Exposure to low concentrations of etoposide reduces the apoptotic capability of leukaemic cell lines

Liu, Wai M.; Oakley, PR; Joel, SP

doi:10.1038/sj.leu.2402621

Cited by 13 publications

(9 citation statements)

References 35 publications

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“…Bleibel et al 15 reported half maximal inhibitory concentrations (IC_50) slightly below 1 μM, suggesting that effects are also present at LC of etoposide. These conclusions are confirmed by Liu et al, 16 who also found that a lower limit for etoposide-induced proliferation and viability reduction occurs at ∼0.02 μM and also shows effects on the cell cycle at concentrations <1 μM (although for different cell lines). Even lower concentrations were reported to cause changes in phenotype and potentially also cause drug resistance or cause secondary leukemia.…”

supporting

confidence: 79%

Supervised classification of etoposide-treated in vitro adherent cells based on noninvasive imaging morphology

et al. 2017

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Abstract. Single-cell studies using noninvasive imaging is a challenging, yet appealing way to study cellular characteristics over extended periods of time, for instance to follow cell interactions and the behavior of different cell types within the same sample. In some cases, e.g., transplantation culturing, real-time cellular monitoring, stem cell studies, in vivo studies, and embryo growth studies, it is also crucial to keep the sample intact and invasive imaging using fluorophores or dyes is not an option. Computerized methods are needed to improve throughput of image-based analysis and for use with noninvasive microscopy such methods are poorly developed. By combining a set of well-documented image analysis and classification tools with noninvasive microscopy, we demonstrate the ability for long-term image-based analysis of morphological changes in single cells as induced by a toxin, and show how these changes can be used to indicate changes in biological function. In this study, adherent cell cultures of DU-145 treated with low-concentration (LC) etoposide were imaged during 3 days. Single cells were identified by image segmentation and subsequently classified on image features, extracted for each cell. In parallel with image analysis, an MTS assay was performed to allow comparison between metabolic activity and morphological changes after long-term low-level drug response. Results show a decrease in proliferation rate for LC etoposide, accompanied by changes in cell morphology, primarily leading to an increase in cell area and textural changes. It is shown that changes detected by image analysis are already visible on day 1 for 0.25-μM etoposide, whereas effects on MTS and viability are detected only on day 3 for 5-μM etoposide concentration, leading to the conclusion that the morphological changes observed occur before and at lower concentrations than a reduction in cell metabolic activity or viability. Three classifiers are compared and we report a best case sensitivity of 88% and specificity of 94% for classification of cells as treated/untreated.

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confidence: 79%

Supervised classification of etoposide-treated in vitro adherent cells based on noninvasive imaging morphology

et al. 2017

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“…Our analyses show that POx formulation increased drug exposure in the CNS, in both medulloblastoma and forebrain and reduced systemic exposure, providing an explanation for both improved anti-tumor effect and reduced toxicity. Although low doses of vismodegib can induce a pharmacodynamic response, exposure to sub-optimal concentrations of cytotoxic drugs is associated with development of resistance and failure to respond to treatment (25,26).…”

Section: Discussionmentioning

confidence: 99%

Poly(2-oxazoline) nanoparticle delivery enhances the therapeutic potential of vismodegib for medulloblastoma by improving CNS pharmacokinetics and reducing systemic toxicity

Hwang

Dismuke²,

Tikunov³

et al. 2020

Preprint

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We report a novel, nanoparticle formulation of the SHH pathway inhibitor vismodegib that improves efficacy for medulloblastoma treatment while reducing toxicity. Systemic therapies for brain tumors are complicated by restricted blood-brain barrier (BBB) permeability and doselimiting extraneural toxicity, therefore improved delivery approached are needed. Here we show how a nanoparticle delivery system addresses these obstacles, bringing new efficacy to previously ineffective therapy. Vismodegib has been a promising agent for patients with SHHsubgroup medulloblastoma and is FDA-approved for basal cell carcinoma. However, vismodegib has limited benefit for patients with SHH-driven medulloblastoma, due to off-target toxicities and the development of resistance during therapy. We encapsulated vismodegib in polyoxazoline block copolymer micelles (POx-vismo). We then evaluated POx-vismo using transgenic mice engineered to develop endogenous medulloblastomas, testing the novel agent in a preclinical model with native vasculature and tumor microenvironment. POx-vismo showed improved CNS pharmacokinetics and reduced systemic and bone toxicity. Mechanistic studies show that POx nanoparticles did not enter the CNS, but rather acted within the vascular compartment to improve drug delivery by decreasing drug binding to serum proteins and reducing the volume of distribution. POx-vismo demonstrated improved efficacy, extending the survival of medulloblastoma-bearing mice. Our results show the potential for a simple, non-targeted nanoparticle formulation to improve systemic brain tumor therapy, and specifically to enhance vismodegib therapy for SHH-driven cancers.

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“…These results could have important implications for elucidating the mechanisms associated with the development of secondary malignancies (principally acute mielocitic leukemia) that are associated with the use of etoposide as an antineoplastic drug [50]. …”

Section: Resultsmentioning

confidence: 99%

DNA-AP sites generation by Etoposide in whole blood cells

Rojas

Mussali

Tovar³

et al. 2009

BMC Cancer

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BackgroundEtoposide is currently one of the most commonly used antitumor drugs. The mechanisms of action proposed for its antitumor activity are based mainly on its interaction with topoisomerase II. Etoposide effects in transformed cells have been described previously. The aim of the present study was to evaluate the genotoxic effects of this drug in non-transformed whole blood cells, such as occurs as collateral damage induced by some chemotherapies.MethodsTo determine etoposide genotoxicity, we employed Comet assay in two alkaline versions. To evaluate single strand breaks and delay repair sites we use pH 12.3 conditions and pH >13 to evidence alkali labile sites. With the purpose to quantified apurinic or apyrimidine (AP) sites we employed a specific restriction enzyme. Etoposide effects were determined on whole blood cells cultured in absence or presence of phytohemagglutinin (PHA) treated during 2 and 24 hours of cultured.ResultsAlkaline (pH > 13) single cell gel electrophoresis (SCGE) assay experiments revealed etoposide-induced increases in DNA damage in phytohemaglutinine (PHA)-stimulated blood and non-stimulated blood cells. When the assay was performed at a less alkaline pH, 12.3, we observed DNA damage in PHA-stimulated blood cells consistent with the existence of alkali labile sites (ALSs). In an effort to elucidate the molecular events underlying this result, we applied exonuclease III (Exo III) in conjunction with a SCGE assay, enabling detection of DNA-AP sites along the genome. More DNA AP-sites were revealed by Exo III and ALSs were recognized by the SCGE assay only in the non-stimulated blood cells treated with etoposide.ConclusionOur results indicate that etoposide induces DNA damage specifically at DNA-AP sites in quiescent blood cells. This effect could be involved in the development of secondary malignancies associated with etoposide chemotherapy.

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Exposure to low concentrations of etoposide reduces the apoptotic capability of leukaemic cell lines

Cited by 13 publications

References 35 publications

Supervised classification of etoposide-treated in vitro adherent cells based on noninvasive imaging morphology

Supervised classification of etoposide-treated in vitro adherent cells based on noninvasive imaging morphology

Poly(2-oxazoline) nanoparticle delivery enhances the therapeutic potential of vismodegib for medulloblastoma by improving CNS pharmacokinetics and reducing systemic toxicity

DNA-AP sites generation by Etoposide in whole blood cells

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