Potentialization of anticancer agents by identification of new chemosensitizers active under hypoxia

Marx, Sébastien; Gysel, Mégane Van; Breuer, Aurélie; Maso, Thomas Dal; Michiels, Carine; Calvé, Benjamin Le

doi:10.1016/j.bcp.2019.01.004

Cited by 4 publications

(4 citation statements)

References 73 publications

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“…A crucial driving force in the progression towards a more aggressive and resistant tumor phenotype is the adaptation of neoplastic cells to a state of reduced oxygen availability defined as hypoxia [47–52]. At least half of all solid tumors, including breast cancer, enclose hypoxic regions varying in amount and size, and recurring tumors often exhibit a hypoxic fraction higher than primary tumors [53].…”

Section: Cd133 As a Marker Of Malignant Progression Induced By Lowmentioning

confidence: 99%

CD133 in Breast Cancer Cells: More than a Stem Cell Marker

Brugnoli

Grassilli

Al-Qassab

et al. 2019

Journal of Oncology

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Initially correlated with hematopoietic precursors, the surface expression of CD133 was also found in epithelial and nonepithelial cells from adult tissues in which it has been associated with a number of biological events. CD133 is expressed in solid tumors as well, including breast cancer, in which most of the studies have been focused on its use as a surface marker for the detection of cells with stem-like properties (i.e., cancer stem cells (CSCs)). Differently with other solid tumors, very limited and in part controversial are the information about the significance of CD133 in breast cancer, the most common malignancy among women in industrialized countries. In this review, we summarize the latest findings about the implication of CD133 in breast tumors, highlighting its role in tumor cells with a triple negative phenotype in which it directly regulates the expression of proteins involved in metastasis and drug resistance. We provide updates about the prognostic role of CD133, underlining its value as an indicator of increased malignancy of both noninvasive and invasive breast tumor cells. The molecular mechanisms at the basis of the regulation of CD133 levels in breast tumors have also been reviewed, highlighting experimental strategies capable to restrain its level that could be taken into account to reduce malignancy and/or to prevent the progression of breast tumors.

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Section: Cd133 As a Marker Of Malignant Progression Induced By Lowmentioning

confidence: 99%

CD133 in Breast Cancer Cells: More than a Stem Cell Marker

Brugnoli

Grassilli

Al-Qassab

et al. 2019

Journal of Oncology

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“…In our study, HDC1 was shown to have bactericidal activity on AB5075-VUB with an IC 50 of 48.23 µM. As the compound was previously found to be cytotoxic in HEPG2 cells at 50 µM, this limits the potential of HDC1 as a new antimicrobial without further modification of the molecule ( Marx et al., 2019 ). Differences in active concentrations of HDC1 between cancer and bacterial cells could be attributed to cell size and target(s) presence and/or abundance, altered metabolism states and the presence or absence of post-translational modifications.…”

Section: Discussionmentioning

confidence: 71%

Antimicrobial Activity of a Repurposed Harmine-Derived Compound on Carbapenem-Resistant Acinetobacter baumannii Clinical Isolates

Breine

Gysel

Elsocht

et al. 2022

Front. Cell. Infect. Microbiol.

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ObjectivesThe spread of antibiotic resistant bacteria is an important threat for human health. Acinetobacter baumannii bacteria impose such a major issue, as multidrug- to pandrug-resistant strains have been isolated, rendering some infections untreatable. In this context, carbapenem-resistant A. baumannii bacteria were ranked as top priority by both WHO and CDC. In addition, A. baumannii bacteria survive in harsh environments, being capable of resisting to disinfectants and to persist prolonged periods of desiccation. Due to the high degree of variability found in A. baumannii isolates, the search for new antibacterials is very challenging because of the requirement of drug target conservation amongst the different strains. Here, we screened a chemical library to identify compounds active against several reference strains and carbapenem-resistant A. baumannii bacteria.MethodsA repurposing drug screen was undertaken to identify A. baumannii growth inhibitors. One hit was further characterized by determining the IC50 and testing the activity on 43 modern clinical A. baumannii isolates, amongst which 40 are carbapenem-resistant.ResultsThe repurposing screen led to the identification of a harmine-derived compound, called HDC1, which proves to have bactericidal activity on the multidrug-resistant AB5075-VUB reference strain with an IC50 of 48.23 µM. In addition, HDC1 impairs growth of 43 clinical A. baumannii isolates.ConclusionsWe identified a compound with inhibitory activity on all tested strains, including carbapenem-resistant clinical A. baumannii isolates.

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“…In this context, this work aims to repurpose molecules from our in-house chemical library and evaluate them for their ability to inhibit SerB2's activity [23]. The strategy to repurpose already existing drugs and assess their efficiency on Mtb can save time in the drug discovery process and has already led to successful outcomes [24][25][26][27].…”

Section: Introductionmentioning

confidence: 99%

“…Our chemical library is enriched with a great range of chemical scaffolds synthesized as part of drug discovery and medicinal chemistry programs from our group [23]. A basic set of a hundred molecules was selected and screened on purified SerB2.…”

Section: Introductionmentioning

confidence: 99%

Identification and Repurposing of Trisubstituted Harmine Derivatives as Novel Inhibitors of Mycobacterium tuberculosis Phosphoserine Phosphatase

et al. 2020

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Mycobacterium tuberculosis is still the deadliest bacterial pathogen worldwide and the increasing number of multidrug-resistant tuberculosis cases further complicates this global health issue. M. tuberculosis phosphoserine phosphatase SerB2 is a promising target for drug design. Besides being a key essential metabolic enzyme of the pathogen’s serine pathway, it appears to be involved in immune evasion mechanisms. In this work, a malachite green-based phosphatase assay has been used to screen 122 compounds from an internal chemolibrary. Trisubstituted harmine derivatives were found among the best hits that inhibited SerB2 activity. Synthesis of an original compound helped to discuss a brief structure activity relationship evaluation. Kinetics experiments showed that the most potent derivatives inhibit the phosphatase in a parabolic competitive fashion with apparent inhibition constants ( K i ) values in the micromolar range. Their interaction modes with the enzyme were investigated through induced fit docking experiments, leading to results consistent with the experimental data. Cellular assays showed that the selected compounds also inhibited M. tuberculosis growth in vitro. Those promising results may provide a basis for the development of new antimycobacterial agents targeting SerB2.

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Potentialization of anticancer agents by identification of new chemosensitizers active under hypoxia

Cited by 4 publications

References 73 publications

CD133 in Breast Cancer Cells: More than a Stem Cell Marker

CD133 in Breast Cancer Cells: More than a Stem Cell Marker

Antimicrobial Activity of a Repurposed Harmine-Derived Compound on Carbapenem-Resistant Acinetobacter baumannii Clinical Isolates

Identification and Repurposing of Trisubstituted Harmine Derivatives as Novel Inhibitors of Mycobacterium tuberculosis Phosphoserine Phosphatase

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