HOCl-modified phosphatidylcholines induce apoptosis and redox imbalance in HUVEC-ST cells

Robaszkiewicz, Agnieszka; Bartosz, Grzegorz; Pitt, Andrew R.; Thakker, Alpesh; Armstrong, Richard A.; Spickett, Corinne M.; Soszyński, Mirosław

doi:10.1016/j.abb.2014.02.013

Cited by 8 publications

(4 citation statements)

References 47 publications

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“…In particular, changes in erythrocyte shape (echinocyte formation) and aggregation were significantly altered when vesicles containing PC-CH were mixed with the cells. Similar effects were also found [160] when HUVEC-ST (endothelial cells) were treated with PC chlorohydrins. Under these conditions there was a decrease of the mitochondrial potential and an increase in the number of apoptotic cells.…”

Section: In Vitro Generation Of Chlorohydrins (Cell and Tissue Stusupporting

confidence: 81%

Chlorinated Phospholipids and Fatty Acids: (Patho)physiological Relevance, Potential Toxicity, and Analysis of Lipid Chlorohydrins

Schröter

Schiller

2016

Oxidative Medicine and Cellular Longevity

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Chlorinated phospholipids are formed by the reaction of hypochlorous acid (HOCl), generated by the enzyme myeloperoxidase under inflammatory conditions, and the unsaturated fatty acyl residues or the head group. In the first case the generated chlorohydrins are both proinflammatory and cytotoxic, thus having a significant impact on the structures of biomembranes. The latter case leads to chloramines, the properties of which are by far less well understood. Since HOCl is also widely used as a disinfecting and antibacterial agent in medicinal, industrial, and domestic applications, it may represent an additional source of danger in the case of abuse or mishandling. This review discusses the reaction behavior of in vivo generated HOCl and biomolecules like DNA, proteins, and carbohydrates but will focus on phospholipids. Not only the beneficial and pathological (toxic) effects of chlorinated lipids but also the importance of these chlorinated species is discussed. Some selected cleavage products of (chlorinated) phospholipids and plasmalogens such as lysophospholipids, (chlorinated) free fatty acids and α-chloro fatty aldehydes, which are all well known to massively contribute to inflammatory diseases associated with oxidative stress, will be also discussed. Finally, common analytical methods to study these compounds will be reviewed with focus on mass spectrometric techniques.

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Section: In Vitro Generation Of Chlorohydrins (Cell and Tissue Stusupporting

confidence: 81%

Chlorinated Phospholipids and Fatty Acids: (Patho)physiological Relevance, Potential Toxicity, and Analysis of Lipid Chlorohydrins

Schröter

Schiller

2016

Oxidative Medicine and Cellular Longevity

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“…Determination of the mode of cell death was carried out by AnnexinV/propidium iodide staining. Fluorescence was measured by BD LSR II Flow Cytometer according to the protocol described in Robaszkiewicz A et al [13] .…”

Section: Methodsmentioning

confidence: 99%

Downregulation of PARP1 transcription by CDK4/6 inhibitors sensitizes human lung cancer cells to anticancer drug-induced death by impairing OGG1-dependent base excision repair

et al. 2018

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Hallmarks of cancer cells include uncontrolled growth and rapid proliferation; thus, cyclin-dependent kinases are a therapeutic target for cancer treatment. Treating non-small lung cancer cells with sublethal concentrations of the CDK4/6 inhibitors, ribociclib (LEE011) and palbociclib (PD0332991), which are approved by the FDA for anticancer therapies, caused cell cycle arrest in the G1 phase and suppression of poly(ADP-ribose) polymerase 1 (PARP1) transcription by inducing recruitment of the RB1-E2F1-HDAC1-EZH2 repressive complex to the PARP1 promoter. Downregulation of PARP1 made cancer cells vulnerable to death triggered by the anticancer drugs (WP631 and etoposide) and H2O2. All agents brought about redox imbalance and DNA strand breaks. The lack of PARP1 and poly(ADP-ribosyl)ation impaired the 8-oxoguanine glycosylase (OGG1)-dependent base excision DNA repair pathway, which is critical for maintaining the viability of cells treated with CDK4/6 inhibitors during oxidative stress. Upon G1 arrest of PARP1 overexpressing cells, OGG1 formed an immunoprecipitable complex with PARP1. Similar to cells with downregulated PARP1 expression, inhibition of PARP1 or OGG1 in PARP1 overexpressing cells resulted in DNA damage and decreased viability. Thus, PARP1 and OGG1 act in the same regulatory pathway, and PARP1 activity is required for OGG1-mediated repair of oxidative DNA damage in G1-arrested cells. In conclusion, the action of CDK4/6 inhibitors is not limited to the inhibition of cell growth. CDK4/6 inhibitors also lead to accumulation of DNA damage by repressing PARP1 in oxidatively stressed cells. Thus, CDK4/6 inhibitors sensitize G1-arrested cells to anticancer drugs, since these cells require PARP1-OGG1 functional interaction for cell survival.

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“…Mitochondrial superoxide production was monitored on the basis of MitoSOX oxidation as described in Robaszkiewicz et al [31]. Cells were analyzed with a Becton-Dickinson BD FACS Calibur flow cytometer and the acquired data were processed with BD Multiset software version 3.0x for Mac OS X (Becton-Dickinson).…”

Section: Mitochondrial Superoxide Productionmentioning

confidence: 99%

The role of p38 signaling and poly(ADP-ribosyl)ation-induced metabolic collapse in the osteogenic differentiation-coupled cell death pathway

Robaszkiewicz

Valkó

Kovács

et al. 2014

Free Radical Biology and Medicine

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a b s t r a c tOsteogenic differentiation is a multistep process regulated by a diverse set of morphogenic and transcription factors. Previously we identified endogenous hydrogen peroxide-induced poly(ADP-ribose) polymerase-1 (PARP1) activation as a mediator of osteodifferentiation and associated cell death. Here we set out to investigate whether or not activation of PARP1 is dependent on DNA breaks and how PARP1 mediates cell death during osteodifferentiation of mesenchymal stem cells and SAOS-2 cells. Here we show that the MAP kinases p38, JNK, and ERK1/2 become activated during the differentiation process. However, only p38 activation depended both on hydrogen peroxide production and on PARP1 activation as the hydrogen peroxide decomposing enzyme catalase, the PARP inhibitor PJ34, and the silencing of PARP1 suppressed p38 activation. Inhibition of p38 suppressed cell death and inhibited osteogenic differentiation (calcium deposition, alkaline phosphatase activity, and marker gene expression) providing further support for the close coupling of osteodifferentiation and cell death. Metabolic collapse appears to be central in the hydrogen peroxide-PARP1-p38 pathway as silencing PARP1 or inhibition of p38 prevented differentiation-associated loss of cellular NAD, inhibition of mitochondrial respiration, and glycolytic activity. We also provide evidence that endogenous hydrogen peroxide produced by the differentiating cells is sufficient to cause detectable DNA breakage. Moreover, p38 translocates from the cytoplasm to the nucleus where it interacts and colocalizes with PARP1 as detected by immunoprecipitation and immunofluorescence, respectively. In summary, hydrogen peroxide-induced PARP1 activation leads to p38 activation and this pathway is required both for the successful completion of the differentiation process and for the associated cell death.

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HOCl-modified phosphatidylcholines induce apoptosis and redox imbalance in HUVEC-ST cells

Cited by 8 publications

References 47 publications

Chlorinated Phospholipids and Fatty Acids: (Patho)physiological Relevance, Potential Toxicity, and Analysis of Lipid Chlorohydrins

Chlorinated Phospholipids and Fatty Acids: (Patho)physiological Relevance, Potential Toxicity, and Analysis of Lipid Chlorohydrins

Downregulation of PARP1 transcription by CDK4/6 inhibitors sensitizes human lung cancer cells to anticancer drug-induced death by impairing OGG1-dependent base excision repair

The role of p38 signaling and poly(ADP-ribosyl)ation-induced metabolic collapse in the osteogenic differentiation-coupled cell death pathway

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