all cancer cases with approximately 2.3 million new cases among women during the last year alone
Due to the fact that no data are available on whether Notch activity has an impact on the success or failure of received treatment in patients with luminal-type BC, in our current study we examined whether reduction or increase in Notch1 activity affects the Histone deacetylase inhibitors (HDIs)/CDDP
The anti-proliferative effect of CDDP, valproic acid (VPA), and Suberoylanilide hydroxamic acid (SAHA) was analyzed in MCF7 cells with increased and decreased Notch1 activity, versus native cells, using the MTT (3-(4,5dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay in order to establish the IC50 value for each analyzed compound in all lines (Table 1)
Summary
Female breast cancer (BC) was the leading cause of cancer incidence globally in 2020 It accounted for 11.7% of all cancer cases with approximately 2.3 million new cases among women during the last year alone. It was the fifth leading cause of cancer mortality, with 685,000 deaths worldwide [1]. BC is a heterogeneous disease with variable biological behavior, morphological features, and response to therapy. The current routine histological analyses for detection of the presence or absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) represent the earliest attempts to provide a more personalized approach to BC therapy, based on molecular drivers of the disease [2].
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