Cytotoxic and radiosensitising effects of a novel thioredoxin reductase inhibitor in breast cancer

SummaryRadiotherapy is an effective treatment modality for breast cancer but, unfortunately, not all patients respond fully with a significant number experiencing local recurrences. Overexpression of thioredoxin and thioredoxin reductase has been reported to cause multidrug and radiation resistance - their inhibition may therefore improve therapeutic efficacy. Novel indolequinone compounds have been shown, in pancreatic cancer models, to inhibit thioredoxin reductase activity and exhibit potent anticancer activity. The present study evaluates, using in vitro breast cancer models, the efficacy of a novel indolequinone compound (IQ9) as a single agent and in combination with ionising radiation using a variety of endpoint assays including cell proliferation, clonogenic survival, enzyme activity, and western blotting. Three triple-negative breast cancer (MDA-MB-231, MDA-MB-468, and MDA-MB-436) and two luminal (MCF-7 and T47D) breast cancer cell lines were used. Results show that treatment with IQ9 significantly inhibited thioredoxin reductase activity, and inhibited cell growth and colony formation of breast cancer cells with IC50 values in the low micromolar ranges. Enhanced radiosensitivity of triple-negative breast cancer cells was observed, with sensitiser enhancement ratios of 1.20–1.43, but with no evident radiosensitisation of luminal breast cancer cell lines. IQ9 upregulated protein expression of thioredoxin reductase in luminal but not in triple-negative breast cancer cells which may explain the observed differential radiosensitisation. This study provides important evidence of the roles of the thioredoxin system as an exploitable radiobiological target in breast cancer cells and highlights the potential therapeutic value of indolequinones as radiosensitisers.***This study was not part of a clinical trial. Clinical trial registration number: N/A

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Methionine restriction exposes a targetable redox vulnerability of triple-negative breast cancer cells by inducing thioredoxin reductase

Breast Cancer Research and Treatment ◽

10.1007/s10549-021-06398-y ◽

2021 ◽

Author(s):

Dmitry Malin ◽

Yoonkyu Lee ◽

Olga Chepikova ◽

Elena Strekalova ◽

Alexis Carlson ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Triple Negative ◽

Thioredoxin Reductase ◽

Methionine Restriction

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Effects of SAHA and EGCG on Growth Potentiation of Triple-Negative Breast Cancer Cells

Cancers ◽

10.3390/cancers11010023 ◽

2018 ◽

Vol 11 (1) ◽

pp. 23 ◽

Cited By ~ 24

Author(s):

Kayla Lewis ◽

Harrison Jordan ◽

Trygve Tollefsbol

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

White Women ◽

Triple Negative ◽

The United States ◽

Growth Potential ◽

Breast Cancer Cell Lines

Triple-negative breast cancer comprises approximately 15–20% of all breast cancers diagnosed and is nearly twice as common in black women than white women in the United States. We evaluated the effects of two epigenetic-modifying compounds on markers of growth potential in several triple-negative breast cancer cell lines. Suberoylanilide hydroxamic acid (SAHA), a histone deacetylase (HDAC) inhibitor currently used in the treatment of cutaneous T cell lymphoma, was administered to triple-negative breast cancer cells alone or in combination with epigallocatechin-3-gallate (EGCG), a DNA methyltransferase (DNMT) inhibitor isolated from green tea. The compounds affected the expression of oncogenic miR-221/222 and tumor suppressors, p27 and PTEN, in addition to estrogen receptor alpha (ERα). E-cadherin expression was increased while N-cadherin was decreased, indicating a more epithelial phenotype. In addition, the activity of DNMTs was diminished with the treatments, and there was a significant enrichment of AcH3 within the promoter of p27 and PTEN, suggesting a role of epigenetic mechanisms for the aforementioned changes. These results translated to reduced migration of the triple-negative breast cancer cells with the treatments. Together, these findings support the role of SAHA and EGCG in limiting growth and proliferation of breast cancer cells.

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Salicin a promising ER, PR and HER2 binding molecule proving lethal against Hormone + and triple negative breast cancer cells

International Journal of Ayurvedic Medicine ◽

10.47552/ijam.v12i1.1755 ◽

2021 ◽

Vol 12 (1) ◽

pp. 73-83

Author(s):

Mrudul Pravinbhai Vekaria ◽

Pravin Tirgar

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Mechanism Of Action ◽

Breast Cancer Cells ◽

Triple Negative ◽

Minimum Energy ◽

Good Choice ◽

Breast Cancer Cell Lines ◽

Mcf 7

Therapeutics against breast cancer is a major research field, due to inefficiency or partial efficiency of existing therapeutics. An urge to discover better therapeutics always persists. Our objective is to study salicin against breast cancer cells, in order to find its therapeutic properties. To study the effect of salicin on breast cancer cells, we performed MTT assay on MCF-7 (hormone positive) and MDA-MB-231 (triple negative) breast cancer cell lines, we did brine shrimp lethality test (BSLT) assay to see the lethal effects of salicin. By the help of bioinformatics we tried to locate the targets that delineate salicin activity. Salicin was docked with estrogen receptor (ER), progesterone receptor (PR) and Human epidermal growth factor receptor 2 (HER2) to study its binding efficiency and possible targets of salicin. Salicin remarkably reduces cell viability both in MCF-7 and MDA-MB-231, along with being lethal to brine shrimps. These results together opine that salicin can be an effective therapeutics against breast cancer cells. The mechanism of action of salicin is probably through ER, PR and HER2 receptors because it can efficiently bind these receptors with minimum energy required for binding. This explains that salicin can easily bind to these receptors. These results together opine that salicin can be an effective therapeutics against breast cancer cells. The mechanism of action of salicin is probably through ER, PR and HER2 receptors because it can efficiently bind these receptors with minimum binding energy. ER, PR and HER2 are major reasons behind the disease pathogenicity depending on the type of breast cancer. According to our results salicin may either induce apoptosis or reduce cellular mitosis both via P53 dependent and independent pathway, which makes salicin a good choice of both hormone positive and negative breast cancer cells.

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Interplay between Epigenetics, Expression of Estrogen Receptor- α, HER2/ERBB2 and Sensitivity of Triple Negative Breast Cancer Cells to Hormonal Therapy

Cancers ◽

10.3390/cancers11010013 ◽

2018 ◽

Vol 11 (1) ◽

pp. 13 ◽

Cited By ~ 8

Author(s):

Wafaa S Ramadan ◽

Cijo George Vazhappilly ◽

Ekram M Saleh ◽

Varsha Menon ◽

Aya M. AlAzawi ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Hormonal Therapy ◽

Breast Cancer Cells ◽

Triple Negative ◽

Breast Cancer Cell Lines ◽

Pronounced Increase ◽

Epigenetic Markers ◽

Epigenetic Modifiers

Triple negative breast cancer (TNBC) cells are resistant to hormonal/targeted therapies. This study aims to investigate epigenetic differences between TNBC and other types of breast cancer and the effect of epigenetic modulation on the response of TNBC cells to hormonal therapy. Thus, we investigated (i) the expression of different epigenetic markers, (ii) the effect of epigenetic modifying agents on the expression of ERα and HER2/ERBB2 and (iii) the effect on the response to tamoxifen in four breast cancer cell lines with different hormonal receptor status. Our results revealed a differential expression patterns of epigenetic markers in the four breast cancer cells. In TNBC cells, histone deacetylases (HDAC) 1 and 2 were less expressed, whereas HDACs 4 and 6 were overexpressed. Interestingly, treatment with epigenetic modifiers resulted in (i) a pronounced increase in the expression of ERα and HER2/ERBB2 along with (ii) an increase in the sensitivity of TNBC cells to tamoxifen. Collectively, this study indicates a different epigenetic background for TNBC cells, which represses the expression of ERα and HER2/ERBB2. Furthermore, we provide here the rationale for the use of epigenetic modifiers to enhance the response of TNBC to hormonal therapy through upregulation of ERα.

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BSCI-15. Osteopontin plays a crucial role in invasiveness of triple negative breast cancer cells in the context of human microglia

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab071.014 ◽

2021 ◽

Vol 3 (Supplement_3) ◽

pp. iii4-iii4

Author(s):

Kamil Wojnicki ◽

Agata Kochalska ◽

Katarzyna Poleszak ◽

Adria-Jaume Roura ◽

Ewa Matyja ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Triple Negative Breast Cancer ◽

Breast Cancer Cells ◽

Triple Negative ◽

Metastatic Breast ◽

Breast Cancer Cell Lines ◽

Breast Cancers ◽

Human Microglia

Abstract The triple-negative breast cancer (TNBC) is the most malignant among breast cancers and has the high risk of developing metastasis into the brain. Metastases of breast cancers are increasing and pose a clinical challenge as the current treatments are not effective due to the unique brain microenvironment for metastatic breast cancer cells. While the contribution of brain macrophages to the formation of the metastatic niche is established, factors responsible for the crosstalk between cells remain elusive. SPP1 encoding a secreted phosphoprotein 1 (ostepontin) is highly overexpressed in malignant breast cancers. We evaluated the role of SPP1 in invasion and metastasis of human breast cancer cells. We found the increased invasion of triple-negative MDA-MB-231 (MDA-231) cells in the presence of human microglial HMSV40 cells. Using Western blot analysis demonstrated the elevated levels of focal adhesion kinase (FAK) and signal transducer and activator of transcription 3 (STAT3) in MDA-231 cells in co-cultures. Moreover, blocking SPP1 and integrin interactions with the synthetic RGD peptide, efficiently diminished both basic and microglia-induced invasion of MDA-231. To assess the role of SPP1 in cell invasion, we established the MDA-231 cells with knocked-down SPP1 expression using shRNA (shSPP1). Interestingly, the shSPP1 cells were unresponsive towards HMSV40 microglia. We have previously found that an antibiotic minocycline reduces SPP1 expression in glioma cells. We performed cell toxicity studies on 4 breast cancer cell lines and various non-malignant cells. All tested malignant cancer cells were more sensitize to minocycline than non-cancerous cells and breast cancer cells derived from TNBC were the most susceptible. Altogether, we demonstrate that microglia support invasion of breast cancer cells via SPP1/osteopontin triggering the integrin signalling, and minocycline by downregulating SPP1 expression may reduce both basic and microglia-induced cancer invasion. Therefore, we purpose that minocycline could be a new therapeutics targeting metastatic brain cancers.

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