Sulforaphane-Induced Cell Cycle Arrest and Senescence are accompanied by DNA Hypomethylation and Changes in microRNA Profile in Breast Cancer Cells

Lewińska, Anna; Adamczyk‐Grochala, Jagoda; Deręgowska, Anna; Wnuk, Maciej

doi:10.7150/thno.20657

Cited by 144 publications

(98 citation statements)

References 74 publications

(82 reference statements)

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“…Nevertheless, AZ is already in clinical use for other conditions and thus can be readily repurposed. In comparison, SFN, as a recognized epigenetic modulator that can suppress miRNA and growth factors supporting cancer stem cells in diverse cancers [53,54], as well as targeting survival pathways, is significantly more potent as an anti-tumor agent. Recent studies on pancreatic cancer demonstrating that SFN induces ROS formation via metabolic effects may account for the observed anti-tumor effects similar to those reported here on bronchial carcinoids [55].…”

Section: Discussionmentioning

confidence: 99%

Human bronchial carcinoid tumor initiating cells are targeted by the combination of acetazolamide and sulforaphane

et al. 2019

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Background Bronchial carcinoids are neuroendocrine tumors that present as typical (TC) and atypical (AC) variants, the latter being more aggressive, invasive and metastatic. Studies of tumor initiating cell (TIC) biology in bronchial carcinoids has been hindered by the lack of appropriate in-vitro and xenograft models representing the bronchial carcinoid phenotype and behavior. Methods Bronchial carcinoid cell lines (H727, TC and H720, AC) were cultured in serum-free growth factor supplemented medium to form 3D spheroids and serially passaged up to the 3rd generation permitting expansion of the TIC population as verified by expression of stemness markers, clonogenicity in-vitro and tumorigenicity in both subcutaneous and orthotopic (lung) models. Acetazolamide (AZ), sulforaphane (SFN) and the AZ + SFN combination were evaluated for targeting TIC in bronchial carcinoids. Results Data demonstrate that bronchial carcinoid cell line 3rd generation spheroid cells show increased drug resistance, clonogenicity, and tumorigenic potential compared with the parental cells, suggesting selection and expansion of a TIC fraction. Gene expression and immunolabeling studies demonstrated that the TIC expressed stemness factors Oct-4, Sox-2 and Nanog. In a lung orthotopic model bronchial carcinoid, cell line derived spheroids, and patient tumor derived 3rd generation spheroids when supported by a stroma, showed robust tumor formation. SFN and especially the AZ + SFN combination were effective in inhibiting tumor cell growth, spheroid formation and in reducing tumor formation in immunocompromised mice. Conclusions Human bronchial carcinoid tumor cells serially passaged as spheroids contain a higher fraction of TIC exhibiting a stemness phenotype. This TIC population can be effectively targeted by the combination of AZ + SFN. Our work portends clinical relevance and supports the therapeutic use of the novel AZ+ SFN combination that may target the TIC population of bronchial carcinoids.

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Section: Discussionmentioning

confidence: 99%

Human bronchial carcinoid tumor initiating cells are targeted by the combination of acetazolamide and sulforaphane

et al. 2019

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“…Moreover, SFN induced a decrease in m6A RNA methylation pattern that is also considered as an epigenetic regulation at the RNA level, recently discovered. So, SFN may promote genetic instability directly or indirectly by SFNmediated DNA hypomethylation and/or diminution in m6A RNA methylation pools (Lewinska et al 2017). Interestingly, in another study, authors demonstrated that SNF upregulates miR-140, which is a negative regulator of cancer stem cell formation in basal-like early stage breast cancer.…”

Section: Phytochemicals Modulating the Epigenetic Alterations Of Dna mentioning

confidence: 98%

Phytochemicals in cancer prevention: modulating epigenetic alterations of DNA methylation

Pop

Enciu

Tarcomnicu³

et al. 2019

Phytochem Rev

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Cancer can take many years to develop from initiation to progression. The long period of development might represent an opportunity to use multi-functional, multi-targeted preventive drugs to block or reverse tumorigenesis. One path to cancer prevention could be to target and reverse the early epigenetic alterations. Unlike genetic mutations, they are potentially reversible and can be restored to their normal state. Epidemiological studies have revealed the close link between rich diets in bioactive compounds and the low incidence of different types of cancer. Thus, the study regarding the impact of bioactive nutrients on the epigenome has become widespread, with focus on the modulation of epigenetic mechanisms of gene expression, such as genomic DNA methylation. Following altered activity and expression of DNA methyl transferases and ten-eleven translocation enzymes, different types of cancers exert local DNA hypermethylation of gene promoters of tumor suppressor genes or of non-coding RNAs (microRNAs and long-noncoding RNAs), as well as global hypomethylation. Recently, the potential of phytochemicals to modulate epigenetic events in human health has become evident, although specific molecular mechanisms are still unclear. Phytochemicals and other bioactive dietary compounds can restore global and gene-specific promoter DNA methylation patterns by reactivating DNA methyltransferases or by providing the provision of methyl groups. Several natural products, such as EGCG, curcumin, sulforaphane, have shown DNMT inhibitory activity, but this property needs more in-depth investigations. This review focuses on the impact of modified DNA methylation pattern on early carcinogenesis and summarizes the effects/mechanism of phytochemical interventions on this type of epigenetic alterations.

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“…It has been reported that genetic aberrations such as impairment in the expression of miRNAs contribute to the development of this cancer (Imani, Wu, & Fu, 2018). Sulforaphane is a potential antitumor agent that considerably diminishes the expression of four miRNAs involved in the breast cancer development, miRNA-23b, miRNA-92b, miRNA-381, and miRNA-382, leading to the inhibition of breast cancer progression (Lewinska, Adamczyk-Grochala, Deregowska, & Wnuk, 2017). Cancer cells use Wnt signaling pathway in order to improve their malignancy.…”

Section: Mirnas and Sulforaphanementioning

confidence: 99%

MicroRNAs as novel targets of sulforaphane in cancer therapy: The beginning of a new tale?

Rafiei

Ashrafizadeh

Ahmadi

2020

Phytotherapy Research

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Effective management and treatment of cancer depend on developing novel antitumor drugs with the capability of targeting various molecular pathways. Identification and subsequent targeting of these pathways are of importance in cancer therapy. MicroRNAs (miRNAs) are small noncoding RNA molecules responsible for post‐transcriptional regulation of genes. Notably, miRNAs participate in a number of biological processes such as proliferation, apoptosis, differentiation, and cell cycle regulation. So, any impairment in the expression and function of miRNAs is associated with development of disorders, particularly cancer. Naturally occurring nutraceutical compounds have attracted much attention due to their great antitumor activity. Among them, sulforaphane isolated from Brassica oleracea (broccoli) is of interest due to its therapeutic and biological activities such as antidiabetic, antioxidant, anti‐inflammatory, hepatoprotection, and cardiprotection. Sulforaphane has demonstrated great antitumor activity and is able to significantly inhibit proliferation, viability, migration, malignancy, and epithelial‐to‐mesenchymal transition of cancer cells. These antitumor effects have widely been investigated, and it appears that there is a need for a precise review to demonstrate the molecular pathway that sulforaphane follows to exert its antitumor activity. At the present review, we focus on the modulatory impact of sulforaphane on miRNAs and exhibit that how various miRNAs in different cancers are regulated by sulforaphane.

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Sulforaphane-Induced Cell Cycle Arrest and Senescence are accompanied by DNA Hypomethylation and Changes in microRNA Profile in Breast Cancer Cells

Cited by 144 publications

References 74 publications

Human bronchial carcinoid tumor initiating cells are targeted by the combination of acetazolamide and sulforaphane

Human bronchial carcinoid tumor initiating cells are targeted by the combination of acetazolamide and sulforaphane

Phytochemicals in cancer prevention: modulating epigenetic alterations of DNA methylation

MicroRNAs as novel targets of sulforaphane in cancer therapy: The beginning of a new tale?

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