scholarly journals Unlocking the Secrets of Cancer Stem Cells with γ-Secretase Inhibitors: A Novel Anticancer Strategy

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 972
Author(s):  
Maryam Ghanbari-Movahed ◽  
Zahra Ghanbari-Movahed ◽  
Saeideh Momtaz ◽  
Kaitlyn L. Kilpatrick ◽  
Mohammad Hosein Farzaei ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Notch Signaling ◽  
English Language ◽  
Inhibitory Effect ◽  
Notch Signaling Pathway ◽  
In Vivo Studies ◽  
Targeting Therapy

The dysregulation of Notch signaling is associated with a wide variety of different human cancers. Notch signaling activation mostly relies on the activity of the γ-secretase enzyme that cleaves the Notch receptors and releases the active intracellular domain. It is well-documented that γ-secretase inhibitors (GSIs) block the Notch activity, mainly by inhibiting the oncogenic activity of this pathway. To date, several GSIs have been introduced clinically for the treatment of various diseases, such as Alzheimer’s disease and various cancers, and their impacts on Notch inhibition have been found to be promising. Therefore, GSIs are of great interest for cancer therapy. The objective of this review is to provide a systematic review of in vitro and in vivo studies for investigating the effect of GSIs on various cancer stem cells (CSCs), mainly by modulation of the Notch signaling pathway. Various scholarly electronic databases were searched and relevant studies published in the English language were collected up to February 2020. Herein, we conclude that GSIs can be potential candidates for CSC-targeting therapy. The outcome of our study also indicates that GSIs in combination with anticancer drugs have a greater inhibitory effect on CSCs.

Targeting cancer stem cells with a pan-BCL-2 inhibitor in preclinical and clinical settings in patients with gastroesophageal carcinoma

Gut ◽  
2021 ◽  
pp. gutjnl-2020-321175
Author(s):  
Shumei Song ◽  
Qiongrong Chen ◽  
Yuan Li ◽  
Guang Lei ◽  
Ailing Scott ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Antitumour Activity ◽  
Clinical Specimen ◽  
Therapy Resistance ◽  
In Vivo Studies ◽  
Induced Apoptosis

ObjectiveGastro-oesophageal cancers (GEC) are resistant to therapy and lead to poor prognosis. The cancer stem cells (CSCs) and antiapoptotic pathways often confer therapy resistance. We sought to elucidate the antitumour action of a BCL-2 inhibitor, AT101 in GEC in vitro, in vivo and in a clinical trial.MethodsExtensive preclinical studies in vitro and in vivo were carried out to establish the mechanism action of AT101 on targeting CSCs and antiapoptotic proteins. A pilot clinical trial in patients with GEC was completed with AT-101 added to standard chemoradiation.ResultsOverexpression of BCL-2 and MCL-1 was noted in gastric cancer tissues (GC). AT-101 induced apoptosis, reduced proliferation and tumour sphere formation in MCL-1/BCL-2 high GC cells. Interestingly, AT101 dramatically downregulated genes (YAP-1/Sox9) that control CSCs in GEC cell lines regardless of BCL-2/MCL-1 expression. Addition of docetaxel to AT-101 amplified its antiproliferation and induced apoptosis effects. In vivo studies confirmed the combination of AT101 and docetaxel demonstrated stronger antitumour activity accompanied with significant decrease of CSCs biomarkers (YAP1/SOX9). In a pilot clinical trial, 13 patients with oesophageal cancer (EC) received AT101 orally concurrently with chemoradiation. We observed dramatic clinical complete responses and encouraging overall survival in these patients. Clinical specimen analyses revealed that AT-101 dramatically reduced the expression of CSCs genes in treated EC specimens indicating antitumour activity of AT101 relies more on its anti-CSCs activity.ConclusionsOur preclinical and clinical data suggest that AT-101 overcomes resistance by targeting CSCs pathways suggesting a novel mechanism of action of AT101 in patients with GEC.

scholarly journals RBP-J Deficiency Promoted The Proliferation and Differentiation of CD133-Positive Ependymal Cells In Vitro and In Vivo Studies

2021 ◽  
Author(s):  
Xin Ye ◽  
Mengyi Li ◽  
Wei Bian ◽  
Junwei Li ◽  
Ting Zhang ◽  
...  
Keyword(s):  
Notch Signaling ◽  
Signaling Pathway ◽  
Notch Signaling Pathway ◽  
In Vivo Studies ◽  
Ependymal Cells ◽  
Ependymal Layer ◽  
Proliferation And Differentiation ◽  
Mature Neurons

Abstract Although the ependymal cells were reported to have the characteristics of neural stem cells (NSCs), the properties of CD133-ependymal cells have not been uncovered, in particular, it is largely unknown about the effect of Notch signaling pathway on the neurogenesis of CD133-positive ependymal cells. By using the transgenic mouse and primarily cultured ependymal cells, we found that the immunoreactivity for prominin-1/CD133 was exclusively localized in the subventricular zone (SVZ) and ependymal layer of ventricles, moreover, most CD133-positive ependymal cells were co-labeled with Nestin. In addition, RBP-J, a key nuclear effector of Notch signaling pathway, was highly active in CD133-positive ependymal cells. Our results demonstrated that CD133-positive ependymal cells can differentiate into the immature and mature neurons, in particular, the number of CD133-positive ependymal cells differentiating into the immature and mature neurons was significantly increased following the deficiency or interference of RBP-J in vivo or in vitro. By using real-time qPCR and Western blot, we found that RBP-J and Hes1 were down-regulated while Notch1 was up-regulated in the expression levels of mRNAs and proteins following the deficiency or interference of RBP-J in vivo or in vitro. These results demonstrated RBP-J deficiency promoted the proliferation and differentiation of CD133-positive ependymal cells. Therefore, we speculated that RBP-J could maintain CD133-positive ependymal cells in the characteristics of NSCs possibly by regulating Notch1/RBP-J/Hes1 pathway.

scholarly journals Cancer Stem Cells: Powerful Targets to Improve Current Anticancer Therapeutics

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Rayana L. Bighetti-Trevisan ◽  
Lucas O. Sousa ◽  
Rogerio M. Castilho ◽  
Luciana O. Almeida
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cancer Cells ◽  
Resistance Mechanisms ◽  
In Vivo Studies ◽  
Tumor Resistance ◽  
Therapeutic Implications ◽  
Anticancer Therapeutics

A frequent observation in several malignancies is the development of resistance to therapy that results in frequent tumor relapse and metastasis. Much of the tumor resistance phenotype comes from its heterogeneity that halts the ability of therapeutic agents to eliminate all cancer cells effectively. Tumor heterogeneity is, in part, controlled by cancer stem cells (CSC). CSC may be considered the reservoir of cancer cells as they exhibit properties of self-renewal and plasticity and the capability of reestablishing a heterogeneous tumor cell population. The endowed resistance mechanisms of CSC are mainly attributed to several factors including cellular quiescence, accumulation of ABC transporters, disruption of apoptosis, epigenetic reprogramming, and metabolism. There is a current need to develop new therapeutic drugs capable of targeting CSC to overcome tumor resistance. Emerging in vitro and in vivo studies strongly support the potential benefits of combination therapies capable of targeting cancer stem cell-targeting agents. Clinical trials are still underway to address the pharmacokinetics, safety, and efficacy of combination treatment. This review will address the main characteristics, therapeutic implications, and perspectives of targeting CSC to improve current anticancer therapeutics.

scholarly journals Participation of BMI-1 protein in cancer

2017 ◽  
Vol 71 (0) ◽  
pp. 0-0 ◽  
Author(s):  
Agnieszka Zaczek ◽  
Paweł Jóźwiak ◽  
Anna Krześlak
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
In Vivo Studies ◽  
Histone H2a ◽  
Cellular Processes ◽  
Promising Target ◽  
Polycomb Repressive Complex 1

BMI-1 (B-lymphoma Mo-MLV insertion region 1) protein is a constituent of Polycomb Repressive Complex 1 (PRC1) that via ubiquitination of histone H2A affects expression of many genes. BMI-1 is involved in cellular processes such as DNA repair, proliferation, growth, senescence and apoptosis. BMI-1 plays a key role in biology of stem cells including cancer stem cells by regulation of their self-renewal and differentiation. Accumulating evidence has revealed that overexpression of BMI-1 in many human cancers correlates with disease progression and therapy failure. The results of in vitro and in vivo studies confirm the involvement of BMI-1 in tumor initiation as well as invasion, metastasis and chemoresistance. Taking into account significant role of BMI1 in tumorigenesis, especially associated with cancer stem cells, it seems that this gene may be a promising target of anticancer therapies.

Phenolic Acids Exert Anticholinesterase and Cognition-Improving Effects

2018 ◽  
Vol 15 (6) ◽  
pp. 531-543 ◽  
Author(s):  
Dominik Szwajgier ◽  
Ewa Baranowska-Wojcik ◽  
Kamila Borowiec
Keyword(s):  
Phenolic Acids ◽  
Ex Vivo ◽  
Amyloid Β ◽  
Inhibitory Effect ◽  
In Vivo Studies ◽  
Amyloid Β Peptide ◽  
Beneficial Effects ◽  
Aβ Fibrils

Numerous authors have provided evidence regarding the beneficial effects of phenolic acids and their derivatives against Alzheimer's disease (AD). In this review, the role of phenolic acids as inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) is discussed, including the structure-activity relationship. In addition, the inhibitory effect of phenolic acids on the formation of amyloid β-peptide (Aβ) fibrils is presented. We also cover the in vitro, ex vivo, and in vivo studies concerning the prevention and treatment of the cognitive enhancement.

scholarly journals STEM-26. SMALL MOLECULE DRUG CBL0137 INHIBITS THE FACT COMPLEX AND SENSITIZES GLIOBLASTOMA CANCER STEM CELLS TO RADIOTHERAPY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii201-ii202
Author(s):  
Miranda Tallman ◽  
Abigail Zalenski ◽  
Amanda Deighen ◽  
Morgan Schrock ◽  
Sherry Mortach ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
High Rate ◽  
Orthotopic Model ◽  
In Vivo Models ◽  
Specific Cytotoxicity ◽  
Treatment Paradigm ◽  
Cancer Agent

Abstract Glioblastoma (GBM) is a malignant brain tumor with nearly universal recurrence. GBM cancer stem cells (CSCs), a subpopulation of radio- and chemo-resistant cancer cells capable of self-renewal, contribute to the high rate of recurrence. The anti-cancer agent, CBL0137, inhibits the FACT (facilitates chromatin transcription) complex leading to cancer cell specific cytotoxicity. Here, we show that CBL0137 sensitized GBM CSCs to radiotherapy using both in vitro and in vivo models. Treatment of CBL0137 combined with radiotherapy led to increased DNA damage in GBM patient specimens and failure to resolve the damage led to decreased cell viability. Using clonogenic assays, we confirmed that CBL0137 radiosensitized the CSCs. To validate that combination therapy impacted CSCs, we used an in vivo subcutaneous model and showed a decrease in the frequency of cancer stem cells present in tumors as well as decreased tumor volume. Using an orthotopic model of GBM, we confirmed that treatment with CBL0137 followed by radiotherapy led to significantly increased survival compared to either treatment alone. Radiotherapy remains a critical component of patient care for GBM, even though there exists a resistant subpopulation. Radio-sensitizing agents, including CBL0137, pose an exciting treatment paradigm to increase the efficacy of irradiation, especially by inclusively targeting CSCs.

scholarly journals STEM-20. RADIO-SENSITIZING GLIOBLASTOMA CANCER STEM CELLS BY INHIBITION OF FACT

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi237-vi238
Author(s):  
Miranda Montgomery ◽  
Abigail Zalenski ◽  
Amanda Deighen ◽  
Sherry Mortach ◽  
Treg Grubb ◽  
...  
Keyword(s):  
Stem Cells ◽  
Dna Damage ◽  
Cancer Stem Cells ◽  
Combination Therapy ◽  
High Rate ◽  
Primary Role ◽  
Cancer Cell Growth ◽  
Treatment Paradigm

Abstract Glioblastoma (GBM) has a particularly high rate of recurrence with a 5-year overall survival rate of approximately 5%. This is in part due to a sub-population of cancer stem cells (CSC), which are both radioresistant and chemotherapeutically resistant to conventional treatments. Here we investigated CBL0137, a small molecule form of curaxin, in combination with radiotherapy as a means to radiosensitize CSCs. CBL0137 sequesters FACT (facilitates chromatin transcription) complex to chromatin, which leads to activation of p53 and inhibition of NF-κB. This sequestering of FACT results in cytotoxicity especially within tumor cells and prevents FACT from performing its primary role as a histone chaperone, as well as inhibits its part in the DNA damage response pathway. We show that when combined with radiotherapy, CBL0137 administration limited the ability of CSCs to identify and repair damaged DNA. CSCs treated in vitro with CBL0137 and irradiation showed an increased inhibition of cancer cell growth and decreased viability compared to irradiation or drug alone. Combination therapy also showed more DNA damage in the CSCs than with either agent alone. Based on our in vitro evidence for the efficacy of combination therapy to target CSCs, we moved forward to test the treatment in vivo. Using a subcutaneous model, we show that the amount of CD133+ cells (a marker for GMB CSCs) was reduced in irradiation plus CBL0137 compared to either treatment alone. Survival studies demonstrated that irradiation plus CBL0137 compared to irradiation alone or CBL0137 alone increase lifespan. Here we show the ability of CBL0137, in combination with irradiation, to target patient GBM CSCs both in vitro and in vivo. This work establishes a new treatment paradigm for GBM that inclusively targets CSCs and may ultimately reduce tumor recurrence.

scholarly journals Targeting specificity of dendritic cells on breast cancer stem cells: in vitro and in vivo evaluations

2015 ◽  
pp. 323 ◽  
Author(s):  
Phuc Pham ◽  
Sinh Nguyen ◽  
Viet Pham ◽  
Ngoc Phan ◽  
Huyen Nguyen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Dendritic Cells ◽  
Cancer Stem Cells ◽  
Breast Cancer Stem Cells

scholarly journals Genome-wide CRISPR-Cas9 screen identified KLF11 as a druggable suppressor for sarcoma cancer stem cells

2021 ◽  
Vol 7 (5) ◽  
pp. eabe3445
Author(s):  
Yicun Wang ◽  
Jinhui Wu ◽  
Hui Chen ◽  
Yang Yang ◽  
Chengwu Xiao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Negative Feedback ◽  
Direct Interaction ◽  
Therapy Resistance ◽  
Negative Regulator ◽  
Chemotherapy Response ◽  
Genome Wide

Cancer stem cells (CSCs) are involved in tumorigenesis, recurrence, and therapy resistance. To identify critical regulators of sarcoma CSCs, we performed a reporter-based genome-wide CRISPR-Cas9 screen and uncovered Kruppel-like factor 11 (KLF11) as top candidate. In vitro and in vivo functional annotation defined a negative role of KLF11 in CSCs. Mechanistically, KLF11 and YAP/TEAD bound to adjacent DNA sites along with direct interaction. KLF11 recruited SIN3A/HDAC to suppress the transcriptional output of YAP/TEAD, which, in turn, promoted KLF11 transcription, forming a negative feedback loop. However, in CSCs, this negative feedback was lost because of epigenetic silence of KLF11, causing sustained YAP activation. Low KLF11 was associated with poor prognosis and chemotherapy response in patients with sarcoma. Pharmacological activation of KLF11 by thiazolidinedione effectively restored chemotherapy response. Collectively, our study identifies KLF11 as a negative regulator in sarcoma CSCs and potential therapeutic target.

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