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1.
iScience ; 27(2): 108807, 2024 Feb 16.
Article in English | MEDLINE | ID: mdl-38303726

ABSTRACT

Glioblastoma (GBM) is the most aggressive brain tumor, presenting major challenges due to limited treatment options. Standard care includes radiation therapy (RT) to curb tumor growth and alleviate symptoms, but its impact on GBM is limited. In this study, we investigated the effect of RT on immune suppression and whether extracellular vesicles (EVs) originating from GBM and taken up by the tumor microenvironment (TME) contribute to the induced therapeutic resistance. We observed that (1) ionizing radiation increases immune-suppressive markers on GBM cells, (2) macrophages exacerbate immune suppression in the TME by increasing PD-L1 in response to EVs derived from GBM cells which is further modulated by RT, and (3) RT increases CD206-positive macrophages which have the most potential in inducing a pro-oncogenic environment due to their increased uptake of tumor-derived EVs. In conclusion, RT affects GBM resistance by immuno-modulating EVs taken up by myeloid cells in the TME.

2.
Heliyon ; 9(4): e15055, 2023 Apr.
Article in English | MEDLINE | ID: mdl-37082641

ABSTRACT

HIV infection progressively weakens the immune system by infecting and destroying cells involved in host defense. Viral infection symptoms are generated and aggravated as immunosuppression progresses, triggered by the presence of opportunistic infections: among these is leishmaniasis, a disease caused by the intracellular parasite Leishmania. The incidence of this co-infection is growing progressively due to the geographic distribution overlap. Both pathogens infect monocytes/macrophages and dendritic cells, although they can also modulate the activity of other cells without co-infecting, such as T and B lymphocytes. Leishmania/HIV co-infection could be described as a system comprising modulations of cell surface molecule expression, production of soluble factors, and intracellular death activities, leading ultimately to the potentiation of infectivity, replication, and spread of both pathogens. This review describes the cytokine/chemokine response in Leishmania/HIV infection and co-infection, discussing how these molecules modulate the course of the disease and analyzing the therapeutic potential of targeting this network.

3.
Mol Neurobiol ; 59(9): 5326-5365, 2022 Sep.
Article in English | MEDLINE | ID: mdl-35696013

ABSTRACT

Gliomas are the most frequent type of tumor in the central nervous system, which exhibit properties that make their treatment difficult, such as cellular infiltration, heterogeneity, and the presence of stem-like cells responsible for tumor recurrence. The response of this type of tumor to chemoradiotherapy is poor, possibly due to a higher repair activity of the genetic material, among other causes. The DNA double-strand breaks are an important type of lesion to the genetic material, which have the potential to trigger processes of cell death or cause gene aberrations that could promote tumorigenesis. This review describes how the different cellular elements regulate the formation of DNA double-strand breaks and their repair in gliomas, discussing the therapeutic potential of the induction of this type of lesion and the suppression of its repair as a control mechanism of brain tumorigenesis.


Subject(s)
Glioma , Neoplasm Recurrence, Local , Carcinogenesis/genetics , DNA , DNA Breaks, Double-Stranded , DNA Repair , Glioma/genetics , Glioma/pathology , Glioma/therapy , Humans
4.
Cell Chem Biol ; 29(8): 1333-1340.e5, 2022 08 18.
Article in English | MEDLINE | ID: mdl-35649410

ABSTRACT

We describe a generalizable time-resolved Förster resonance energy transfer (TR-FRET)-based platform to profile the cellular action of heterobifunctional degraders (or proteolysis-targeting chimeras [PROTACs]) that is capable of both accurately quantifying protein levels in whole-cell lysates in less than 1 h and measuring small-molecule target engagement to endogenous proteins, here specifically for human bromodomain-containing protein 4 (BRD4). The detection mix consists of a single primary antibody targeting the protein of interest, a luminescent donor-labeled anti-species nanobody, and a fluorescent acceptor ligand. Importantly, our strategy can readily be applied to other targets of interest and will greatly facilitate the cell-based profiling of small-molecule inhibitors and PROTACs in a high-throughput format with unmodified cell lines. We furthermore validate our platform in the characterization of celastrol, a p-quinone methide-containing pentacyclic triterpenoid, as a broad cysteine-targeting E3 ubiquitin ligase warhead for potent and efficient targeted protein degradation.


Subject(s)
Nuclear Proteins , Transcription Factors , Cell Cycle Proteins/metabolism , Humans , Nuclear Proteins/metabolism , Pentacyclic Triterpenes , Proteolysis , Transcription Factors/metabolism , Ubiquitin-Protein Ligases/metabolism
5.
Mol Neurobiol ; 58(7): 3252-3269, 2021 Jul.
Article in English | MEDLINE | ID: mdl-33665742

ABSTRACT

Gliomas constitute the most frequent tumors of the brain. High-grade gliomas are characterized by a poor prognosis caused by a set of attributes making treatment difficult, such as heterogeneity and cell infiltration. Additionally, there is a subgroup of glioma cells with properties similar to those of stem cells responsible for tumor recurrence after treatment. Since proteasomal degradation regulates multiple cellular processes, any mutation causing disturbances in the function or expression of its elements can lead to various disorders such as cancer. Several studies have focused on protein degradation modulation as a mechanism of glioma control. The ubiquitin proteasome system is the main mechanism of cellular proteolysis that regulates different events, intervening in pathological processes with exacerbating or suppressive effects on diseases. This review analyzes the role of proteasomal degradation in gliomas, emphasizing the elements of this system that modulate different cellular mechanisms in tumors and discussing the potential of distinct compounds controlling brain tumorigenesis through the proteasomal pathway.


Subject(s)
Antineoplastic Agents/therapeutic use , Brain Neoplasms/metabolism , Glioblastoma/metabolism , Proteasome Endopeptidase Complex/metabolism , Proteasome Inhibitors/therapeutic use , Ubiquitin/metabolism , Animals , Antineoplastic Agents/pharmacology , Brain Neoplasms/drug therapy , Glioblastoma/drug therapy , Humans , Proteasome Inhibitors/pharmacology , Ubiquitin/antagonists & inhibitors
6.
ACS Chem Biol ; 15(6): 1445-1454, 2020 06 19.
Article in English | MEDLINE | ID: mdl-32338864

ABSTRACT

We have previously identified the natural product obtusaquinone (OBT) as a potent antineoplastic agent with promising in vivo activity in glioblastoma and breast cancer through the activation of oxidative stress; however, the molecular properties of this compound remained elusive. We used a multidisciplinary approach comprising medicinal chemistry, quantitative mass spectrometry-based proteomics, functional studies in cancer cells, and pharmacokinetic analysis, as well as mouse xenograft models to develop and validate novel OBT analogs and characterize the molecular mechanism of action of OBT. We show here that OBT binds to cysteine residues with a particular affinity to cysteine-rich Keap1, a member of the CUL3 ubiquitin ligase complex. This binding promotes an overall stress response and results in ubiquitination and proteasomal degradation of Keap1 and downstream activation of the Nrf2 pathway. Using positron emission tomography (PET) imaging with the PET-tracer 2-[18F]fluoro-2-deoxy-d-glucose (FDG), we confirm that OBT is able to penetrate the brain and functionally target brain tumors. Finally, we show that an OBT analog with improved pharmacological properties, including enhanced potency, stability, and solubility, retains the antineoplastic properties in a xenograft mouse model.


Subject(s)
Antineoplastic Agents/pharmacology , Cinnamates/pharmacology , Cyclohexanones/pharmacology , Kelch-Like ECH-Associated Protein 1/metabolism , Proteolysis/drug effects , Animals , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Cinnamates/pharmacokinetics , Cyclohexanones/pharmacokinetics , Cysteine/metabolism , Humans , Mice , Neoplasms/drug therapy , Neoplasms/metabolism
7.
Invest. clín ; 63(3): 243-261, set. 2022. tab, graf
Article in English | LILACS-Express | LILACS | ID: biblio-1534661

ABSTRACT

Abstract Tetrahydroquinoline derivatives are interesting structures exhibiting a wide range of biological activities, including antitumor effects. In this investigation, the effect of the synthesized tetrahydroquinolines JS-56 and JS-92 on apoptosis, intracellular Ca2+ concentration ([Ca2+]i), and the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) activity was determined on MCF-7 breast cancer cells. Colorimetric assays were used to assess MCF-7 cells viability and SERCA activity. Fura-2 and rhodamine 123 were used to measure the intracellular Ca2+ concentration and the mitochondrial electrochemical potential, respec tively. TUNEL assay was used to analyze DNA fragmentation, while caspase activity and NF-κB-dependent gene expression were assessed by luminescence. In silico models were used for molecular docking analysis. These compounds increase intracellular Ca2+ concentration; the main contribution is the Ca2+ entry from the extracellular milieu. Both JS-56 and JS-92 inhibit the activity of SERCA and dissipate the mitochondrial electrochemical potential through processes dependent and independent of the Ca2+ uptake by this organelle. Furthermore, JS-56 and JS-92 generate cytotoxicity in MCF-7 cells. The effect of JS-92 is higher than JS-56. Both compounds activate caspases 7 and 9, cause DNA fragmentation, and potentiate the effect of phorbol 12-myristate-13-acetate on NF-κB-dependent gene expression. Molecular docking analysis suggests that both compounds have a high interaction for SERCA, similar to thapsigargin. Both tetrahydroquinoline derivatives induced cell death through a combination of apoptotic events, increase [Ca2+]i, and inhibit SERCA activity by direct interaction.


Resumen Los derivados de tetrahidroquinolina son estructuras interesantes que exhiben una amplia gama de actividades biológicas, incluyendo efectos antitumorales. Se determinó el efecto de las tetrahidroquinolinas sintetizadas JS-56 y JS-92 sobre la apoptosis, concentración intracelular de Ca2+ ([Ca2+]i) y la actividad Ca2+-ATPasa del retículo sarco(endo)plásmico (SERCA) en células de cáncer de mama MCF-7. Se usaron ensayos colorimétricos para evaluar la viabilidad de las células MCF-7 y la actividad SERCA. Se emplearon Fura-2 y rodamina 123 para medir la concentración de Ca2+ intracelular y el potencial electroquímico mitocondrial, respectivamente. El ensayo TUNEL se utilizó para analizar la fragmentación del ADN, mientras que la actividad de caspasas y la expresión génica dependiente de NF-κB se evaluaron mediante luminiscencia. Modelos in silico permitieron el análisis del acoplamiento molecular. Estos compuestos aumentan la concentración de Ca2+ intracelular; la principal contribución es la entrada de Ca2+ desde el medio extracelular. Tanto JS-56 como JS-92 inhiben la actividad de SERCA y disipan el potencial electroquímico mitocondrial a través de procesos dependientes e independientes de la captación de Ca2+ por este orgánulo. Además, JS-56 y JS-92 generan citotoxicidad en células MCF-7. El efecto de JS-92 es mayor que JS-56. Ambos compuestos activan las caspasas 7 y 9, provocan la fragmentación del ADN y potencian el efecto del 12-miristato-13-acetato de forbol en la expresión génica dependiente de NF-κB. El análisis de acoplamiento molecular sugiere que ambos compuestos tienen una alta interacción con SERCA, similar a la tapsigargina. Ambos derivados de tetrahidroquinolina indujeron la muerte celular a través de una combinación de eventos apoptóticos, aumento de [Ca2+]i e inhibición de la actividad SERCA por interacción directa.

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