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Induction of cell death and modulation of Annexin A1 by phytoestrogens in human leukemic cell lines

Sabran A, Kumolosasi E, Jantan I, Jamal JA, Azmi N, Jasamai M

Saudi Pharm J, 2021 Jan;29(1):73-84.
PMID: 33603542 DOI: 10.1016/j.jsps.2020.12.011

Background: Phytoestrogens are polyphenolic plant compounds which are structurally similar to the endogenous mammalian estrogen, 17β-estradiol. Annexin A1 (ANXA1) is an endogenous protein which inhibits cyclo-oxygenase 2 (COX-2) and phospholipase A2, signal transduction, DNA replication, cell transformation, and mediation of apoptosis.
Objective: This study aimed to determine the effects of selected phytoestrogens on annexin A1 (ANXA1) expression, mode of cell death and cell cycle arrest in different human leukemic cell lines.
Methods: Cells viability were examined by MTT assay and ANXA1 quantification via Enzyme-linked Immunosorbent Assay. Cell cycle and apoptosis were examined by flow cytometer and phagocytosis effect was evaluated using haematoxylin-eosin staining.
Results: Coumestrol significantly (p cells death may be related with their ability to reduce the levels of ANXA1. These findings can be used as a new approach in cancer treatment particularly in leukemia.

Matched MeSH terms: Cell Death
Potential of Gold Candidates against Human Colon Cancer

Abbasi M, Yaqoob M, Haque RA, Iqbal MA

Mini Rev Med Chem, 2021;21(1):69-78.
PMID: 32767935 DOI: 10.2174/1389557520666200807130721

Development of novel metallodrugs with pharmacological profile plays a significant role in modern medicinal chemistry and drug design. Metal complexes have shown remarkable clinical results in current cancer therapy. Gold complexes have attained attention due to their high antiproliferative potential. Gold-based drugs are used for the treatment of rheumatoid arthritis. Gold-containing compounds with selective and specific targets are capable to assuage the symptoms of a range of human diseases. Gold (I) species with labile ligands (such as Cl in TEPAuCl) interact with isolated DNA; therefore, this biomolecule has been considered as a target for gold drugs. Gold (I) has a high affinity towards sulfur and selenium. Due to this, gold (I) drugs readily interact with cysteine or selenocysteine residue of the enzyme to form protein-gold(I) thiolate or protein-gold (I) selenolate complexes that lead to inhibition of the enzyme activity. Au(III) compounds due to their square-planner geometriesthe same as found in cisplatin, represent a good source for the development of anti-tumor agents. This article aims to review the most important applications of gold products in the treatment of human colon cancer and to analyze the complex interplay between gold and the human body.

Matched MeSH terms: Cell Death/drug effects
Fulltext Green Biosynthesis, Antioxidant, Antibacterial, and Anticancer Activities of Silver Nanoparticles of Luffa acutangula Leaf Extract

Nallappan D, Fauzi AN, Krishna BS, Kumar BP, Reddy AVK, Syed T, et al.

Biomed Res Int, 2021;2021:5125681.
PMID: 34631882 DOI: 10.1155/2021/5125681

Studies on green biosynthesis of newly engineered nanoparticles for their prominent medicinal applications are being the torch-bearing concerns of the state-of-the-art research strategies. In this concern, we have engineered the biosynthesized Luffa acutangula silver nanoparticles of flavonoid O-glycosides in the anisotropic form isolated from aqueous leave extracts of Luffa acutangula, a popular traditional and ayurvedic plant in south-east Asian countries. These were structurally confirmed by Ultraviolet-visible (UV-Vis), Fourier transform infrared spectroscopy accessed with attenuated total reflection (FTIR-ATR) spectral analyses followed by the scanning electron microscopic (SEM) and the X-ray diffraction (XRD) crystallographic studies and found them with the face-centered cubic (fcc) structure. Medicinally, we have explored their significant antioxidant (DPPH and ABTS assays), antibacterial (disc diffusion assay on E. coli, S. aureus, B. subtilis, S. fecilis, and S. boydii), and anticancer (MTT assay on MCF-7, MDA-MB-231, U87, and DBTRG cell lines) potentialities which augmented the present investigation. The molecular docking analysis of title compounds against 3NM8 (DPPH) and 1DNU (ABTS) proteins for antioxidant activity; 5FGK (Gram-Positive Bacteria) and 1AB4 (Gram-Negative Bacteria) proteins for antibacterial activity; and 4GBD (MCF-7), 5FI2 (MDA-MB-231), 1D5R (U87), and 5TIJ (DBTRG) proteins for anticancer activity has affirmed the promising ligand-protein binding interactions among the hydroxy groups of the title compounds and aspartic acid of the concerned enzymatic proteins. The binding energy varying from -9.1645 to -7.7955 for Cosmosioside (1, Apigenin-7-glucoside) and from -9.2690 to -7.8306 for Cynaroside (2, Luteolin-7-glucoside) implies the isolated compounds as potential bioactive compounds. In addition, the performed studies like QSAR, ADMET, bioactivity properties, drug scores, and toxicity risks confirmed them as potential drug candidates and aspartic acid receptor antagonists. This research auxiliary augmented the existing array of phytological nanomedicines with new drug candidates that are credible with multiple bioactivities.

Matched MeSH terms: Cell Death/drug effects
Fulltext Green Synthesis of Fe3O4 Nanoparticles Stabilized by a Garcinia mangostana Fruit Peel Extract for Hyperthermia and Anticancer Activities

Yusefi M, Shameli K, Su Yee O, Teow SY, Hedayatnasab Z, Jahangirian H, et al.

Int J Nanomedicine, 2021;16:2515-2532.
PMID: 33824589 DOI: 10.2147/IJN.S284134

INTRODUCTION: Fe3O4 nanoparticles (Fe3O4 NPs) with multiple functionalities are intriguing candidates for various biomedical applications.
MATERIALS AND METHODS: This study introduced a simple and green synthesis of Fe3O4 NPs using a low-cost stabilizer of plant waste extract rich in polyphenols content with a well-known antioxidant property as well as anticancer ability to eliminate colon cancer cells. Herein, Fe3O4 NPs were fabricated via a facile co-precipitation method using the crude extract of Garcinia mangostana fruit peel as a green stabilizer at different weight percentages (1, 2, 5, and 10 wt.%). The samples were analyzed for magnetic hyperthermia and then in vitro cytotoxicity assay was performed.
RESULTS: The XRD planes of the samples were corresponding to the standard magnetite Fe3O4 with high crystallinity. From TEM analysis, the green synthesized NPs were spherical with an average size of 13.42±1.58 nm and displayed diffraction rings of the Fe3O4 phase, which was in good agreement with the obtained XRD results. FESEM images showed that the extract covered the surface of the Fe3O4 NPs well. The magnetization values for the magnetite samples were ranging from 49.80 emu/g to 69.42 emu/g. FTIR analysis verified the functional groups of the extract compounds and their interactions with the NPs. Based on DLS results, the hydrodynamic sizes of the Fe3O4 nanofluids were below 177 nm. Furthermore, the nanofluids indicated the zeta potential values up to -34.92±1.26 mV and remained stable during four weeks of storage, showing that the extract favorably improved the colloidal stability of the Fe3O4 NPs. In the hyperthermia experiment, the magnetic nanofluids showed the acceptable specific absorption rate (SAR) values and thermosensitive performances under exposure of various alternating magnetic fields. From results of in vitro cytotoxicity assay, the killing effects of the synthesized samples against HCT116 colon cancer cells were mostly higher compared to those against CCD112 colon normal cells. Remarkably, the Fe3O4 NPs containing 10 wt.% of the extract showed a lower IC50 value (99.80 µg/mL) in HCT116 colon cancer cell line than in CCD112 colon normal cell line (140.80 µg/mL).
DISCUSSION: This research, therefore, introduced a new stabilizer of Garcinia mangostana fruit peel extract for the biosynthesis of Fe3O4 NPs with desirable physiochemical properties for potential magnetic hyperthermia and colon cancer treatment.

Matched MeSH terms: Cell Death/drug effects
Fulltext Evaluation of Antitumor Efficacy of Chitosan-Tamarind Gum Polysaccharide Polyelectrolyte Complex Stabilized Nanoparticles of Simvastatin

Malviya R, Raj S, Fuloria S, Subramaniyan V, Sathasivam K, Kumari U, et al.

Int J Nanomedicine, 2021;16:2533-2553.
PMID: 33824590 DOI: 10.2147/IJN.S300991

PURPOSE: The present study was intended to fabricate chitosan (Ch)-tamarind gum polysaccharide (TGP) polyelectrolyte complex stabilized cubic nanoparticles of simvastatin and evaluate their potential against human breast cancer cell lines.
MATERIALS AND METHODS: The antisolvent precipitation method was used for formulation of nanoparticles. Factorial design (32) was utilized as a tool to analyze the effect of Ch and TGP concentration on particle size and entrapment efficiency of nanoparticles.
RESULTS: Formulated nanoparticles showed high entrapment efficiency (67.19±0.42-83.36±0.23%) and small size (53.3-383.1 nm). The present investigation involved utilization of two biological membranes (egg and tomato) as biological barriers for drug release. The study revealed that drug release from tomato membranes was retarded (as compared to egg membranes) but the release pattern matched that of egg membranes. All formulations followed the Baker-Lansdale model of drug release irrespective of the two different biological barriers. Stability studies were carried out for 45 days and exhibited less variation in particle size as well as a reduction in entrapment efficiency. Simvastatin loaded PEC stabilized nanoparticles exhibited better control on growth of human breast cancer cell lines than simple simvastatin. An unusual anticancer effect of simvastatin nanoparticles is also supported by several other research studies.
CONCLUSION: The present study involves first-time synthesis of Ch-TGP polyelectrolyte complex stabilized nanoparticles of simvastatin against MCF-7 cells. It recommends that, in future, theoretical modeling and IVIVC should be carried out for perfect designing of delivery systems.

Matched MeSH terms: Cell Death/drug effects
Fulltext Ethanol Induces Microglial Cell Death via the NOX/ROS/PARP/TRPM2 Signalling Pathway

Sha'fie MSA, Rathakrishnan S, Hazanol IN, Dali MHI, Khayat ME, Ahmad S, et al.

Antioxidants (Basel), 2020 Dec 09;9(12).
PMID: 33317056 DOI: 10.3390/antiox9121253

Microglial cells are the primary immune cell resident in the brain. Growing evidence indicates that microglial cells play a prominent role in alcohol-induced brain pathologies. However, alcohol-induced effects on microglial cells and the underlying mechanisms are not fully understood, and evidence exists to support generation of oxidative stress due to NADPH oxidases (NOX_-mediated production of reactive oxygen species (ROS). Here, we investigated the role of the oxidative stress-sensitive Ca2+-permeable transient receptor potential melastatin-related 2 (TRPM2) channel in ethanol (EtOH)-induced microglial cell death using BV2 microglial cells. Like H2O2, exposure to EtOH induced concentration-dependent cell death, assessed using a propidium iodide assay. H2O2/EtOH-induced cell death was inhibited by treatment with TRPM2 channel inhibitors and also treatment with poly(ADP-ribose) polymerase (PARP) inhibitors, demonstrating the critical role of PARP and the TRPM2 channel in EtOH-induced cell death. Exposure to EtOH, as expected, led to an increase in ROS production, shown using imaging of 2',7'-dichlorofluorescein fluorescence. Consistently, EtOH-induced microglial cell death was suppressed by inhibition of NADPH oxidase (NOX) as well as inhibition of protein kinase C. Taken together, our results suggest that exposure to high doses of ethanol can induce microglial cell death via the NOX/ROS/PARP/TRPM2 signaling pathway, providing novel and potentially important insights into alcohol-induced brain pathologies.

Matched MeSH terms: Cell Death
Fatty acid binding protein 7 mediates linoleic acid-induced cell death in triple negative breast cancer cells by modulating 13-HODE

Kwong SC, Abd Jamil AH, Rhodes A, Taib NA, Chung I

Biochimie, 2020 Dec;179:23-31.
PMID: 32931863 DOI: 10.1016/j.biochi.2020.09.005

Different fatty acids have distinct effects on the survival of breast cancer cells, which could be mediated by fatty acid binding proteins (FABPs), a family of lipid chaperones. Due to the diverse structures of the members of FABP family, each FABP demonstrates distinct binding affinities to different fatty acids. Of note, FABP7 is predominantly expressed in triple negative breast cancer (TNBC), the most aggressive subtype of breast cancer. Yet, the role of FABP7 in modulating the effects of fatty acids on TNBC survival was unclear. In contrast to the high expression of FABP7 in human TNBC tumours, FABP7 protein was undetectable in TNBC cell lines. Hence, a FABP7 overexpression model was used for this study, in which the transduced TNBC cell lines (MDA-MB-231 and Hs578T) were treated with various mono- and polyunsaturated fatty acids. Oleic acid (OA), docosahexaenoic acid (DHA) and arachidonic acid (AA) inhibited TNBC cell growth at high concentrations, with no differences resulted from FABP7 overexpression. Interestingly, overexpression of FABP7 augmented linoleic acid-induced cell death in MDA-MB-231 cells. The increased cell death may be explained by a decrease in 13-HODE, a pro-tumorigenic oxidation product of linoleic acid. The phenotype was, however, attenuated with a rescue treatment using 25 nM 13-HODE. The decrease in 13-HODE was potentially due to fatty acid partitioning modulated by FABP7, as demonstrated by a 3-fold increase in fatty acid oxidation. Our findings suggest that linoleic acid could be a potential therapeutic strategy for FABP7-overexpressing TNBC patients.

Matched MeSH terms: Cell Death
Fulltext Anticancer Drug Discovery from Microbial Sources: The Unique Mangrove Streptomycetes

Law JW, Law LN, Letchumanan V, Tan LT, Wong SH, Chan KG, et al.

Molecules, 2020 Nov 17;25(22).
PMID: 33212836 DOI: 10.3390/molecules25225365

Worldwide cancer incidence and mortality have always been a concern to the community. The cancer mortality rate has generally declined over the years; however, there is still an increased mortality rate in poorer countries that receives considerable attention from healthcare professionals. This suggested the importance of the prompt detection, effective treatment, and prevention strategies. The genus Streptomyces has been documented as a prolific producer of biologically active secondary metabolites. Streptomycetes from mangrove environments attract researchers' attention due to their ability to synthesize diverse, interesting bioactive metabolites. The present review highlights research on mangrove-derived streptomycetes and the production of anticancer-related compounds from these microorganisms. Research studies conducted between 2008 and 2019, specifically mentioning the isolation of streptomycetes from mangrove areas and described the successful purification of compound(s) or generation of crude extracts with cytotoxic activity against human cancer cell lines, were compiled in this review. It is anticipated that there will be an increase in prospects for mangrove-derived streptomycetes as one of the natural resources for the isolation of chemotherapeutic agents.

Matched MeSH terms: Cell Death/drug effects
Fulltext SARS CoV-2 aggravates cellular metabolism mediated complications in COVID-19 infection

Singh Y, Gupta G, Kazmi I, Al-Abbasi FA, Negi P, Chellappan DK, et al.

Dermatol Ther, 2020 11;33(6):e13871.
PMID: 32558055 DOI: 10.1111/dth.13871

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the primary causative organism in corona virus disease-19 (COVID-19) infections, is a novel member of the human coronavirus family which was first identified in Wuhan, China, towards the end of 2019. This letter reveals new vital missing links in our current understanding of the mechanisms that lead to cell death triggered by ferroptotic stress in COVID-19 infection. It further reveal the importance of homocysteine mediated trans-sulfuration pathway in COVID-19 infection. Hence, Vitamin B6, folic acid, and Vitamin B12 should be incorporated in the treatment regimen for SARS CoV-2 infections to suppress complications, as the virus mediates altered host cell metabolism.

Matched MeSH terms: Cell Death/physiology*
Virgin Coconut Oil-Induced Neuroprotection in Lipopolysaccharide-Challenged Rats is Mediated, in Part, Through Cholinergic, Anti-Oxidative and Anti-Inflammatory Pathways

Rahim NS, Lim SM, Mani V, Hazalin NAMN, Majeed ABA, Ramasamy K

J Diet Suppl, 2020 Oct 14.
PMID: 33962540 DOI: 10.1080/19390211.2020.1830223

Neuroinflammation is associated with neuronal cell death and could lead to chronic neurodegeneration. This study investigated the neuroprotective potential of virgin coconut oil (VCO) against lipopolysaccharide (LPS)-induced cytotoxicity of neuroblastoma SK-N-SH cells. The findings were validated using Wistar rats, which were fed with 1-10 g/kg VCO for 31 days, exposed to LPS (0.25 mg/kg) and subjected to the Morris Water Maze Test. Brain homogenate was subjected to biochemical analyses and gene expression studies. α-Tocopherol (α-T; 150 mg/kg) served as the positive control. VCO (100 µg/mL) significantly (p

Matched MeSH terms: Cell Death
Fulltext Phosphoinositide-dependent Kinase-1 (PDPK1) regulates serum/glucocorticoid-regulated Kinase 3 (SGK3) for prostate cancer cell survival

Nalairndran G, Hassan Abdul Razack A, Mai CW, Fei-Lei Chung F, Chan KK, Hii LW, et al.

J Cell Mol Med, 2020 Oct;24(20):12188-12198.
PMID: 32926495 DOI: 10.1111/jcmm.15876

Prostate cancer (PCa) is the most common malignancy and is the second leading cause of cancer among men globally. Using a kinome-wide lentiviral small-hairpin RNA (shRNA) library screen, we identified phosphoinositide-dependent kinase-1 (PDPK1) as a potential mediator of cell survival in PCa cells. We showed that knock-down of endogenous human PDPK1 induced significant tumour-specific cell death in PCa cells (DU145 and PC3) but not in the normal prostate epithelial cells (RWPE-1). Further analyses revealed that PDPK1 mediates cancer cell survival predominantly via activation of serum/glucocorticoid-regulated kinase 3 (SGK3). Knock-down of endogenous PDPK1 in DU145 and PC3 cells significantly reduced SGK3 phosphorylation while ectopic expression of a constitutively active SGK3 completely abrogated the apoptosis induced by PDPK1. In contrast, no such effect was observed in SGK1 and AKT phosphorylation following PDPK1 knock-down. Importantly, PDPK1 inhibitors (GSK2334470 and BX-795) significantly reduced tumour-specific cell growth and synergized docetaxel sensitivity in PCa cells. In summary, our results demonstrated that PDPK1 mediates PCa cells' survival through SGK3 signalling and suggest that inactivation of this PDPK1-SGK3 axis may potentially serve as a novel therapeutic intervention for future treatment of PCa.

Matched MeSH terms: Cell Death/drug effects
Fulltext In Silico Analyses and Cytotoxicity Study of Asiaticoside and Asiatic Acid from Malaysian Plant as Potential mTOR Inhibitors

Zulkipli NN, Zakaria R, Long I, Abdullah SF, Muhammad EF, Wahab HA, et al.

Molecules, 2020 Sep 02;25(17).
PMID: 32887218 DOI: 10.3390/molecules25173991

Natural products remain a popular alternative treatment for many ailments in various countries. This study aimed to screen for potential mammalian target of rapamycin (mTOR) inhibitors from Malaysian natural substance, using the Natural Product Discovery database, and to determine the IC50 of the selected mTOR inhibitors against UMB1949 cell line. The crystallographic structure of the molecular target (mTOR) was obtained from Protein Data Bank, with Protein Data Bank (PDB) ID: 4DRI. Everolimus, an mTOR inhibitor, was used as a standard compound for the comparative analysis. Computational docking approach was performed, using AutoDock Vina (screening) and AutoDock 4.2.6 (analysis). Based on our analysis, asiaticoside and its derivative, asiatic acid, both from Centella asiatica, revealed optimum-binding affinities with mTOR that were comparable to our standard compound. The effect of asiaticoside and asiatic acid on mTOR inhibition was validated with UMB1949 cell line, and their IC50 values were 300 and 60 µM, respectively, compared to everolimus (29.5 µM). Interestingly, this is the first study of asiaticoside and asiatic acid against tuberous sclerosis complex (TSC) disease model by targeting mTOR. These results, coupled with our in silico findings, should prompt further studies, to clarify the mode of action, safety, and efficacy of these compounds as mTOR inhibitors.

Matched MeSH terms: Cell Death/drug effects
Fulltext Bioactivities of Lyngbyabellins from Cyanobacteria of Moorea and Okeania Genera

Fathoni I, Petitbois JG, Alarif WM, Abdel-Lateff A, Al-Lihaibi SS, Yoshimura E, et al.

Molecules, 2020 Sep 01;25(17).
PMID: 32882989 DOI: 10.3390/molecules25173986

Cyanobacteria are reported as rich sources of secondary metabolites that provide biological activities such as enzyme inhibition and cytotoxicity. Ten depsipeptide derivatives (lyngbyabellins) were isolated from a Malaysian Moorea bouillonii and a Red Sea Okeania sp.: lyngbyabellins G (1), O (2), P (3), H (4), A (7), 27-deoxylyngbyabellin A (5), and homohydroxydolabellin (6). This study indicated that lyngbyabellins displayed cytotoxicity, antimalarial, and antifouling activities. The isolated compounds were tested for cytotoxic effect against human breast cancer cells (MCF7), for antifouling activity against Amphibalanus amphitrite barnacle larvae, and for antiplasmodial effect towards Plasmodium falciparum. Lyngbyabellins A and G displayed potent antiplasmodial effect against Plasmodium, whereas homohydroxydolabellin showed moderate effect. For antifouling activity, the side chain decreases the activity slightly, but the essential feature is the acyclic structure. As previously reported, the acyclic lyngbyabellins are less cytotoxic than the corresponding cyclic ones, and the side chain increases cytotoxicity. This study revealed that lyngbyabellins, despite being cytotoxic agents as previously reported, also exhibit antimalarial and antifouling activities. The unique chemical structures and functionalities of lyngbyabellin play an essential role in their biological activities.

Matched MeSH terms: Cell Death/drug effects
Fulltext A meta-analysis on immune checkpoint inhibitor efficacy for advanced non-small cell lung cancer between East Asians versus non-East Asians

Peng S, Ying AF, Tai BC, Soo RA

Transl Lung Cancer Res, 2020 Aug;9(4):1124-1137.
PMID: 32953491 DOI: 10.21037/tlcr-20-246

Background: We conducted a meta-analysis to assess the efficacy of immune checkpoint inhibitors (ICIs) (PD-1/L1 and CTLA-4 inhibitors) in first and subsequent lines in East Asians and non-East Asians.
Methods: We searched PubMed-MEDLINE, Embase and Scopus, from inception to 20 Sep 2019, and reviewed major conferences' abstracts, for randomised controlled trials of ICI in advanced-stage NSCLC (Stage IIIB or IV) without EGFR mutation that reported hazard ratios (HRs) stratified by geographical region including the region "Asia" or "East Asia". The primary outcome measures were overall survival (OS) and progression-free survival (PFS). The pooled HR and its 95% confidence interval (CI) for OS and PFS in East Asians and non-East Asians were calculated using a random effect model and the difference compared using an interaction test.
Results: A total of 5,465 patients from 7 randomised controlled trials involving CTLA-4 and/or PD-1/L1 inhibitors were included, with 1,740 (32%) East Asians and 3,725 (68%) non-East Asians. ICI was associated with an improvement in OS and PFS for both East Asian (OS HR, 0.74; 95% CI, 0.65-0.85; PFS HR, 0.56; 95% CI, 0.40-0.79) and non-East Asian patients (OS HR, 0.78; 95% CI, 0.72-0.85; PFS HR, 0.69; 95% CI, 0.56-0.85), with no significant difference between the two groups (Pinteraction=0.55 for OS; Pinteraction=0.33 for PFS). Subgroup analyses showed a statistically significant superior PFS (but not OS) for East Asians than non-East Asians in trials that used immune checkpoint inhibitor in the first-line treatment (Pinteraction=0.02). No significant regional difference was found in further subgroups of pure ICI and combination of ICI with chemotherapy.
Conclusions: There is no significant difference in response to ICI between East Asians and non-East Asians with advanced stage NSCLC, and the statistically significant subgroup difference in PFS in the first line use of ICI may not be clinically significant.

Matched MeSH terms: Programmed Cell Death 1 Receptor
Fulltext Bystander Effect Induced in Breast Cancer (MCF-7) and Human Osteoblast Cell Lines (hFOB 1.19) with HDR-Brachytherapy

Zainudin Nh M, R A, W N R

J Biomed Phys Eng, 2020 Jun;10(3):319-328.
PMID: 32637376 DOI: 10.31661/jbpe.v0i0.1135

Background: Radiation induced bystander effects (RIBEs) occurs in unirradiated cells exhibiting indirect biological effect as a consequence of signals from other irradiated cells in the population.
Objective: In this study, bystander effects in MCF-7 breast cancer cells and hFOB 1.19 normal osteoblast cells irradiated with gamma emitting HDR Brachytherapy Ir-192 source were investigated.
Material and Methods: In this in-vitro study, bystander effect stimulation was conducted using medium transfer technique of irradiated cells to the non-irradiated bystander cells. Cell viability, reactive oxygen species (ROS) generation and colony forming assay was employed to evaluate the effect.
Results: Results indicate that the exposure to the medium irradiated MCF-7 induced significant bystander killing and decreased the survival fraction of bystander MCF-7 and hFOB from 1.19 to 81.70 % and 65.44 %, respectively. A significant decrease in survival fraction was observed for hFOB 1.19 bystander cells (p < 0.05). We found that the rate of hFOB 1.19 cell growth significantly decreases to 85.5% when added with media from irradiated cells. The ROS levels of bystander cells for both cell lines were observed to have an increase even after 4 h of treatment. Our results suggest the presence of bystander effects in unirradiated cells exposed to the irradiated medium.
Conclusion: These data provide evidence that irradiated MCF-7 breast cancer cells can induce bystander death in unirradiated MCF-7 and hFOB 1.19 bystander cells. Increase in cell death could also be mediated by the ROS generation during the irradiation with HDR brachytherapy.

Matched MeSH terms: Cell Death
Fulltext Evaluation of phytoestrogens in inducing cell death mediated by decreasing Annexin A1 in Annexin A1-knockdown leukemia cells

Hasan M, Kumolosasi E, Jasamai M, Jamal JA, Azmi N, Rajab NF

Daru, 2020 Jun;28(1):97-108.
PMID: 31912375 DOI: 10.1007/s40199-019-00320-0

BACKGROUND: Phytoestrogens are plant compounds that are structurally similar to estrogen and that possess anti-cancer properties. Previous studies have reported that coumestrol, daidzein and genistein could induce cell death by reducing Annexin A1 protein in leukemic cell lines. Annexin A1 (ANXA1) is involved in cell progression, metastasis, and apoptosis in several types of cancer cells. The present study sought to investigate if the effects of phytoestrogens on apoptosis, cell cycle arrest and phagocytosis in ANXA1-knockdown leukemic cells are mediated through ANXA1 or occurred independently.
METHODS: Transfection of ANXA1 siRNA was conducted to downregulate ANXA1 expression in Jurkat, K562 and U937 cells. Apoptosis and cell cycle assays were conducted using flow cytometry. Western blot was performed to evaluate ANXA1, caspases and Bcl-2 proteins expression. Phagocytosis was determined using hematoxylin and eosin staining.
RESULTS: The expression of ANXA1 after the knockdown was significantly downregulated in all cell lines. Genistein significantly induced apoptosis associated with an upregulation of procaspase-3, -9, and - 1 in Jurkat cells. The Bcl-2 expression showed no significant difference in Jurkat, K562 and U937 cells. Treatment with phytoestrogens increased procaspase-1 expression in Jurkat and U937 cells while no changes were detected in K562 cells. Flow cytometry analysis demonstrated that after ANXA1 knockdown, coumestrol and genistein caused cell cycle arrest at G2/M phase in selected type of cells. The percentage of phagocytosis and phagocytosis index increased after the treatment with phytoestrogens in all cell lines.
CONCLUSION: Phytoestrogens induced cell death in ANXA1-knockdown leukemia cells, mediated by Annexin A1 proteins. Graphical abstract.

Matched MeSH terms: Cell Death/drug effects
Gene expression changes in human bronchial epithelial cells (BEAS-2B) and human pulmonary alveolar epithelial cells (HPAEpiC) after interaction with Cladosporium sphaerospermum

Lo SG, Wong SF, Mak JW, Choo KK, Ng KP

Med Mycol, 2020 Apr 01;58(3):333-340.
PMID: 31309220 DOI: 10.1093/mmy/myz061

Cladosporium is one of the most abundant spore. Fungi of this genus can cause respiratory allergy and intrabronchial lesion. We studied the differential expression of host genes after the interaction of Cladosporium sphaerospermum conidia with Human Bronchial Epithelial Cells (BEAS-2B) and Human Pulmonary Alveolar Epithelial Cells (HPAEpiC). C. sphaerospermum conidia were harvested and co-cultured with BEAS-2B cells or HPAEpiC cells for 48 hours respectively. This culture duration was chosen as it was associated with high germination rate. RNA was extracted from two biological replicates per treatment. RNA of BEAS-2B cells was used to assess changes in gene expression using AffymetrixGeneChip® Human Transcriptome Array 2.0. After co-culture with Cladosporium spores, 68 individual genes were found differentially expressed (P ≤ 0.05) and up-regulated ≥ 1.5 folds while 75 genes were found differentially expressed at ≤ -1.5 folds compared with controls. Reverse transcription and qPCR were performed on the RNA collected from both BEAS-2B cells and HPAEpiC cells to validate the microarray results with 7 genes. Based on the findings, infected pulmonary epithelial cells exhibited an increase in cell death-related genes and genes associated with innate immunity.

Matched MeSH terms: Cell Death
Fulltext Inhibitory Effects of Raw-Extract Centella asiatica (RECA) on Acetylcholinesterase, Inflammations, and Oxidative Stress Activities via In Vitro and In Vivo

Hafiz ZZ, Amin M'M, Johari James RM, Teh LK, Salleh MZ, Adenan MI

Molecules, 2020 Feb 17;25(4).
PMID: 32079355 DOI: 10.3390/molecules25040892

Centella asiatica (C. asiatica) is one of the medicinal plants that has been reported to exert comprehensive neuroprotection in vitro and in vivo. In view of this, the present study was performed to investigate the effect of ethanolic extract of C. asiatica, designated as raw-extract of C. asiatica (RECA) in reducing the acetylcholinesterase (AChE), inflammations, and oxidative stress activities via both in vitro (SH-SY5Y and RAW 264.7 cells) and in vivo (Sprague Dawley rats). Quantitative high-performance liquid chromatography analysis reveals that RECA contains a significantly high proportion of glycosides than the aglycones with madecassoside as the highest component, followed by asiaticoside. Treatment of SH-SY5Y cells with RECA significantly reduced the AChE activity in a concentration-dependent manner with an IC50 value of 31.09 ± 10.07 µg/mL. Furthermore, the anti-inflammatory and antioxidant effects of RECA were evaluated by lipopolysaccharides (LPS)-stimulated RAW 264.7 cells. Our results elucidated that treatment with RECA significantly suppressed the level of pro-inflammatory cytokine/mediators and oxidative stress released in a concentration-dependent manner. Interestingly, these patterns of inhibition were consistent as observed in the LPS-induced neuroinflammation Sprague Dawley rats' model. The highest concentration used in the two models presented the most significant results. Herein, our findings strongly suggest that RECA may offer therapeutic potential for the treatment of Alzheimer's disease through inhibiting the AChE, inflammation, and oxidative stress activities.

Matched MeSH terms: Cell Death/drug effects
Fulltext Geranylated 4-phenylcoumarins extracted from Mesua elegans induced caspase-independent cell death in prostate cancer cell lines through calpain-2 and cathepsin B

Sapili H, Ho CS, Malagobadan S, Arshad NM, Nagoor NH

Sci Rep, 2020 01 22;10(1):986.
PMID: 31969640 DOI: 10.1038/s41598-020-57781-6

Geranylated 4-phenylcoumarins DMDP-1 and DMDP-2 isolated from Mesua elegans were elucidated for their role in inducing caspase-independent programmed cell death (CI-PCD) in prostate cancer cell lines, PC-3 and DU 145, respectively. Cell homeostasis disruption was demonstrated upon treatment, as shown by the increase in calcium ion through colourimetric assay and endoplasmic reticulum (ER) stress markers GRP 78 and p-eIF2α through western blot. Subsequently, cytoplasmic death protease calpain-2 also showed increased activity during DMDP-1 & -2 treatments, while lysosomic death protease cathepsin B activity was significantly increased in PC-3 treated with DMDP-1. Flow cytometry showed a reduction in mitochondrial membrane potential in both cell lines, while western blotting showed translocation of mitochondrial death protease AIF into the cytoplasm in its truncated form. Furthermore, DMDP-1 & -2 treatments caused significant increase in superoxide level and oxidative DNA damage. Concurrent inhibition of calpain-2 and cathepsin B during the treatment showed an attenuation of cell death in both cell lines. Hence, DMDP-1 & -2 induce CI-PCD in prostate cancer cell lines through calpain-2 and cathepsin B.

Matched MeSH terms: Cell Death/drug effects*
Mechanisms of action of amyloid-beta and its precursor protein in neuronal cell death

Leong YQ, Ng KY, Chye SM, Ling APK, Koh RY

Metab Brain Dis, 2020 01;35(1):11-30.
PMID: 31811496 DOI: 10.1007/s11011-019-00516-y

Extracellular senile plaques and intracellular neurofibrillary tangles are the neuropathological findings of the Alzheimer's disease (AD). Based on the amyloid cascade hypothesis, the main component of senile plaques, the amyloid-beta (Aβ) peptide, and its derivative called amyloid precursor protein (APP) both have been found to place their central roles in AD development for years. However, the recent therapeutics have yet to reverse or halt this disease. Previous evidence demonstrates that the accumulation of Aβ peptides and APP can exert neurotoxicity and ultimately neuronal cell death. Hence, we discuss the mechanisms of excessive production of Aβ peptides and APP serving as pathophysiologic stimuli for the initiation of various cell signalling pathways including apoptosis, necrosis, necroptosis and autophagy which lead to neuronal cell death. Conversely, the activation of such pathways could also result in the abnormal generation of APP and Aβ peptides. An elucidation of actions of APP and its metabolite, Aβ, could be vital in suggesting novel therapeutic opportunities.

Matched MeSH terms: Cell Death/physiology

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