Development of an advanced nanoformulation for the intracellular delivery of a caspase-3 selective activity-based probe

Cogo, Francesco; Poręba, Marcin; Rut, Wioletta; Groborz, Katarzyna; Smyth, Peter; Johnston, Michael C.; Williams, Richard V.; Longley, Daniel B.; Burden, Roberta E.; Salvesen, Guy S.; Drąg, Marcin; Scott, Christopher J.

doi:10.1039/c8nr07859a

Cited by 7 publications

(5 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Radiotherapy is employed in cancer treatment to trigger cancer cell death via apoptosis and/or necrosis [31,32]. To date, caspase-3 has been considered to be a core executioner caspase cascade responsible for apoptosis [33] and its activity is widely used to evaluate the efficacy of anti-cancer therapeutics [34,35]. In the present study we demonstrated that caspase-3 coupling DDR in dying NSCLC cells stimulated the proliferation of adjacent living tumor cell, which suggests a favorable role of caspase-3 in tumor relapse following clinical treatment.…”

Section: Discussionmentioning

confidence: 99%

Caspase-3 Silencing Attenuates Tumor Repopulation Via Impairing Radiation-Induced DNA Damage Response and Downstream Pathway in Non-Small-Cell Lung Cancer

Zhao¹,

Wang²,

Zhao³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Radiotherapy is an effective treatment on non-small-cell lung cancer (NSCLC). However, radiation-induced dying tumor cells are postulated to generate potent growth signals to stimulate the repopulation of adjacent surviving tumor cells, which may promote tumor recurrence. We investigated the role of caspase-3-centered molecular mechanism in NSCLC repopulation after radiotherapy.Methods: The stable caspase-3 knockout (Casp3 KO) NSCLC cells were compared with wild-type cells for growth-promoting effect after radiotherapy using in vitro repopulation model. Western blotting, quantitative real-time PCR, enzyme-linked immunosorbent assay and luciferase reporter assay were used to identify the possible molecules and pathway. To elucidate the function of caspase-3 in tumor repopulation, a series of in vitro assays were performed with Casp3 KO NSCLC cells. Finally, tumor cell growth rate of Casp3 KO and wild-type tumor cells in vivo was tested using xenograft tumor assay and key proteins were further confirmed in tumor tissues with or without radiotherapy.Results: We found that radiation induced DNA damage response (DDR) and caspase-3 activation, as well as promoted tumor repopulation in NSCLC cells. Unexpectedly, depleting caspase-3 significantly attenuated ataxia-telangiectasia mutated kinase (ATM)/p53-mediated DDR via attenuating endonuclease G (EndoG) nuclear migration, thus decreasing the growth-promoting effect of irradiated dying cells. Moreover, we identified p53 as a regulator of the Cox-2/PGE2 axis, which was probably involved in caspase-3-centered tumor repopulation after radiotherapy. Additionally, depleting caspase-3 in NSCLC cells showed impaired tumor growth in nude mice model.Conclusions: Our findings demonstrated that caspase-3 was implicated in tumor repopulation and that was accompanied by promoting DDR and downstream Cox-2/PGE2 axis activation in NSCLC cells. This hitherto undescribed signaling pathway mediated by caspase-3 may deepen insight into the radiobiology and provide therapeutic targets to reduce NSCLC recurrence after radiotherapy.

show abstract

Section: Discussionmentioning

confidence: 99%

Caspase-3 Silencing Attenuates Tumor Repopulation Via Impairing Radiation-Induced DNA Damage Response and Downstream Pathway in Non-Small-Cell Lung Cancer

Zhao¹,

Wang²,

Zhao³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…When UPP is inhibited, the degradation of intracellular abnormal proteins, such as caspase 3, reduces ( 42 ). Activated caspase 3 decomposes substrates in the cytoplasm and nucleus, resulting in chromosome condensation, mitochondrial swelling and ultimately apoptosis ( 43 ). Caspase 3 can thereby reduce extracellular matrix secretion through the lysis of cells involved in its generation ( 44 ).…”

Section: Discussionmentioning

confidence: 99%

Proteasome inhibitor MG132 inhibits the process of renal interstitial fibrosis

et al. 2019

View full text Add to dashboard Cite

The proteasome inhibitor pathway serves a crucial role in cell cycle progression and apoptosis, and in the activation of transcription factors and cytokines in tumor cells. The aim of the current study was to investigate the effect of the proteasome inhibitor, MG132, on transforming growth factor (TGF)-β1-induced expression of extracellular matrix proteins in rat renal interstitial fibroblasts (NRK-49F cells) and to better elucidate the mechanism by which MG132 functions. The level of connective tissue growth factor (CTGF), α-smooth muscle actin (SMA), fibronectin (FN) and collagen type III (Col III) in the MG132-pretreated groups was significantly decreased compared with groups treated with TGF-β1 alone. MG132 significantly decreased mRNA and the protein levels of fibrosis-associated factors induced by TGF-β1 treatment. The MG132-pretreated groups exhibited lower phosphorylated-mothers against decapentaplegic homolog (p-Smad)2, p-Smad3 and FN protein expression compared with the groups treated with TGF-β1 alone. In conclusion, MG132 reduced mRNA and protein expression of fibrosis-associated factors. It can successfully inhibit the inflammatory reaction induced by TGF-β via the Smad signaling pathway. These results indicate that MG132 appears to have a potent effect in counteracting renal fibrosis. MG132 may be applied in the treatment of patients with chronic kidney disease.

show abstract

“…The development of activatable multifunctional probes for in vivo imaging of caspase-3 represents a significant advancement in detecting and monitoring caspase activity, particularly in assessing the early effects of therapeutics on tumors [108,109]. When formulated into nanoparticles, these probes have effectively overcome the challenge of penetrating cells, allowing for precisely labeling cells in response to apoptotic signals [108]. In addition, the use of ratiometric fluorescence imaging probes enables the real-time quantification of caspase-3 activity, which can offer valuable insights into the stages of apoptosis in living cells [69].…”

Section: Multifunctional Probes For In Vivo Imagingmentioning

confidence: 99%

A Comprehensive Exploration of Caspase Detection Methods: From Classical Approaches to Cutting-Edge Innovations

Zhra,

Qasem,

Aldossari

et al. 2024

IJMS

View full text Add to dashboard Cite

The activation of caspases is a crucial event and an indicator of programmed cell death, also known as apoptosis. These enzymes play a central role in cancer biology and are considered one promising target for current and future advancements in therapeutic interventions. Traditional methods of measuring caspase activity such as antibody-based methods provide fundamental insights into their biological functions, and are considered essential tools in the fields of cell and cancer biology, pharmacology and toxicology, and drug discovery. However, traditional methods, though extensively used, are now recognized as having various shortcomings. In addition, these methods fall short of providing solutions to and matching the needs of the rapid and expansive progress achieved in studying caspases. For these reasons, there has been a continuous improvement in detection methods for caspases and the network of pathways involved in their activation and downstream signaling. Over the past decade, newer methods based on cutting-edge state-of-the-art technologies have been introduced to the biomedical community. These methods enable both the temporal and spatial monitoring of the activity of caspases and their downstream substrates, and with enhanced accuracy and precision. These include fluorescent-labeled inhibitors (FLIs) for live imaging, single-cell live imaging, fluorescence resonance energy transfer (FRET) sensors, and activatable multifunctional probes for in vivo imaging. Recently, the recruitment of mass spectrometry (MS) techniques in the investigation of these enzymes expanded the repertoire of tools available for the identification and quantification of caspase substrates, cleavage products, and post-translational modifications in addition to unveiling the complex regulatory networks implicated. Collectively, these methods are enabling researchers to unravel much of the complex cellular processes involved in apoptosis, and are helping generate a clearer and comprehensive understanding of caspase-mediated proteolysis during apoptosis. Herein, we provide a comprehensive review of various assays and detection methods as they have evolved over the years, so to encourage further exploration of these enzymes, which should have direct implications for the advancement of therapeutics for cancer and other diseases.

show abstract

Development of an advanced nanoformulation for the intracellular delivery of a caspase-3 selective activity-based probe

Abstract: The formulation of the novel activity-based probe CS1 in PEG-PLGA nanoparticles allows intracellular selective labelling of caspase-3 over closely related caspase-7.

Cited by 7 publications

References 52 publications

Caspase-3 Silencing Attenuates Tumor Repopulation Via Impairing Radiation-Induced DNA Damage Response and Downstream Pathway in Non-Small-Cell Lung Cancer

Caspase-3 Silencing Attenuates Tumor Repopulation Via Impairing Radiation-Induced DNA Damage Response and Downstream Pathway in Non-Small-Cell Lung Cancer

Proteasome inhibitor MG132 inhibits the process of renal interstitial fibrosis

A Comprehensive Exploration of Caspase Detection Methods: From Classical Approaches to Cutting-Edge Innovations

Contact Info

Product

Resources

About