Plant lectins: targeting programmed cell death pathways as antitumor agents

Lectins, a group of highly diverse, carbohydrate-binding proteins of non-immune origin that are ubiquitously distributed in plants, animals and fungi, are well-characterized to have numerous links a wide range of pathological processes, most notably cancer. In this review, we present a brief outline of the representative plant lectins including Ricin-B family, proteins with legume lectin domains and GNA family that can induce cancer cell death via targeting programmed cell death pathways. Amongst these above-mentioned lectins, we demonstrate that mistletoe lectins (MLs), Ricin, Concanavalin A (ConA) and Polygonatum cyrtonema lectin (PCL) can lead to cancer cell programmed death via targeting apoptotic pathways. In addition, we show that ConA and PCL can also result in cancer cell programmed death by targeting autophagic pathways. Moreover, we summarize the possible anti-cancer therapeutic implications of plant lectins such as ConA, Phaseolus vulgaris lectin (PHA) and MLs that have been utilized at different stages of preclinical and clinical trials. Together, these findings can provide a comprehensive perspective for further elucidating the roles of plant lectins that may target programmed cell death pathways in cancer pathogenesis and therapeutics. And, this research may, in turn, ultimately help cancer biologists and clinicians to exploit lectins as potential novel antitumor drugs in the future.     

Polygonatum cyrtonema lectin, a potential antineoplastic drug targeting programmed cell death pathways

Polygonatum cyrtonema lectin (PCL), a mannose/sialic acid-binding plant lectin, has recently drawn a rising attention for cancer biologists because PCL bears remarkable anti-tumor activities and thus inducing programmed cell death (PCD) including apoptosis and autophagy in cancer cells. In this review, we focus on exploring the precise molecular mechanisms by which PCL induces cancer cell apoptotic death such as the caspase-dependent pathway, mitochondria-mediated ROS–p38–p53 pathway, Ras–Raf and PI3K–Akt pathways. In addition, we further elucidate that PCL induces cancer cell autophagic death via activating mitochondrial ROS–p38–p53 pathway, as well as via blocking Ras–Raf and PI3K–Akt pathways, suggesting an intricate relationship between autophagic and apoptotic death in PCL-induced cancer cells. In conclusion, these findings may provide a new perspective of Polygonatum cyrtonema lectin (PCL) as a potential anti-tumor drug targeting PCD pathways for future cancer therapeutics.     

Mitochondrial programmed cell death pathways in yeast

Whether or not yeast cell death is altruistic, apoptotic, or otherwise analogous to programmed cell death in mammals is controversial. However, growing attention to cell death mechanisms in yeast has produced several new papers that make a case for ancient origins of programmed death involving mitochondrial pathways conserved between yeast and mammals.     

Caspase-mediated programmed cell death pathways as potential therapeutic targets in cancer

The caspase family is well characterized as playing a crucial role in modulation of programmed cell death (PCD), which is a genetically regulated, evolutionarily conserved process with numerous links to many human diseases, most notably cancer. In this review, we focus on summarizing the intricate relationships between some members of the caspase family and their key apoptotic mediators, involving tumour necrosis factor receptors, the Bcl-2 family, cytochrome c, Apaf-1 and IAPs in cancer initiation and progression. We elucidate new emerging types of cross-talk between several caspases and autophagy-related genes (Atgs) in cancer. Moreover, we focus on presenting several PCD-modulating agents that may target caspases-3, -8 and -9, and their substrates PARP-1 and Beclin-1, which may help us harness caspase-modulated PCD pathways for future drug discovery.     

Yeast programmed cell death: an intricate puzzle

Yeasts as eukaryotic microorganisms with simple, well known and tractable genetics, have long been powerful model systems for studying complex biological phenomena such as the cell cycle or vesicle fusion. Until recently, yeast has been assumed as a cellular 'clean room' to study the interactions and the mechanisms of action of mammalian apoptotic regulators. However, the finding of an endogenous programmed cell death (PCD) process in yeast with an apoptotic phenotype has turned yeast into an 'unclean' but even more powerful model for apoptosis research. Yeast cells appear to possess an endogenous apoptotic machinery including its own regulators and pathway(s). Such machinery may not exactly recapitulate that of mammalian systems but it represents a simple and valuable model which will assist in the future understanding of the complex connections between apoptotic and non-apoptotic mammalian PCD pathways. Following this line of thought and in order to validate and make the most of this promising cell death model, researchers must undoubtedly address the following issues: what are the crucial yeast PCD regulators? How do they play together? What are the cell death pathways shared by yeast and mammalian PCD? Solving these questions is currently the most pressing challenge for yeast cell death researchers.     

A biotinylated peptide,BP21, as a novel potent anti‐anaphylactic agent targeting platelet‐activating factor

Platelet‐activating factor (PAF) is an important mediator of anaphylaxis and is therefore an anti‐anaphylactic drug target. We recently reported that synthetic N‐terminally biotinylated peptides (BP4‐BP29) inhibit PAF by directly interacting with PAF and its metabolite/precursor lyso‐PAF. In this study, we investigated whether the biotinylated peptides can inhibit anaphylactic reactions in vivo. In mouse models of anaphylaxis, one of the peptides, BP21, markedly and dose‐dependently inhibited hypothermia with a maximum dose–response within 30 min after administration, even at doses 20 times lesser than doses of the known PAF antagonist CV‐3988. In contrast, the anti‐hypothermic effect of BGP21, in which the Tyr‐Lys‐Asp‐Gly sequence in BP21 was modified to a Gly‐Gly‐Gly‐Gly sequence, was less than that of BP21. The alanine scanning and shuffling the amino acid residues of BP4 (Tyr‐Lys‐Asp‐Gly) demonstrated that the Tyr‐Lys‐Asp‐Gly consensus sequence is important for the inhibitory effect of the peptide on hypothermia. BP21 also suppressed vascular permeability during anaphylaxis with a maximum dose–response within 30 min of administration. In a rat model of hind paw oedema, BP21 significantly inhibited the oedema induced by PAF but not that induced by the other pro‐inflammatory mediators, such as histamine, serotonin, and bradykinin. Tryptophan fluorescence measurements showed that BP21 interacted with PAF, but not with histamine, serotonin, or bradykinin. In contrast, BGP21 did not interact with PAF. These results suggest that biotinylated peptides, especially BP21, can specifically and markedly inhibit anaphylactic reactions in vivo and that this involves direct interaction of its Tyr‐Lys‐Asp‐Gly region with PAF. Therefore, a biotinylated peptide, BP21, can be used as novel potential anti‐anaphylactic drugs targeting PAF. Copyright © 2017 European Peptide Society and John Wiley & Sons, Ltd.     

Mitochondrial apoptotic pathways induced by Drosophila programmed cell death regulators

Multicellular organisms eliminate unwanted or damaged cells by cell death, a process essential to the maintenance of tissue homeostasis. Cell death is a tightly regulated event, whose alteration by excess or defect is involved in the pathogenesis of many diseases such as cancer, autoimmune syndromes, and neurodegenerative processes. Studies in model organisms, especially in the nematode Caenorhabditis elegans, have been crucial in identifying the key molecules implicated in the regulation and execution of programmed cell death. In contrast, the study of cell death in Drosophila melanogaster, often an excellent model organism, has identified regulators and mechanisms not obviously conserved in other metazoans. Recent molecular and cellular analyses suggest, however, that the mechanisms of action of the main programmed cell death regulators in Drosophila include a canonical mitochondrial pathway.     

Identification of ML-9 as a lysosomotropic agent targeting autophagy and cell death

The growing number of studies suggested that inhibition of autophagy enhances the efficacy of Akt kinase inhibitors in cancer therapy. Here, we provide evidence that ML-9, a widely used inhibitor of Akt kinase, myosin light-chain kinase (MLCK) and stromal interaction molecule 1 (STIM1), represents the ‘two-in-one'' compound that stimulates autophagosome formation (by downregulating Akt/mammalian target of rapamycin (mTOR) pathway) and inhibits their degradation (by acting like a lysosomotropic agent and increasing lysosomal pH). We show that ML-9 as a monotherapy effectively induces prostate cancer cell death associated with the accumulation of autophagic vacuoles. Further, ML-9 enhances the anticancer activity of docetaxel, suggesting its potential application as an adjuvant to existing anticancer chemotherapy. Altogether, our results revealed the complex effect of ML-9 on autophagy and indentified ML-9 as an attractive tool for targeting autophagy in cancer therapy through dual inhibition of both the Akt pathway and the autophagy.     

Oridonin: An active diterpenoid targeting cell cycle arrest, apoptotic and autophagic pathways for cancer therapeutics

It is well-known that cell cycle arrest and/or death play a pivotal role in tumor progression, which has drawn a rising attention for cancer biologists due to their complex and intricate relationships. In this review, we demonstrate the recent research on oridonin, an active diterpenoid with remarkable anti-proliferative activities, and then further explore its molecular mechanisms of cell cycle arrest, apoptosis, autophagy and their cross-talks in various cancer cells, which may provide a new perspective of oridonin as a candidate anti-neoplastic drug for future cancer therapeutics.     

Achievements and perspectives in yeast acetic acid-induced programmed cell death pathways

The use of non-mammalian model organisms, including yeast Saccharomyces cerevisiae, can provide new insights into eukaryotic PCD (programmed cell death) pathways. In the present paper, we report recent achievements in the elucidation of the events leading to PCD that occur as a response to yeast treatment with AA (acetic acid). In particular, ROS (reactive oxygen species) generation, cyt c (cytochrome c) release and mitochondrial function and proteolytic activity will be dealt with as they vary along the AA-PCD time course by using both wild-type and mutant yeast cells. Two AA-PCD pathways are described sharing common features, but distinct from one another with respect to the role of ROS and mitochondria, the former in which YCA1 acts upstream of cyt c release and caspase-like activation in a ROS-dependent manner and the latter in which cyt c release does not occur, but caspase-like activity increases, in a ROS-independent manner.     

Naphthoquinones as allelochemical triggers of programmed cell death

Juglone and plumbagin are plant bioactive derivatives of 1,4-naphthoquinone occurring in plants, whereas lots of these plants belong to invasive species. Clarifying of action of juglone and plumbagin applied on plant cell model represented by tobacco BY-2 cells was the basic aim of this work. It was shown that naphthoquinones are able to induce various structural, functional and enzymatic changes leading to processes of apoptic-like cell death. Using dihydroethidium as fluorescent probe the mechanism of naphthoquinones action was explained. They are able to generate reactive oxygen species, which play important role in processes of programmed cell death. Disruption of mitochondrial respiratory chain was detected too. This study shown that mechanism of naphthoquinones action to plant cells is very complex and predestine them to be very effective compounds in plant competition fight.     

Protozoan parasites: programmed cell death as a mechanism of parasitism

Programmed cell death (PCD) is a potent mechanism to remove parasitized cells, but it has also been shown that protozoan parasites can induce or inhibit apoptosis in host cells. In recent years, it has become clear that unicellular parasites can also undergo PCD, meaning that they commit suicide in response to various stimuli. This review focuses on the role of protozoan PCD and on the interaction between protozoan parasites and the host cell death machinery from the perspective of parasite survival strategies.     

Leaf‐shape remodeling: programmed cell death in fistular leaves of Allium fistulosum

Some species of Allium in Liliaceae have fistular leaves. The fistular lamina of Allium fistulosum undergoes a process from solid to hollow during development. The aims were to reveal the process of fistular leaf formation involved in programmed cell death (PCD) and to compare the cytological events in the execution of cell death to those in the unusual leaf perforations or plant aerenchyma formation. In this study, light and transmission electron microscopy were used to characterize the development of fistular leaves and cytological events. Terminal deoxynucleotidyl transferase‐mediated dUTP nick end labeling (TUNEL) assays and gel electrophoresis were used to determine nuclear DNA cleavage during the PCD. The cavity arises in the leaf blade by degradation of specialized cells, the designated pre‐cavity cells, in the center of the leaves. Nuclei of cells within the pre‐cavity site become TUNEL‐positive, indicating that DNA cleavage is an early event. Gel electrophoresis revealed that DNA internucleosomal cleavage occurred resulting in a characteristic DNA ladder. Ultrastructural analysis of cells at the different stages showed disrupted vacuoles, misshapen nuclei with condensed chromatin, degraded cytoplasm and organelles and emergence of secondary vacuoles. The cell walls degraded last, and residue of degraded cell walls aggregated together. These results revealed that PCD plays a critical role in the development of A. fistulosum fistular leaves. The continuous cavity in A. fistulosum leaves resemble the aerenchyma in the pith of some gramineous plants to improve gas exchange.     

Interdigital cell death function and regulation: new insights on an old programmed cell death model

Interdigital cell death (ICD) is the oldest and best-studied model of programmed cell death (PCD) in vertebrates. The classical view of ICD function is the separation of digits by promotion of tissue regression. However, in addition, ICD can contribute to digit individualization by restricting interdigital tissue growth. Depending on the species, the relative contribution of either regression or growth-restricting functions of ICD to limb morphogenesis may differ. Under normal conditions, most cells appear to die by apoptosis during ICD. Accordingly, components of the apoptotic machinery are found in the interdigits, though their role in the initiation and execution of cell death is yet to be defined. Fgf8 has been identified as a survival factor for the distal mesenchymal cells of the limb such that ICD can initiate following specific downregulation of Fgf8 expression in the ectoderm overlying the interdigital tissue. On the other hand, Bmps may promote cell death directly by acting on the interdigital tissue, or indirectly by downregulating Fgf8 expression in the ectoderm. In addition, retinoic acid can activate ICD directly or through a Bmp-mediated mechanism. Interactions at different levels between these factors establish the spatiotemporal patterning of ICD activation. Defining the regulatory network behind ICD activation will greatly advance our understanding of the mechanisms controlling PCD in general.