Artesunate Induces Oxidative DNA Damage, Sustained DNA Double-Strand Breaks, and the ATM/ATR Damage Response in Cancer Cells

Berdelle, Nicole; Nikolova, Theodora; Quirós, Steve; Efferth, Thomas; Kaina, Bernd

doi:10.1158/1535-7163.mct-11-0534

Cited by 145 publications

(106 citation statements)

References 37 publications

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“…Bioactivated endoperoxides have been shown to generate downstream radical oxygen species, disrupting a number of parasite membranes and enzymes (23). In cancer cells, cytotoxic activity has been shown to arise from ROS-mediated oxidative DNA damage induced by ART (39). Another study showed that genes involved in oxidative stress may also be associated with ART resistance in cancer cells (40).…”

Section: Discussionmentioning

confidence: 99%

Antimalarial Action of Artesunate Involves DNA Damage Mediated by Reactive Oxygen Species

Gopalakrishnan

Kumar

2015

Antimicrob Agents Chemother

131

138

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Artemisinin-based combination therapy (ACT) is the recommended first-line treatment for Plasmodium falciparum malaria. It has been suggested that the cytotoxic effect of artemisinin is mediated by free radicals followed by the alkylation of P. falciparum proteins. The endoperoxide bridge, the active moiety of artemisinin derivatives, is cleaved in the presence of ferrous iron, generating reactive oxygen species (ROS) and other free radicals. However, the emergence of resistance to artemisinin in P. falciparum underscores the need for new insights into the molecular mechanisms of antimalarial activity of artemisinin. Here we show that artesunate (ART) induces DNA double-strand breaks in P. falciparum in a physiologically relevant dose-and time-dependent manner. DNA damage induced by ART was accompanied by an increase in the intracellular ROS level in the parasites. Mannitol, a ROS scavenger, reversed the cytotoxic effect of ART and reduced DNA damage, and modulation of glutathione (GSH) levels was found to impact ROS and DNA damage induced by ART. Accumulation of ROS, increased DNA damage, and the resulting antiparasite effect suggest a causal relationship between ROS, DNA damage, and parasite death. Finally, we also show that ARTinduced ROS production involves a potential role for NADPH oxidase, an enzyme involved in the production of superoxide anions. Our results with P. falciparum provide novel insights into previously unknown molecular mechanisms underlying the antimalarial activity of artemisinin derivatives and may help in the design of next-generation antimalarial drugs against the most virulent Plasmodium species.

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Section: Discussionmentioning

confidence: 99%

Antimalarial Action of Artesunate Involves DNA Damage Mediated by Reactive Oxygen Species

Gopalakrishnan

Kumar

2015

Antimicrob Agents Chemother

131

138

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“…The effects of artesunate on mammalian cell lines show that it can promote oxidative DNA damage (29) and also induce a DSBR response (29,30). However, the far more potent activity of artesunate against Plasmodium asexual blood-stage parasites (in the low nanomolar range in vitro) and the recent identification of a variant kelch protein (PF3D7_1343700) as a candidate molecular marker of artemisinin resistance (31) suggest a primary mode of antimalarial action distinct from DNA damage.…”

Section: Causes Of Double-strand Breaksmentioning

confidence: 99%

DNA Repair Mechanisms and Their Biological Roles in the Malaria Parasite Plasmodium falciparum

Lee

Fidock

2014

Microbiol Mol Biol Rev

103

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SUMMARY Research into the complex genetic underpinnings of the malaria parasite Plasmodium falciparum is entering a new era with the arrival of site-specific genome engineering. Previously restricted only to model systems but now expanded to most laboratory organisms, and even to humans for experimental gene therapy studies, this technology allows researchers to rapidly generate previously unattainable genetic modifications. This technological advance is dependent on DNA double-strand break repair (DSBR), specifically homologous recombination in the case of Plasmodium . Our understanding of DSBR in malaria parasites, however, is based largely on assumptions and knowledge taken from other model systems, which do not always hold true in Plasmodium . Here we describe the causes of double-strand breaks, the mechanisms of DSBR, and the differences between model systems and P. falciparum . These mechanisms drive basic parasite functions, such as meiosis, antigen diversification, and copy number variation, and allow the parasite to continually evolve in the contexts of host immune pressure and drug selection. Finally, we discuss the new technologies that leverage DSBR mechanisms to accelerate genetic investigations into this global infectious pathogen.

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“…The DDR preserves genetic stability by detecting DNA lesions, activating cell cycle checkpoints and promoting DNA damage repair [18][19][20][21]. The common denominator integrating these forms of genotoxic stresses and eliciting the signalling cascade is increased production of ROS as harbinger to DNA damage [22][23][24][25][26][27]. Chemical agents such as drugs used in cancer chemotherapy are also able to induce some form of DNA lesions [28].…”

Section: Introductionmentioning

confidence: 99%

NRF2 inhibition causes repression of ATM and ATR expression leading to aberrant DNA Damage Response

Khalil¹,

Deeni²

2015

Biodiscovery

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Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a master regulator of the antioxidant response (AR) pathway and functions as a transcription factor for basal and oxidative stress-induced expression of a battery of detoxification enzymes and cytoprotective genes. Recent evidence has also demonstrated a role of NRF2 in driving resistance of numerous cancers to chemotherapeutic agents. ATM and ATR are serine/threonine kinases that are activated following DNA damage and function as central components of DNA Damage Response (DDR) pathway. Activities of these kinases cause cell cycle arrest and activate DNA repair signals leading to cytoprotection against genotoxic agents. In this study, we elucidated the roles of ATM-and ATR-dependent DDR and NRF2-mediated AR pathways in promoting cytoprotection following cisplatin challenge in ovarian cancer cell line models. We also determined whether these pathways were inter-dependent for full activation following genotoxic insults and as such demonstrated crosstalk in their signaling mechanism to elicit cytoprotective pathways. Treatment with cisplatin caused NRF2 induction and generation of reactive oxygen species (ROS) that caused cytotoxicity in ovarian cancer cells. This was attenuated by the ROS scavenger N-Acetyl cysteine, implicating NRF2 function in cytoprotection against cisplatin. Treatment with retinoic acid (RA) caused down regulation of NRF2, disruption of AR pathway, significant accumulation of ROS and enhanced cisplatin cytotoxicity. Interestingly, RA treatment also led to repression of total ATM and ATR proteins and aberrant DDR activation following cisplatin challenge. In order to determine whether the RA induced ATM and ATR repression was dependent on NRF2 inhibition, we silenced NRF2 using SiRNA. This caused transcriptional repression of both ATM and ATR expression as determined by their promoter driven luciferase assays. Thus, NRF2 inhibition led to DDR suppression by down-regulating ATM and ATR that led to enhanced cytotoxicity. These findings demonstrate mechanism of crosstalk between the AR and the DDR pathways and extend the scope of NRF2 in promoting cancer therapeutic resistance.

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Artesunate Induces Oxidative DNA Damage, Sustained DNA Double-Strand Breaks, and the ATM/ATR Damage Response in Cancer Cells

Cited by 145 publications

References 37 publications

Antimalarial Action of Artesunate Involves DNA Damage Mediated by Reactive Oxygen Species

Antimalarial Action of Artesunate Involves DNA Damage Mediated by Reactive Oxygen Species

DNA Repair Mechanisms and Their Biological Roles in the Malaria Parasite Plasmodium falciparum

NRF2 inhibition causes repression of ATM and ATR expression leading to aberrant DNA Damage Response

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