scholarly journals Drug-induced permeabilization of parasite's digestive vacuole is a key trigger of programmed cell death in Plasmodium falciparum

2011 ◽  
Vol 2 (10) ◽  
pp. e216-e216 ◽  
Author(s):  
J-H Ch'Ng ◽  
K Liew ◽  
A S-P Goh ◽  
E Sidhartha ◽  
K S-W Tan
Keyword(s):  
Cell Death ◽  
Plasmodium Falciparum ◽  
Programmed Cell Death ◽  
Digestive Vacuole ◽  
Drug Induced

scholarly journals A High-Content Phenotypic Screen Reveals the Disruptive Potency of Quinacrine and 3′,4′-Dichlorobenzamil on the Digestive Vacuole of Plasmodium falciparum

2013 ◽  
Vol 58 (1) ◽  
pp. 550-558 ◽  
Author(s):  
Yan Quan Lee ◽  
Amanda S. P. Goh ◽  
Jun Hong Ch'ng ◽  
François H. Nosten ◽  
Peter Rainer Preiser ◽  
...  
Keyword(s):  
Cell Death ◽  
Plasmodium Falciparum ◽  
Programmed Cell Death ◽  
Screening Method ◽  
Phenotypic Screening ◽  
Proof Of Concept ◽  
Digestive Vacuole ◽  
Content Type ◽  
Cell Death Pathway ◽  
Phenotypic Screen

ABSTRACTPlasmodium falciparumis the etiological agent of malignant malaria and has been shown to exhibit features resembling programmed cell death. This is triggered upon treatment with low micromolar doses of chloroquine or other lysosomotrophic compounds and is associated with leakage of the digestive vacuole contents. In order to exploit this cell death pathway, we developed a high-content screening method to select compounds that can disrupt the parasite vacuole, as measured by the leakage of intravacuolar Ca2+. This assay uses the ImageStream 100, an imaging-capable flow cytometer, to assess the distribution of the fluorescent calcium probe Fluo-4. We obtained two hits from a small library of 25 test compounds, quinacrine and 3′,4′-dichlorobenzamil. The ability of these compounds to permeabilize the digestive vacuole in laboratory strains and clinical isolates was validated by confocal microscopy. The hits could induce programmed cell death features in both chloroquine-sensitive and -resistant laboratory strains. Quinacrine was effective at inhibiting field isolates in a 48-h reinvasion assay regardless of artemisinin clearance status. We therefore present as proof of concept a phenotypic screening method with the potential to provide mechanistic insights to the activity of antimalarial drugs.

Autoregulation of Shh expression and Shh induction of cell death suggest a mechanism for modulating polarising activity during chick limb development

Development ◽  
2000 ◽  
Vol 127 (22) ◽  
pp. 4811-4823 ◽  
Author(s):  
J.J. Sanz-Ezquerro ◽  
C. Tickle
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Sonic Hedgehog ◽  
Limb Development ◽  
Retroviral Vector ◽  
Cellular Mechanism ◽  
Limb Bud ◽  
Drug Induced ◽  
Signalling Molecule ◽  
Vertebrate Limb

The polarising region expresses the signalling molecule sonic hedgehog (Shh), and is an embryonic signalling centre essential for outgrowth and patterning of the vertebrate limb. Previous work has suggested that there is a buffering mechanism that regulates polarising activity. Little is known about how the number of Shh-expressing cells is controlled but, paradoxically, the polarising region appears to overlap with the posterior necrotic zone, a region of programmed cell death. We have investigated how Shh expression and cell death respond when levels of polarising activity are altered, and show an autoregulatory effect of Shh on Shh expression and that Shh affects cell death in the posterior necrotic zone. When we increased Shh signalling, by grafting polarising region cells or applying Shh protein beads, this led to a reduction in the endogenous Shh domain and an increase in posterior cell death. In contrast, cells in other necrotic regions of the limb bud, including the interdigital areas, were rescued from death by Shh protein. Application of Shh protein to late limb buds also caused alterations in digit morphogenesis. When we reduced the number of Shh-expressing cells in the polarising region by surgery or drug-induced killing, this led to an expansion of the Shh domain and a decrease in the number of dead cells. Furthermore, direct prevention of cell death using a retroviral vector expressing Bcl2 led to an increase in Shh expression. Finally, we provide evidence that the fate of some of the Shh-expressing cells in the polarising region is to undergo apoptosis and contribute to the posterior necrotic zone during normal limb development. Taken together, these results show that there is a buffering system that regulates the number of Shh-expressing cells and thus polarising activity during limb development. They also suggest that cell death induced by Shh could be the cellular mechanism involved. Such an autoregulatory process based on cell death could represent a general way for regulating patterning signals in embryos.

scholarly journals Investigating Programmed Cell Death and Tumor Invasion in a Three-Dimensional (3D) Microfluidic Model of Glioblastoma

2020 ◽  
Vol 21 (9) ◽  
pp. 3162
Author(s):  
Ehsan Samiei ◽  
Amir Seyfoori ◽  
Brian Toyota ◽  
Saeid Ghavami ◽  
Mohsen Akbari
Keyword(s):  
Cell Death ◽  
Survival Rate ◽  
Programmed Cell Death ◽  
Tumor Invasion ◽  
3D Model ◽  
Apoptotic Cell ◽  
Simultaneous Detection ◽  
Three Dimensional ◽  
Drug Induced ◽  
Induced Apoptosis

Glioblastoma multiforme (GBM) is a rapidly progressive and deadly form of brain tumor with a median survival rate of ~15 months. GBMs are hard to treat and significantly affect the patient’s physical and cognitive abilities and quality of life. Temozolomide (TMZ)—an alkylating agent that causes DNA damage—is the only chemotherapy choice for the treatment of GBM. However, TMZ also induces autophagy and causes tumor cell resistance and thus fails to improve the survival rate among patients. Here, we studied the drug-induced programmed cell death and invasion inhibition capacity of TMZ and a mevalonate cascade inhibitor, simvastatin (Simva), in a three-dimensional (3D) microfluidic model of GBM. We elucidate the role of autophagy in apoptotic cell death by comparing apoptosis in autophagy knockdown cells (Atg7 KD) against their scrambled counterparts. Our results show that the cells were significantly less sensitive to drugs in the 3D model as compared to monolayer culture systems. An immunofluorescence analysis confirmed that apoptosis is the mechanism of cell death in TMZ- and Simva-treated glioma cells. However, the induction of apoptosis in the 3D model is significantly lower than in monolayer cultures. We have also shown that autophagy inhibition (Atg7 KD) did not change TMZ and Simva-induced apoptosis in the 3D microfluidic model. Overall, for the first time in this study we have established the simultaneous detection of drug induced apoptosis and autophagy in a 3D microfluidic model of GBM. Our study presents a potential ex vivo platform for developing novel therapeutic strategies tailored toward disrupting key molecular pathways involved in programmed cell death and tumor invasion in glioblastoma.

scholarly journals Plasmodium falciparum Replication factor C subunit 1 is involved in genotoxic stress response

2020 ◽  
Author(s):  
O Sheriff ◽  
Y Aniweh ◽  
Soak-Kuan Lai ◽  
HL Loo ◽  
S. K Sze ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cell Death ◽  
Dna Repair ◽  
Plasmodium Falciparum ◽  
Stress Response ◽  
Programmed Cell Death ◽  
Genotoxic Stress ◽  
Antimalarial Drugs ◽  
Protein Levels ◽  
Factor C

AbstractAbout half the world’s population is at risk of malaria, with Plasmodium falciparum malaria being responsible for the most malaria related deaths globally. Antimalarial drugs such as chloroquine and artemisinin are directed towards the proliferating intra-erythrocytic stages of the parasite, which is responsible for all the clinical symptoms of the disease. These antimalarial drugs have been reported to function via multiple pathways, one of which induces DNA damage via the generation of free radicals and reactive oxygen species. An urgent need to understand the mechanistic details of drug response and resistance is highlighted by the decreasing clinical efficacy of the front line drug, Artemisinin.The replication factor C subunit 1 protein is an important component of the DNA replication machinery and DNA damage response mechanism. Here we show the translocation of PfRFC1 from an intranuclear localization to the nuclear periphery indicating an orchestrated progression of distinct patterns of replication in the developing parasites. PfRFC1 responds to genotoxic stress via elevated protein levels in soluble and chromatin bound fractions.Reduction of PfRFC1 protein levels upon treatment with antimalarials suggests an interplay of replication and DNA repair pathways leading to cell death. Additionally, mislocalization of the endogenously tagged protein confirmed its essential role in parasites’ replication and DNA repair. This study provides key insights into DNA replication, DNA damage response and cell death in plasmodium falciparum.ImportanceFrontline drugs have been found to induce DNA damage in the human malaria parasite Plasmodium falciparum. The genotoxic stress response in Plasmodium and the interplay between DNA damage repair, replication and activation of programmed cell death pathways remains largely undescribed. This study shows a distinct pattern of localization of PfRFC1 during replication and DNA repair. PfRFC1 responds to genotoxic stress with an increase in protein expression. Interfering with the RFC complex formation or mislocalization of PfRFC1 is associated with disrupted genotoxic stress response. Additionally, a reduction of PfRFC1 protein levels is observed upon treatment with antimalarial drugs or under apoptosis like conditions, highlighting the role of DEVD/G like motif in mediating programmed cell death in these parasites. This study sheds light on the role of PfRFC1 in differentially responding to replication, genotoxic stress and programmed cell death in Plasmodium parasites.

scholarly journals Conventional calpains and programmed cell death.

2011 ◽  
Vol 58 (3) ◽  
Author(s):  
Paulina Łopatniuk ◽  
Jacek M Witkowski
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
System Development ◽  
Cysteine Proteases ◽  
Drug Induced ◽  
Calcium Dependent ◽  
Immune System Development ◽  
Apoptotic Pathways ◽  
Induced Apoptosis ◽  
And Function

The evidence on the crucial role of a family of calcium-dependent cysteine proteases called calpains in programmed cell death is rich and still growing. However, understanding of the mechanisms of their functions in apoptosis is not full yet. Calpains have been implicated in both physiological and pathological cell death control, especially in various malignancies, but also in the immune system development and function. There is also growing evidence on calpain involvement in apoptosis execution in certain pathological conditions of the central nervous system, in cardiovascular diseases, etc. Understanding of the clinical significance of calpain activation pathways, after intense studies of the influence of calpain activity on drug-induced apoptosis, seems especially important lately, as calpains have become noticed as potential therapeutic targets. To allow pharmacological targeting of these enzymes, thorough knowledge of their patterns of activation and further interactions with already known apoptotic pathways is necessary. A comprehensive summary of both well established and recently obtained information in the field is an important step that may lead to future advances in the use of calpain-targeted agents in the clinic.

scholarly journals Strategies to Treat Pulmonary Hypertension Using Programmed Cell Death-Inducing Anti-Cancer Drugs without Damaging the Heart

2020 ◽  
Author(s):  
Yuichiro J. Suzuki ◽  
Yasmine F. Ibrahim ◽  
Vladyslava Rybka ◽  
Jaquantey R. Bowens ◽  
Adenike S. Falade ◽  
...  
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Vascular Remodeling ◽  
Wall Thickening ◽  
Vascular Cells ◽  
Cancer Drugs ◽  
Drug Induced ◽  
Pulmonary Vascular Remodeling ◽  
Anti Cancer ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a fatal disease without a cure. By the time patients are diagnosed with PAH, thickening of pulmonary arterial (PA) walls and the narrowing of vascular lumen have already developed due to the abnormal growth of pulmonary vascular cells, contributing to the elevated pulmonary vascular resistance and the right ventricle (RV) damage. Therefore, agents that eliminate excess pulmonary vascular wall cells have therapeutic potential, and the apoptosis-based therapy using anti-cancer drugs may be promising for the treatment of PAH. However, cell death agents could also exert adverse effects including cardiotoxicity, complicating the development of such therapies for PAH patients who already have the damaged heart. We tested the concept that programmed cell death-inducing anti-cancer drugs may reduce the PA wall thickening using rat models of PAH. We found that: (i) The treatment of PAH animals with anthracycline-, proteasome inhibitor- or Bcl-2 inhibitor-classes of anti-cancer drugs after the pulmonary vascular remodeling had already developed resulted in the reversal of PA wall thickening and opened up the lumen; (ii) These effects were accompanied by the apoptosis of PA wall cells in PAH rats, but not in normal healthy rats, suggesting the anti-cancer drugs selectively kill remodeled vascular cells; (iii) The RV affected by PAH was not further damaged by anthracyclines or proteasome inhibitors; (iv) While the left ventricle (LV) was damaged by these drugs, we identified cardioprotective agents that protect the heart against drug-induced cell death without affecting the efficacy to reverse the PA remodeling; and (v) docetaxel, not only reversed pulmonary vascular remodeling without exerting RV or LV toxicity, but also repaired the RV damage caused by PAH. Thus, the inclusion of programmed cell death-inducing anti-cancer drugs should be considered for treating PAH patients.

Antibody against single-stranded DNA detects both programmed cell death and drug-induced apoptosis

1994 ◽  
Vol 101 (1) ◽  
pp. 73-78 ◽  
Author(s):  
I. Naruse ◽  
H. Keino ◽  
Y. Kawarada
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Drug Induced ◽  
Single Stranded Dna ◽  
Induced Apoptosis
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