Two Birds with One Stone: NFAT1-MDM2 Dual Inhibitors for Cancer Therapy

Wang, Wei; Zafar, Atif; Rajaei, Mehrdad; Zhang, Ruiwen

doi:10.3390/cells9051176

Cited by 8 publications

(8 citation statements)

References 106 publications

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“…Several therapeutic agents have been used as an inhibitor of NFAT and MDM2. One of the important targets of NFAT and MDM2 is Lin A [ 100 ]. Qin et al [ 95 ] conducted in an vitro study to investigate Lin A’s role in inhibiting the NFAT-MDM2 pathway.…”

Section: Downstream Regulation Of Signaling Pathways By Natural Productsmentioning

confidence: 99%

A Review of Twenty Years of Research on the Regulation of Signaling Pathways by Natural Products in Breast Cancer

et al. 2022

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Breast cancer (BC) is the second leading cause of death among women, and it has become a global health issue due to the increasing number of cases. Different treatment options, including radiotherapy, surgery, chemotherapy and anti-estrogen therapy, aromatase inhibitors, anti-angiogenesis drugs, and anthracyclines, are available for BC treatment. However, due to its high occurrence and disease progression, effective therapeutic options for metastatic BC are still lacking. Considering this scenario, there is an urgent need for an effective therapeutic strategy to meet the current challenges of BC. Natural products have been screened as anticancer agents as they are cost-effective, possess low toxicity and fewer side effects, and are considered alternative therapeutic options for BC therapy. Natural products showed anticancer activities against BC through the inhibition of angiogenesis, cell migrations, proliferations, and tumor growth; cell cycle arrest by inducing apoptosis and cell death, the downstream regulation of signaling pathways (such as Notch, NF-κB, PI3K/Akt/mTOR, MAPK/ERK, and NFAT-MDM2), and the regulation of EMT processes. Natural products also acted synergistically to overcome the drug resistance issue, thus improving their efficacy as an emerging therapeutic option for BC therapy. This review focused on the emerging roles of novel natural products and derived bioactive compounds as therapeutic agents against BC. The present review also discussed the mechanism of action through signaling pathways and the synergistic approach of natural compounds to improve their efficacy. We discussed the recent in vivo and in vitro studies for exploring the overexpression of oncogenes in the case of BC and the current status of newly discovered natural products in clinical investigations.

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Section: Downstream Regulation Of Signaling Pathways By Natural Productsmentioning

confidence: 99%

A Review of Twenty Years of Research on the Regulation of Signaling Pathways by Natural Products in Breast Cancer

et al. 2022

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“…The NFAT family is expressed in several cancer cell types and plays roles in survival, invasive migration, angiogenesis, and inflammatory microenvironment maintenance ( Ryeom et al, 2008 ). In breast cancer cells, a member of the NFAT family, NFAT1, is ubiquitinated by the E3 ubiquitin ligase murine double minute 2 (MDM2) downstream of Akt and GSK-3 signaling ( Wang et al, 2020b ). Activated NFAT1 promotes the migration and invasion of breast cancer cells in vitro ( Jauliac et al, 2002 ).…”

Section: Irf2bp2 In Cancer Immunomodulationmentioning

confidence: 99%

The Transcriptional Co-factor IRF2BP2: A New Player in Tumor Development and Microenvironment

Pastor

Pereira

Viola

2021

Front. Cell Dev. Biol.

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Interferon regulatory factor 2-binding protein 2 (IRF2BP2) encodes a member of the IRF2BP family of transcriptional regulators, which includes IRF2BP1, IRF2BP2, and IRF2BPL (EAP1). IRF2BP2 was initially identified as a transcriptional corepressor that was dependent on Interferon regulatory factor-2 (IRF-2). The IRF2BP2 protein is found in different organisms and has been described as ubiquitously expressed in normal and tumor cells and tissues, indicating a possible role for this transcriptional cofactor in different cell signaling pathways. Recent data suggest the involvement of IRF2BP2 in the regulation of several cellular functions, such as the cell cycle, cell death, angiogenesis, inflammation and immune response, thereby contributing to physiological cell homeostasis. However, an imbalance in IRF2BP2 function may be related to the pathophysiology of cancer. Some studies have shown the association of IRF2BP2 expression in hematopoietic and solid tumors through mechanisms based on gene fusion and point mutations in gene coding sequences, and although the biological functions of these types of hybrid and mutant proteins are not yet known, they are thought to be involved in an increase in the likelihood of tumor development. In this review, we address the possible involvement of IRF2BP2 in tumorigenesis through its regulation of important pathways involved in tumor development.

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“…Overexpression of MDM2 and NFAT1 in cancers is correlated with poor prognosis and inhibition of these proteins is a promising targeting strategy for cancer therapy [ 66 ]. NFAT1 modulates MDM2 transcription and activates MDM2 expression, which leads to an increase in p53 inactivation that drives tumourigenesis.…”

Section: Apoptosismentioning

confidence: 99%

“…The Zhang lab initially identified genistein as an MDM2 and NFAT1 dual inhibitor. They expanded their search to develop small molecules with more potent activity, using a computational structure-based screening of natural products that led to the discovery of JapA, LinA and InuA [ 66 ]. A recent report on LinA showed that it is less sensitive in inducing apoptosis in TNBC cells, hence will not be discussed in this review.…”

Section: Apoptosismentioning

confidence: 99%

Small Molecules Targeting Programmed Cell Death in Breast Cancer Cells

Maniam

2021

IJMS

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Targeted chemotherapy has become the forefront for cancer treatment in recent years. The selective and specific features allow more effective treatment with reduced side effects. Most targeted therapies, which include small molecules, act on specific molecular targets that are altered in tumour cells, mainly in cancers such as breast, lung, colorectal, lymphoma and leukaemia. With the recent exponential progress in drug development, programmed cell death, which includes apoptosis and autophagy, has become a promising therapeutic target. The research in identifying effective small molecules that target compensatory mechanisms in tumour cells alleviates the emergence of drug resistance. Due to the heterogenous nature of breast cancer, various attempts were made to overcome chemoresistance. Amongst breast cancers, triple negative breast cancer (TNBC) is of particular interest due to its heterogeneous nature in response to chemotherapy. TNBC represents approximately 15% of all breast tumours, however, and still has a poor prognosis. Unlike other breast tumours, signature targets lack for TNBCs, causing high morbidity and mortality. This review highlights several small molecules with promising preclinical data that target autophagy and apoptosis to induce cell death in TNBC cells.

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Two Birds with One Stone: NFAT1-MDM2 Dual Inhibitors for Cancer Therapy

Cited by 8 publications

References 106 publications

A Review of Twenty Years of Research on the Regulation of Signaling Pathways by Natural Products in Breast Cancer

A Review of Twenty Years of Research on the Regulation of Signaling Pathways by Natural Products in Breast Cancer

The Transcriptional Co-factor IRF2BP2: A New Player in Tumor Development and Microenvironment

Small Molecules Targeting Programmed Cell Death in Breast Cancer Cells

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