Induction Of Apoptosis Research Articles

Anticancer Effect of Dihydroartemisinin via Dual Control of ROS-induced Apoptosis and Protective Autophagy in Prostate Cancer 22Rv1 Cells.

Dihydroartemisinin (DHA), a natural agent, exhibits potent anticancer activity. However, its biological activity on prostate cancer (PCa) 22Rv1 cells has not been previously investigated. In this study, we demonstrate that DHA induces anticancer effects through the induction of apoptosis and autophagy. Cell viability and proliferation rate were assessed using the CCK-8 assay and cell clone formation assay. The generation of reactive oxygen species (ROS) was detected by flow cytometry. The molecular mechanism of DHA-induced apoptosis and autophagy was examined using Western blot and RT-qPCR. The formation of autophagosomes and the changes in autophagy flux were observed using transmission electron microscopy (TEM) and confocal microscopy. The effect of DHA combined with Chloroquine (CQ) was assessed using the EdU assay and flow cytometry. The expressions of ROS/AMPK/mTOR-related proteins were detected using Western blot. The interaction between Beclin-1 and Bcl-2 was examined using Co-IP. DHA inhibited 22Rv1 cell proliferation and induced apoptosis. DHA exerted its antiprostate cancer effects by increasing ROS levels. DHA promoted autophagy progression in 22Rv1 cells. Inhibition of autophagy enhanced the pro-apoptotic effect of DHA. DHA-induced autophagy initiation depended on the ROS/AMPK/mTOR pathway. After DHA treatment, the impact of Beclin- 1 on Bcl-2 was weakened, and its binding with Vps34 was enhanced. DHA induces apoptosis and autophagy in 22Rv1 cells. The underlying mechanism may involve the regulation of ROS/AMPK/mTOR signaling pathways and the interaction between Beclin-1 and Bcl-2 proteins. Additionally, the combination of DHA and CQ may enhance the efficacy of DHA in inhibiting tumor cell activity.

A Six-gene Prognostic Model Based on Neutrophil Extracellular Traps (NETs)-related Gene Signature for Lung Adenocarcinoma.

Lung adenocarcinoma (LUAD) is one of the most common malignant cancers. Neutrophil extracellular traps (NETs) have been discovered to play a crucial role in the pathogenesis of LUAD. We aimed to establish an innovative prognostic model for LUAD based on the distinct expression patterns of NETs-related genes. The TCGA LUAD dataset was utilized as the training set, while GSE31210, GSE37745, and GSE50081 were undertaken as the verification sets. The patients were grouped into clusters based on the expression signature of NETs-related genes. Differentially expressed genes between clusters were identified through the utilization of the random forest and LASSO algorithms. The NETs score model for LUAD prognosis was developed by multiplying the expression levels of specific genes with their corresponding LASSO coefficients and then summing them. The validity of the model was confirmed by analysis of the survival curves and ROC curves. Additionally, immune infiltration, GSEA, mutation analysis, and drug analysis were conducted. Silencing ABCC2 in A549 cells was achieved to investigate its effect. We identified six novel NETs-related genes, namely UPK1B, SFTA3, GGTLC1, SCGB3A1, ABCC2, and NTS, and developed a NETs score signature, which exhibited a significant correlation with the clinicopathological and immune traits of the LUAD patients. High-risk patients showed inhibition of immune-related processes. Mutation patterns exhibited variability among the different groups. AZD3759, lapatinib, and dasatinib have been identified as potential candidates for LUAD treatment. Moreover, the downregulation of ABCC2 resulted in the induction of apoptosis and suppression of migration and invasion in A549 cells. Altogether, this study has identified a novel NET-score signature based on six novel NET-related genes to predict the prognosis of LUAD and ABCC2 and has also explored a new method for personalized chemo-/immuno-therapy of LUAD.

Design, development of pyrazole-linked spirocyclopropyl oxindole-carboxamides as potential cytotoxic agents and Type III allosteric VEGFR-2 inhibitors.

Tumor progression depends on angiogenesis, which is stimulated by growth factors like VEGF, targeting VEGFR kinase with small molecules is an effective anti-angiogenic therapeutic approach. Sunitinib was rationally modified to spirocyclopropyloxindoline carboxamides and their in vitro cytotoxic profiling were evaluated. The molecular modelling studies enabled the screening of designed analogues and identified possible interactions within the type III allosteric inhibitor binding site of VEGFR-2. The biological screening of compounds 15a-y, revealed the ability of compound 15w to inhibit the cell growth in MCF-7 cells with IC50 value of 3.87 ± 0.19 μM and alongside inhibition of VEGFR-2 kinase at a IC50 concentration of 4.34 ± 0.13 μM was observed. VEGFR-2 inhibition was validated through HUVEC tube formation inhibition assay. 15w also inhibited cell migration in wound healing assay. The qualitative assessment of apoptosis induction by 15w in MCF-7 cells was evaluated through AO/EB and DAPI staining studies, whereas apoptotic quantification and cell cycle analysis were performed through FACS analysis. The current study strives to sequentially optimize the structural attributes of 3-alkenyl oxindole core to surpass the existing challenges of well-known VEGFR-2 inhibitors and compound 15w was identified to be a prominent lead towards the development of clinical drug candidates.

Chemical Implications of apo-8, 6' Carotendial versus Intact Lycopene on Mechanism of Enhanced Cell-cell Communication and Apoptosis Induction in Breast Cancer Cells.

Investigation on carotenoids and its cleavage products is crucial to combat the development of chronic diseases, including cancer. Therefore, this study aimed to explore the effect of lycopene oxidative products versus equivalent concentration of lycopene (LYC) on major molecular events of cancer cells (MCF-7). Primarily, LYC-oxidized products were generated chemically, then collected its rich fraction. Based on cell-based assays, the antiproliferation potency of rich fraction of chemically-oxidized lycopene (COL) identified as apo-8, 6' carotendial was compared with LYC. Interestingly, the inhibition of cell migration by COL strongly demonstrated anti-metastatic activity. Further, the increased connexin-43 expression confirms enhanced gap-junctional communication activity of COL than LYC and control. Fortunately, apo-8, 6' carotendial did not affect normal breast epithelial cells. We anticipated that, the chemical properties of apo-8, 6'-carotendial is similar and mimic a model compound acrolein (α, β-conjugated aldehyde) which is involved in Michael addition/Schiff base formation with specific amino acids and regulates redox signaling, reactive oxygen species sensing and cellular buffering. The chemistry of apo-8, 6' carotendial reveals a greater insight into the mechanism of selective inhibition of cancer cells proliferation. In this context, speculations of putative action of lycopeneoids through chemical biology approach facilitate greater insights in tandem with synthetic chemistry.

Cytoskeleton-associated gelsolin responds to the midgut distention process in saline meal-fed Aedes aegypti and affects arbovirus dissemination from the midgut.

The mosquito, Aedes aegypti, is the principal vector for several arboviruses. The mosquito midgut is the initial tissue that gets infected with an arbovirus acquired along with a blood meal from a vertebrate host. Blood meal ingestion leads to midgut tissue distention thereby increasing the pore size of the surrounding basal lamina. This allows newly synthesized virions to exit the midgut by traversing the distended basal lamina to infect secondary tissues of the mosquito. We conducted a quantitative label-free proteomic time course analysis with saline meal-fed Ae. aegypti females to identify host factors involved in midgut tissue distention. Around 2000 proteins were detected during each of the seven sampling time points and 164 of those were uniquely expressed. Forty-five of 97 differentially expressed proteins were upregulated during the 96-h time course and most of those were involved in cytoskeleton modulation, metabolic activity, and vesicle/vacuole formation. The F-actin-modulating Ae. aegypti (Aa)-gelsolin was selected for further functional studies. Stable knockout of Aa-gelsolin resulted in a mosquito line, which showed distorted actin filaments in midgut-associated tissues likely due to diminished F-actin processing by gelsolin. Zika virus dissemination from the midgut of these mosquitoes was diminished and delayed. The loss of Aa-gelsolin function was associated with an increased induction of apoptosis in midgut tissue indicating an involvement of Aa-gelsolin in apoptotic signaling in mosquitoes. Here, we used proteomics to discover a novel host factor, Aa-gelsolin, which affects the midgut escape barrier for arboviruses in mosquitoes and apoptotic signaling in the midgut.

Glyoxal oxidase-mediated detoxification of reactive carbonyl species contributes to virulence, stress tolerance, and development in a pathogenic fungus.

Reactive carbonyl and oxygen species (RCS/ROS), often generated as metabolic byproducts, particularly under conditions of pathology, can cause direct damage to proteins, lipids, and nucleic acids. Glyoxal oxidases (Gloxs) oxidize aldehydes to carboxylic acids, generating hydrogen peroxide (H2O2). Although best characterized for their roles in lignin degradation, Glox in plant fungal pathogens are known to contribute to virulence, however, the mechanism underlying such effects are unclear. Here, we show that Glox in the insect pathogenic fungus, Metarhizium acridum, is highly expressed in mycelia and during formation of infection structures (appressoria), with the enzyme localizing to the cell membrane. MaGlox targeted gene disruption mutants showed RCS and ROS accumulation, resulting in cell toxicity, induction of apoptosis and increased autophagy, inhibiting normal fungal growth and development. The ability of the MaGlox mutant to scavenge RCS was significantly reduced, and the mutant exhibited increased susceptibility to aldehydes, oxidative and cell wall perturbing agents but not toward osmotic stress, with altered cell wall contents. The ΔMaGlox mutant was impaired in its ability to penetrate the host cuticle and evade host immune defense resulting in attenuated pathogenicity. Overexpression of MaGlox promoted fungal growth and conidial germination, increased tolerance to H2O2, but had little to other phenotypic effects. Transcriptomic analyses revealed downregulation of genes related to cell wall synthesis, conidiation, stress tolerance, and host cuticle penetration in the ΔMaGlox mutant. These findings demonstrate that MaGlox-mediated scavenging of RCS is required for virulence, and contributes to normal fungal growth and development, stress resistance.

Induction of Apoptosis and ROS Production in Liver Cancer Cells by Saponin Fraction from Alcea rosea L. Seeds

Background: Natural compounds are essential targets in anticancer research due to the toxic effects of current chemotherapy and drug resistance. Methods: Saponin extraction from Alcea rosea L. was carried out using 20% methanol and liquid-liquid extraction coupled with the Solid phase extraction (SPE) approach. The saponin fraction was explored for its cytotoxic activity against Huh-7 and MDA-MB-231 cancer cell lines and a non–cancer cell line (HUVEC). The cytotoxic activity and oxidative stress were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) and 2,7 dichlorofluorescein diacetate dyes respectively. The apoptotic potential was investigated using DAPI and acridine orange-ethidium bromide dual staining. Result: The saponin fraction exhibited cytotoxic potential against the cell lines investigated. The IC50 values of the saponin fraction were 49.02, 300 and 325 µg\mL against Huh-7, MDA-MB-231 and HUVEC cell lines, respectively. The cytotoxicity for the extract was dose-dependent. The saponin fraction calculated selectivity index (SI) value indicated high selectivity towards Huh-7 cells (SI = 6.62) compared with normal HUVEC cells. Huh-7 cells treated with saponin fraction showed cellular and nuclear morphological changes, such as apoptotic body formation and chromatin condensation, as observed using light and fluorescent microscopy. However, further investigation is required to assess the the saponin fraction as a potential therapeutic agent.

Efficacy and Mechanism of Core Traditional Chinese Medicines for Treating Malignant Lymphoma based on Efficacy Studies: A Study Supported by Network Pharmacology and Molecular Docking.

The burden of malignant lymphoma in China is greater than the global equivalent. The randomized controlled trials provide medical evidence that TCM can improve the short-term effects and long-term survival of patients with lymphoma. However, the mechanisms underlying remain undefined. Evidence-based data mining for traditional Chinese medicine (TCM) on improving short-term effects and long-term survival in malignant lymphoma treatment was performed in this study. In addition, the mechanisms of TCM through network pharmacology and molecular docking were explored. The China national knowledge infrastructure, Wanfang Data, China Science and Technology Journal Database, PubMed, and Web of Science databases were searched to select TCM formulas with short-term effects and long-term survival benefits in the treatment of malignant lymphomas. We then analyzed and visualized the tropism of taste, frequency of drug use, dosage, clustering, association rules mining (minimum support threshold as 0.20, the minimum confidence threshold as 0.80 and lift >1), and complex networks for potential core herb compositions using Excel, IBM SPSS Statistics 26, and IBM SPSS Modeler 18. TCM systems pharmacology, GeneCards, Online Mendelian Inheritance in Man, and other databases were used to screen potential core active ingredients and malignant lymphoma-related targets. The intersection targets were used to construct a protein interaction network using Cytoscape to obtain the key targets. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment were used to analyze the core target, and molecular docking of key components and targets was performed using CB-Dock2. Twenty-four Chinese herbal formulae were included, encompassing 107 herbs with mainly cold and warm properties and bitter and sweet flavors. They were associated with the yin meridians of the liver, spleen, and lungs. The TCMs underwent association rule analysis, identified 27 association rules, including 12 herb pairs and 13 angle medicine, and clustered into eight classes by clustering analysis. Combined with the results from mining analysis, Pinelliae (Ban-xia), Poria (Fu-ling), Atractylodis macrocephalae (Bai-zhu), Curcumae (E-zhu), and Sparganii (San-leng) were the potential core herbs According to network pharmacology and molecular docking, the main core components of the potential core drugs are hederagenin, cerevisterol, 14- acetyl-12-senecioyl-2E,8E,10E-atractylentriol, 12,13-epoxy-9-hydroxynonadeca-7,10-dienoic acid, cavidine, and baicalein. These core drugs are mainly involved in the pathways of EGFR tyrosine kinase inhibitor resistance, PD-1/L1, natural killer cell-mediated cytotoxicity, NF-κB, epithelial cell signaling in H. pylori infections, and Th17 cell differentiation. They aid in regulating the transmembrane receptor protein tyrosine kinase signaling pathway, ERBB signaling pathway, PI3K signaling pathway, and phosphorylation process. Ten key components and eight key targets, including baicalein and hederagenin, demonstrated strong binding activity. Collectively, some core herbs exerted anti-tumor effects through immune and inflammatory pathway modulation, inhibition of immune escape, and induction of cell apoptosis. These findings support future evidence-based research on malignant lymphoma treatment using TCM.

Rhus coriaria induces autophagic and apoptotic cell death in pancreatic cancer cells

Background:Pancreatic cancer is a leading cause of cancer-related mortality worldwide with increasing global incidence. We previously reported the anticancer effect of Rhus coriaria ethanolic extract (RCE) in triple negative breast and colon cancer cells. Herein, we investigated the anticancer effect of RCE on human pancreatic cancer cells.Methods: Cell viability was measured using Cell Titer-Glo and staining of viable and dead cells based on differential permeability to two DNA binding dyes. Cell cycle distribution and annexin V staining was carried out in Muse cell analyzer. Protein level was determined by Western blot. Tumor growth was assessed by in ovo chick embryo chorioallantoic membrane assay.Results: We found that RCE significantly inhibited the viability and colony growth of pancreatic cancer cells (Panc-1, Mia-PaCa-2, S2-013, AsPC-1). The antiproliferative effects of RCE in pancreatic cancer cells (Panc-1 and Mia-PaCa-2) were mediated through induction of G1 cell cycle arrest, Beclin-1-independent autophagy, and apoptosis. RCE activated both the extrinsic and intrinsic pathways of apoptosis and regulated the Bax/Bcl-2 apoptotic switch. Mechanistically, we found that RCE inhibited the AKT/mTOR pathway, downstream of which, inactivation of the cell cycle regulator p70S6K and downregulation of the antiapoptotic protein survivin was observed. Additionally, we found that RCE-induced autophagy preceded apoptosis. Further, we confirmed the anticancer effect of RCE in a chick embryo xenograft model and found that RCE inhibited the growth of pancreatic cancer xenografts without affecting embryo survival.Conclusion: Collectively, our findings demonstrate that Rhus coriaria exerts potent anti-pancreatic cancer activity though cell cycle impairment, autophagy, and apoptosis, and is hence a promising source of anticancer phytochemicals.

Exploring the Therapeutic Potential of 5-Fluorouracil-Loaded Calcium Carbonate Nanoparticles Combined with Natural Compound Thymoquinone for Colon Cancer Treatment

Given the need for novel and effective therapies for colon cancer, this study aimed to investigate the effects of 5-fluorouracil-loaded calcium carbonate nanoparticles (5FU-CaCO3np) combined with thymoquinone (TQ) against colon cancer. A shaking incubator and a high-speed homogenizer were used to prepare the optimal 5FU-CaCO3np, with characterizations of physicochemical properties, in vitro drug release profile, and biocompatibility. In vitro experiments and molecular docking were employed to evaluate the therapeutic potential of the combination for colon cancer treatment. Study results revealed that 5FU-CaCO3np with a size of approximately 130 nm was synthesized using the high-speed homogenizer. Its favorable biocompatibility, pH sensitivity, and sustained release properties facilitated reduced toxic side effects of 5-FU on NIH3T3 normal cells and enhanced inhibitory effects on CT26 colon cancer cells. The combination of 5FU-CaCO3np (1.875 μM) and TQ (30 μM) showed significantly superior anti-colon cancer effects to 5FU-CaCO3np alone in terms of cell proliferation and migration inhibition, cell apoptosis induction, and spheroid growth suppression in CT26 cells (p < 0.05), with strong interactions between the drugs and targets (E-cadherin, Bcl-2, PCNA, and MMP-2). These results provide evidence for 5FU-CaCO3np as a novel regimen against colon cancer. Combining 5FU-CaCO3np and TQ may offer a new perspective for colon cancer therapy.

Cytometry investigation of myo-inositol-induced growth inhibition, apoptosis induction and cell cycle arrest in the human prostate cancer cell line (DU-145).

Cytometry investigation of myo-inositol-induced growth inhibition, apoptosis induction and cell cycle arrest in the human prostate cancer cell line (DU-145).

Bacterial surface derived extracellular vesicles: A ground‐breaking approach in cancer therapy

AbstractConventional cancer therapies are often limited by inherent and acquired drug resistance, non‐specific toxicity, and suboptimal drug delivery. Bacterial extracellular vesicles (BEVs), including outer membrane vesicles and membrane vesicles, present a novel therapeutic strategy for cancer treatment. BEVs were found in both Gram‐negative and Gram‐positive bacteria. This article provides a classified investigation of the therapeutic potential of BEVs in cancer treatment. We discuss the molecular mechanisms underlying their observed anti‐tumor effects, including the induction of apoptosis in cancer cells, suppression of angiogenesis within the tumor microenvironment, and stimulation of both innate and adaptive anti‐tumor immune responses. Moreover, BEVs being biocompatible opens avenue for targeted drug delivery systems, potentially improving the therapeutic index of conventional chemotherapeutics. Challenges to clinical translation, such as BEV heterogeneity and potential immunogenicity, are addressed. We also explore future directions for research and development, comprehensively highlighting how BEVs transform the landscape of precision oncology and cancer treatment, eventually improving patient outcomes.

Synthesis, biological evaluation, and molecular docking studies of novel N-substituted piperazine-tethered thiophene-3-carboxamide selenides as potent antiproliferative agents with EGFR kinase inhibitory activity

In the context of structural investigation and optimization of various potential EGFR inhibitors, a novel series of asymmetrical piperazine-tethered trisubstituted thiophene-3-carboxamide selenide derivatives were synthesized and evaluated for their antiproliferative potential against selected human cancer cell lines. These derivatives, built based on a previously identified hit molecule, were synthesized via multiple-step reactions, including optimization of the C-Se cross-coupling reaction. Two compounds, 17i and 18i, displayed significant cytotoxicity (IC50 value: 4.82 ± 0.80 µM and 1.43 ± 0.08 µM) against HCT116 and A549 cancer cell lines, respectively. Quantitative analysis of apoptotic stages using Annexin V-FITC/PI double staining validated their apoptotic potential. Further, compound 18i demonstrated a remarkable inhibition of EGFR kinase, with an IC50 concentration of 42.3 nM. The lead compound 18i, with remarkable in vitro cytotoxicity, apoptosis induction capability, and EGFR inhibition, emerges as a promising candidate for anticancer therapy.

Exploring the therapeutic potential of a novel series of imidazothiadiazoles targeting focal adhesion kinase (FAK) for pancreatic cancer treatment: Synthesis, mechanistic Insights and promising antitumor and safety profile

ABSTRACT Focal Adhesion Kinase (FAK) is a non-receptor protein tyrosine kinase that plays a crucial role in various oncogenic processes related to cell adhesion, migration, proliferation, and survival. The strategic targeting of FAK represents a burgeoning approach to address resistant tumors, such as pancreatic ductal adenocarcinoma (PDAC). Herein, we report a new series of twenty imidazo[2,1-b][1,3,4]thiadiazole derivatives assayed for their antiproliferative activity against the National Cancer Institute (NCI-60) panel and a wide panel of PDAC models. Lead compound 10l exhibited effective antiproliferative activity against immortalized (SUIT-2, CAPAN-1, PANC-1, PATU-T, BxPC-3), primary (PDAC-3) and gemcitabine-resistant clone (PANC-1-GR) PDAC cells, eliciting IC50 values in the low micromolar range (1.04-3.44 µM), associated with a significant reduction in cell-migration and spheroid shrinkage in vitro. High-throughput kinase arrays revealed a significant inhibition of the FAK signalling network, associated to induction of cell cycle arrest in G2/M phase, suppression of tumor cell invasion and apoptosis induction. The high selectivity index/toxicity prompted studies using PDAC mouse xenografts, demonstrating significant inhibition of tumor growth and safety. In conclusion, compound 10l displayed antitumor activity and safety in both in vitro and in vivo models, emerging as a highly promising lead for the development of FAK inhibitors in PDAC.

Silibinin Induces Both Apoptosis and Necroptosis with Potential Anti-tumor Efficacy in Lung Cancer.

Lung cancer incidence is steadily on the rise, posing a growing threat to human health. The search for therapeutic drugs from natural active substance and elucidating their mechanism have been the focus of anti-tumor research. In our work, Silibinin (SiL) was chosen as a possible substance that could inhibit lung cancer. and its effects on inducing tumor cell death have been studied. CCK-8 analysis and morphological observation were used to assess the cytotoxic impacts of SiL on lung cancer cells in vitro. The alterations in mitochondrial membrane potential (MMP) and apoptosis rate of cells were detected by flow cytometry. The level of lactate dehydrogenase (LDH) release out of cells was measured. The expression changes of apoptosis or necroptosis-related proteins were detected using western blotting. Protein interactions among RIPK1, RIPK3 and MLKL were analyzed using the co-immunoprecipitation technique. In vivo, SiL was evaluated for its antitumor effects using LLC tumor-bearing mice with mouse lung cancer. With an increased dose of SiL, the proliferation ability of A549 cells was considerably inhibited, and the accompanying cell morphology changed. The results of flow cytometry showed that after SiL treatment, MMP levels decreased, and the proportion of cells undergoing apoptosis increased. The proteins associated with apoptosis were upregulated and activated. The amount of LDH released from the cells increased following SiL treatment, accompanied by augmented expression and phosphorylation levels of necroptosis-related proteins. The co-IP assay further confirmed necrosome formation induced by SiL. Furthermore, Necrosulfonamide (an MLKL inhibitor) increased the apoptotic rate of SiL-treated cells and aggravated the cytotoxic effect of SiL, indicating that necroptosis blockade could switch cell death to apoptosis and increase the inhibitory effect of SiL on A549 cells. In LLC-bearing mice, gastric administration of SiL significantly inhibited tumor growth. This study helped clarify the anti-tumor mechanism of SiL against lung cancer, elucidating its role in dual induction of apoptosis and necroptosis. In particular, necroptosis blockade could switch cell death to apoptosis and increase the inhibitory effect of SiL. Our work provided an experimental basis for the research on cell death induced by SiL and revealed its possible applications for improving the management of lung cancer.</p>.

Alliums as Potential Antioxidants and Anticancer Agents

The genus Allium plants, including onions, garlic, leeks, chives, and shallots, have long been recognized for their potential health benefits, particularly in oxidative and cancer prevention. Among them, onions and garlic have been extensively studied, unveiling promising biological activities that are indicative of their potential as potent antioxidant and anticancer agents. Research has revealed a rich repository of bioactive compounds in Allium species, highlighting their antioxidative properties and diverse mechanisms that target cancer cells. Compounds such as allicin, flavonoids, and organosulfur compounds (OSCs) exhibit notable antioxidant and anticancer properties, affecting apoptosis induction, cell cycle arrest, and the inhibition of tumor proliferation. Moreover, their antioxidant and anti-inflammatory attributes enhance their potential in cancer therapy. Studies exploring other Allium species beyond onions and garlic have revealed similar biological activities, suggesting a broad spectrum of natural products that could serve as promising candidates for developing novel anticancer treatments. Understanding the multifaceted potential of Allium plants will pave the way for innovative strategies in oxidative and cancer treatment and prevention, offering new avenues for pharmaceutical research and dietary interventions. Therefore, in this review, we compile an extensive analysis of the diversity of various Allium species, emphasizing their remarkable potential as effective agents.

Indications of programmed cell death in wheat roots upon exposure to silver nanoparticles

Programmed cell death (PCD) can occur at every developmental stage as a plant’s response to various biotic and abiotic environmental factors. Silver nanoparticles (AgNPs) are widely used in consumer products and possess antimicrobial properties, making them important in assessing nanoparticle effects on plants. In the present study, we examined the impact of AgNPs (0, 0.5, 1, 5, 10, and 20 mg L-1) on wheat root PCD by evaluating parameters such as the mitotic index, chromosomal behaviors, nuclear deformation, cytochrome c release, caspase-1-like activity, and the expression of cysteine protease genes (TaVPE4, TaMCA1, and TaMCA4). Our findings revealed a dose-dependent decrease in the mitotic index ratio and increased chromosomal abnormalities induced by AgNPs. Additionally, we observed various hallmarks of PCD, including chromatin condensation, slight DNA smear, reduction in mitochondrial inner membrane potential, and cytochrome c release to the cytoplasm as well as increased caspase-1-like activity and TaVPE4 gene expression. Notably, the gene expressions of TaMCA1 and TaMCA4 were found to be antagonistically regulated by AgNPs, further indicating the induction of PCD by AgNP treatment. Overall, our study provides evidence of AgNP-induced PCD in wheat roots, elucidating the involvement of cysteine protease genes in this process.

Novel Thienopyrimidine-Hydrazinyl Compounds Induce DRP1-Mediated Non-Apoptotic Cell Death in Triple-Negative Breast Cancer Cells

Apoptosis induction with taxanes or anthracyclines is the primary therapy for TNBC. Cancer cells can develop resistance to anticancer drugs, causing them to recur and metastasize. Therefore, non-apoptotic cell death inducers could be a potential treatment to circumvent apoptotic drug resistance. In this study, we discovered two novel compounds, TPH104c and TPH104m, which induced non-apoptotic cell death in TNBC cells. These lead compounds were 15- to 30-fold more selective in TNBC cell lines and significantly decreased the proliferation of TNBC cells compared to that of normal mammary epithelial cell lines. TPH104c and TPH104m induced a unique type of non-apoptotic cell death, characterized by the absence of cellular shrinkage and the absence of nuclear fragmentation and apoptotic blebs. Although TPH104c and TPH104m induced the loss of the mitochondrial membrane potential, TPH104c- and TPH104m-induced cell death did not increase the levels of cytochrome c and intracellular reactive oxygen species (ROS) and caspase activation, and cell death was not rescued by incubating cells with the pan-caspase inhibitor, carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (Z-VAD-FMK). Furthermore, TPH104c and TPH104m significantly downregulated the expression of the mitochondrial fission protein, DRP1, and their levels determined their cytotoxic efficacy. Overall, TPH104c and TPH104m induced non-apoptotic cell death, and further determination of their cell death mechanisms will aid in the development of new potent and efficacious anticancer drugs to treat TNBC.

Discovery of NO Donor-Aurovertin Hybrids as Dual Ferroptosis and Apoptosis Inducers for Treating Triple Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly lethal malignancy, and its clinical management encounters severe challenges due to its high metastatic propensity and the absence of effective therapeutic targets. To improve druggability of aurovertin B (AVB), a natural polyketide with a significant antiproliferative effect on TNBC, a series of NO donor/AVB hybrids were synthesized and tested for bioactivities. Among them, compound 4d significantly inhibited the proliferation and metastasis of TNBC in vitro and in vivo with better safety than that of AVB. The structure-activity relationship analysis suggested that the types of NO donor and the linkers had considerable effects on the activities. Mechanistic investigations unveiled that 4d induced apoptosis and ferroptosis by the reduction of mitochondrial membrane potential and the down-regulation of GPX4, respectively. The antimetastatic effect of 4d was associated with the upregulation of DUSP1. Overall, these compelling results underscore the tremendous potential of 4d for treating TNBC.

Prospects of compounds of herbal plants as anticancer agents: a comprehensive review from molecular pathways

Cancer refers to the proliferation and multiplication of aberrant cells inside the human body, characterized by their capacity to proliferate and infiltrate various anatomical regions. Numerous biochemical pathways and signaling molecules have an impact on the cancer auto biogenesis process. The regulation of crucial cellular processes necessary for cell survival and proliferation, which are triggered by phytochemicals, is significantly influenced by signaling pathways. These pathways or components are regulated by phytochemicals. Medicinal plants are a significant reservoir of diverse anticancer medications employed in chemotherapy. The anticancer effects of phytochemicals are mediated by several methods, including induction of apoptosis, cessation of the cell cycle, inhibition of kinases, and prevention of carcinogenic substances. This paper analyzes the phytochemistry of seven prominent plant constituents, namely, alkaloids, tannins, flavonoids, phenols, steroids, terpenoids, and saponins, focusing on the involvement of the MAPK/ERK pathway, TNF signaling, death receptors, p53, p38, and actin dynamics. Hence, this review has examined a range of phytochemicals, encompassing their structural characteristics and potential anticancer mechanisms. It has underscored the significance of plant-derived bioactive compounds in the prevention of cancer, utilizing diverse molecular pathways. In addition, this endeavor also seeks to incentivize scientists to carry out clinical trials on anticancer medications derived from plants.