Harmine induces anticancer activity in breast cancer cells via targeting TAZ

Ding, Yu; He, Ju-Liang; Huang, Juan; Yu, Tong; Shi, Xin; Zhang, Tianzhu; Ge, Yan; Chen, Shanshan; Peng, Caixia

doi:10.3892/ijo.2019.4777

Cited by 35 publications

(34 citation statements)

References 54 publications

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“…Previous studies have shown that, at high concentrations (above 15-20 uM), harmine exerts significant anti-proliferative and cytotoxic (pro-apoptotic) activities in different types of cancer, consistently with our observations. In these studies, harmine acted with IC50s ranging from 50 to 160 uM [40][41][42]. At high concentrations, harmine was found to act by several mechanisms, described in different cell types and experimental conditions.…”

Section: Discussionmentioning

confidence: 95%

“…At high concentrations, harmine was found to act by several mechanisms, described in different cell types and experimental conditions. These mechanisms include inhibition of the expression levels of the TAZ transcriptional co-activator [40], the epithelial-mesenchymal transcription factor TWIST [42] and STAT3 transcription factor [41], inhibition of the phosphorylation of ERK and Akt [40,43], as well as inhibition of the anti-apoptotic Bcl2 protein and induction of the pro-apoptotic Bax protein [40]. However, those mechanisms were not observed at lower harmine concentrations.…”

Section: Discussionmentioning

confidence: 99%

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The β-carboline Harmine Induces Actin Dynamic Remodeling and Abrogates the Malignant Phenotype in Tumorigenic Cells

Moigne

Subra

Karam

et al. 2020

Cells

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Numerous studies have shown that alteration of actin remodeling plays a pivotal role in the regulation of morphologic and phenotypic changes leading to malignancy. In the present study, we searched for drugs that can regulate actin polymerization and reverse the malignant phenotype in cancer cells. We developed a cell-free high-throughput screening assay for the identification of compounds that induce the actin polymerization in vitro, by fluorescence anisotropy. Then, the potential of the hit compound to restore the actin cytoskeleton and reverse the malignant phenotype was checked in EWS-Fli1-transformed fibroblasts and in B16-F10 melanoma cells. A β-carboline extracted from Peganum harmala (i.e., harmine) is identified as a stimulator of actin polymerization through a mechanism independent of actin binding and requiring intracellular factors involved in a process that regulates actin kinetics. Treatment of malignant cells with non-cytotoxic concentrations of harmine induces the recovery of a non-malignant cell morphology accompanied by reorganization of the actin cytoskeleton, rescued cell–cell adhesion, inhibition of cell motility and loss of anchorage-independent growth. In conclusion, harmine induces the reversion of the malignant phenotype by a process involving the modulation of actin dynamics and is a potential anti-tumor agent acting principally through a non-cytotoxic process.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

The β-carboline Harmine Induces Actin Dynamic Remodeling and Abrogates the Malignant Phenotype in Tumorigenic Cells

Moigne

Subra

Karam

et al. 2020

Cells

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“…In addition to inducing Twist1 degradation, harmine can also inhibit breast cancer cell proliferation and migration by inhibiting the expression of TAZ [ 27 ]. TAZ is a downstream effector of the Hippo pathway that plays an important role in mammalian development [ 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…In MDA-MB-231 breast cancer cells that overexpress breast cancer resistance protein (BCRP), harmine inhibits BCRP [ 26 ]. Harmine is also reported to antagonize transcriptional coactivator with PDZ-binding motif (TAZ), suppress breast cancer cell proliferation and migration, and promote cancer cell apoptosis in vitro [ 27 ]. Recently, in an unbiased screen, harmine was identified as the first pharmacologic inhibitor of Twist1 with significant anti-tumor activity in oncogene-driven lung cancer [ 28 ].…”

Section: Introductionmentioning

confidence: 99%

Harmine inhibits breast cancer cell migration and invasion by inducing the degradation of Twist1

et al. 2021

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Breast cancer is the leading cause of cancer-related deaths in the United States. The majority of deaths (90%) in breast cancer patients is caused by invasion and metastasis–two features related to the epithelial-to-mesenchymal transition (EMT). Twist1 is a key transcription factor that promotes the EMT, which leads to cell migration, invasion, cancer metastasis, and therapeutic resistance. Harmine is a beta-carboline alkaloid found in a variety of plants and was recently shown to be able to induce degradation of Twist Family BHLH Transcription Factor 1 (Twist1) in non-small cell lung cancer cells (NSCLC). In this study, we show that harmine can inhibit migration and invasion of both human and mouse breast cancer cells in a dose-dependent manner. Further study shows that this inhibition is most likely achieved by inducing a proteasome-dependent Twist1 degradation. At the concentrations tested, harmine did not affect the viability of cells significantly, suggesting that its inhibition of cancer cell migration and invasion is largely independent of its cytotoxicity, but due to its ability to affect regulators of EMT such as Twist1. This result may facilitate the development of strategies that target Twist1 to treat metastatic breast cancer, as Twist1 is expressed at a high level in metastatic breast cancer cells but not in normal cells.

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“…It causes DNA frameshift mutation and cytotoxic effects that is occurred by a signi cant inhibition of telomerase activity [9] [10]. Also, harmine was found to induce apoptosis in human breast cancer cell line by downregulation of TAZ gene which encodes tafazzin protein [11].…”

Section: Introductionmentioning

confidence: 99%

Loading Harmine On Nanographene Changes The Inhibitory Effects of Free Harmine Against MCF7 and Fibroblast Cells

Mortazavi

Heidari

Rabiei

et al. 2021

Preprint

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Today cancer is one of the main causes of death all over the world. Chemotherapy, which is one of the main therapies in the treatment of cancer, causes several side effects by damaging healthy cells. Therefore, carbon nanomaterial systems have been developed to optimize therapeutics procedures with the least negative consequences. Targeting nanographene oxide (NGO) with folic acid (FA) molecules allows the recognition of MCF-7 cells, which are folic acid receptor (FR) positive. Harmine is a pharmacologically active secondary metabolite that is produced by Peganum harmala. It is found that this metabolite induces apoptosis to human breast cancer cell lines by intercalating DNA molecules. In this study, harmine was loaded on FA-NGO (FA-NGO/harmine) via π-π stacking and hydrophobic interactions and the cytotoxicity against MCF-7, as FR positive cancerous cell, and fibroblast cells, as normal FR negative cell, were investigated. The in vitro studies illustrated that FA-NGO/harmine have remarkably higher cytotoxicity against MCF-7 cells, about 60% cell loss, in comparison with free harmine with 40% cell loss (in the concentration of 40 μg. mL-1). However, the released amount of harmine into normal fibroblast cells was considerably low, only 28% cell loss in dose of 40 μg. mL-1. Our results suggest that the controlled release of harmine into FR positive cancerous cells might have a substantially high cytotoxicity effect.

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Harmine induces anticancer activity in breast cancer cells via targeting TAZ

Cited by 35 publications

References 54 publications

The β-carboline Harmine Induces Actin Dynamic Remodeling and Abrogates the Malignant Phenotype in Tumorigenic Cells

The β-carboline Harmine Induces Actin Dynamic Remodeling and Abrogates the Malignant Phenotype in Tumorigenic Cells

Harmine inhibits breast cancer cell migration and invasion by inducing the degradation of Twist1

Loading Harmine On Nanographene Changes The Inhibitory Effects of Free Harmine Against MCF7 and Fibroblast Cells

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