Inhibition of Notch signaling pathway using γ-secretase inhibitor delivered by a low dose of Triton-X100 in cultured oral cancer cells

Nasrin, Aklima; Hassan, Mahbub

doi:10.1016/j.bbrc.2017.12.082

Cited by 7 publications

(6 citation statements)

References 30 publications

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“…In our study, HES1 activation by 18Co‐CM in Caco‐2 cells was reduced by inhibitors of STAT3 and gamma‐secretase, which suggests that IL‐6/IL‐8‐induced STAT3 activation and subsequent increases in Notch ligands, may be upstream of HES1 activation. We also found that a gamma‐secretase inhibitor decreased the CSC populations of CRC cell lines (data not shown), which is consistent with several prior cancer treatment studies and clinical trials that used gamma‐secretase inhibitors to block Notch pathway activation 32–36 …”

Section: Discussionsupporting

confidence: 89%

IL‐6 and IL‐8, secreted by myofibroblasts in the tumor microenvironment, activate HES1 to expand the cancer stem cell population in early colorectal tumor

Kim

Seo

Kwon

et al. 2021

Molecular Carcinogenesis

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Interaction between a tumor and its microenvironment is important for tumor initiation and progression. Cancer stem cells (CSCs) within the tumor interact with a microenvironmental niche that controls their maintenance and differentiation. We investigated the CSC‐promoting effect of factors released from myofibroblasts into the microenvironment of early colorectal cancer tumors and its molecular mechanism. By messenger RNA microarray analysis, expression of HES1, a Notch signaling target, significantly increased in Caco‐2 cells cocultured with 18Co cells (pericryptal myofibroblasts), compared to its expression in Caco‐2 cells cultured alone. Caco‐2 cells cultured in 18Co‐conditioned media (CM) showed a significant increase in CD133+CD44+ cells and HES1 expression compared to that in Caco‐2 cells cultured in regular media. Significant amounts of interleukin‐6 (IL‐6) and IL‐8 were detected in 18Co‐CM compared to levels in regular media. The 18Co‐CM‐induced increase in CD133+CD44+ cells was attenuated by IL‐6‐ and IL‐8‐neutralizing antibodies. Furthermore, these neutralizing antibodies and inhibitors of STAT3 and gamma‐secretase reduced the expression of HES1 induced in Caco‐2 cells cultured in 18Co‐CM. Immunohistochemical analysis of human tissues revealed that IL‐6, IL‐8, and HES1 expression increased from normal to adenoma, and from adenoma to cancer tissues. In addition, IL‐6 and HES1 expression was positively correlated in early colorectal cancer tissues. In conclusion, the increase of CSCs by myofibroblasts could be mediated by IL‐6/IL‐8‐induced HES1 activation in the tumor microenvironment. Based on these data, the IL‐6/IL‐8‐mediated Notch/HES1 and STAT3 pathway, through which CSCs interact with their microenvironment, might be a potential target for the prevention and treatment of colorectal tumors.

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Section: Discussionsupporting

confidence: 89%

IL‐6 and IL‐8, secreted by myofibroblasts in the tumor microenvironment, activate HES1 to expand the cancer stem cell population in early colorectal tumor

Kim

Seo

Kwon

et al. 2021

Molecular Carcinogenesis

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“…Hence, if traces of the detergent were still present in the ~10 µM protein preparations, the concentrations of remaining Triton detergent were below the detection limit of the method (~0.001%, or ~16–20 µM). Given that purified toxin stocks are further diluted over 100-fold when assayed for biological activity, protein or LPS content, such low amounts of detergent are well below the effective cytolytic concentration [28] and are very unlikely to interfere in any of these assays.…”

Section: Resultsmentioning

confidence: 99%

Rapid Purification of Endotoxin-Free RTX Toxins

Staněk

Mašín

Osička

et al. 2019

Toxins

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Cytolytic leukotoxins of the repeat in toxin (RTX) family are large proteins excreted by gram-negative bacterial pathogens through the type 1 secretion system (T1SS). Due to low yields and poor stability in cultures of the original pathogens, it is useful to purify recombinant fatty-acylated RTX cytolysins from inclusion bodies produced in E. coli. Such preparations are, however, typically contaminated by high amounts of E. coli lipopolysaccharide (LPS or endotoxin). We report a simple procedure for purification of large amounts of biologically active and endotoxin-free RTX toxins. It is based on the common feature of RTX cytolysins that are T1SS-excreted as unfolded polypeptides and fold into a biologically active toxin only upon binding of calcium ions outside of the bacterial cell. Mimicking this process, the RTX proteins are solubilized from inclusion bodies with buffered 8 M urea, bound onto a suitable chromatographic medium under denaturing conditions and the contaminating LPS is removed through extensive on-column washes with buffers containing 6 to 8 M urea and 1% Triton X-100 or Triton X-114. Extensive on-column rinsing with 8 M urea buffer removes residual detergent and the eluted highly active RTX protein preparations then contain only trace amounts of LPS. The procedure is exemplified using four prototypic RTX cytolysins, the Bordetella pertussis CyaA and the hemolysins of Escherichia coli (HlyA), Kingella kingae (RtxA), and Actinobacillus pleuropneumoniae (ApxIA).

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“…The majority of clinical studies aiming to inhibit Notch have principally been focused on the use of γ-secretase inhibitors, which impede the proteolytic processing and activation of the Notch receptor. 61 In a recent study, surface-modified silica NPs were manufactured and utilized for the specific delivery of N-[N-(3,5difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT; γ-secretase inhibitor) to overcome challenges in oral administration caused by drug degradation at low pH and reduced permeability through the mucus layers. In the study, silica NPs were surface modified with polyethylenimine (PEI), PEG, and folic acid (FA) (~400 nm) with the aim of better facilitating binding to negatively charged cells and reducing uptake by the reticuloendothelial system.…”

Section: Neoplasmsmentioning

confidence: 99%

Nanodelivery systems and stabilized solid-drug nanoparticles for orally administered medicine: current landscape

Kermanizadeh¹,

Powell²,

Stone³

2018

IJN

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The use of nanoparticles as a means of targeted delivery of therapeutics and imaging agents could greatly enhance the transport of biologically active contents to specific target tissues, while avoiding or reducing potentially undesired side effects. Generally speaking, the oral route of administration is associated with good patient compliance, as it is convenient, economical, noninvasive, and does not require special training. Here, we review the progress of the utilization of nanodelivery-system carriers or stabilized solid-drug nanoparticles following oral administration, with particular attention on toxicological data. Mechanisms of cytotoxicity are discussed and the problem of extrapolating knowledge to human scenarios highlighted. Additionally, issues associated with administration of drugs via the oral route are underlined, while strategies utilized to overcome these are highlighted. This review aims to offer a balanced overview of strategies currently being used in the application of nanosize constructs for oral medical applications.

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Inhibition of Notch signaling pathway using γ-secretase inhibitor delivered by a low dose of Triton-X100 in cultured oral cancer cells

Cited by 7 publications

References 30 publications

IL‐6 and IL‐8, secreted by myofibroblasts in the tumor microenvironment, activate HES1 to expand the cancer stem cell population in early colorectal tumor

IL‐6 and IL‐8, secreted by myofibroblasts in the tumor microenvironment, activate HES1 to expand the cancer stem cell population in early colorectal tumor

Rapid Purification of Endotoxin-Free RTX Toxins

Nanodelivery systems and stabilized solid-drug nanoparticles for orally administered medicine: current landscape

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