scholarly journals The Multifaceted Roles of Pyroptotic Cell Death Pathways in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1313
Author(s):  
Man Wang ◽  
Shuai Jiang ◽  
Yinfeng Zhang ◽  
Peifeng Li ◽  
Kun Wang
Keyword(s):  
Cell Death ◽  
Biological Significance ◽  
Chemotherapeutic Agents ◽  
The Body ◽  
Cell Swelling ◽  
Pathogen Invasion ◽  
Membrane Rupture ◽  
Cancer Management ◽  
Cell Death Pathways ◽  
Cancer Pathogenesis

Cancer is a category of diseases involving abnormal cell growth with the potential to invade other parts of the body. Chemotherapy is the most widely used first-line treatment for multiple forms of cancer. Chemotherapeutic agents act via targeting the cellular apoptotic pathway. However, cancer cells usually acquire chemoresistance, leading to poor outcomes in cancer patients. For that reason, it is imperative to discover other cell death pathways for improved cancer intervention. Pyroptosis is a new form of programmed cell death that commonly occurs upon pathogen invasion. Pyroptosis is marked by cell swelling and plasma membrane rupture, which results in the release of cytosolic contents into the extracellular space. Currently, pyroptosis is proposed to be an alternative mode of cell death in cancer treatment. Accumulating evidence shows that the key components of pyroptotic cell death pathways, including inflammasomes, gasdermins and pro-inflammatory cytokines, are involved in the initiation and progression of cancer. Interfering with pyroptotic cell death pathways may represent a promising therapeutic option for cancer management. In this review, we describe the current knowledge regarding the biological significance of pyroptotic cell death pathways in cancer pathogenesis and also discuss their potential therapeutic utility.

scholarly journals Positive allosteric modulation of P2X7 promotes apoptotic cell death over lytic cell death responses in macrophages

2019 ◽  
Vol 10 (12) ◽  
Author(s):  
Stefan Bidula ◽  
Kshitija Dhuna ◽  
Ray Helliwell ◽  
Leanne Stokes
Keyword(s):  
Cell Death ◽  
Mitochondrial Membrane ◽  
Caspase 3 ◽  
Allosteric Modulation ◽  
Cell Swelling ◽  
Dependent Manner ◽  
Apoptosis Pathway ◽  
Membrane Rupture ◽  
Cell Death Pathways ◽  
Intrinsic Apoptosis Pathway

AbstractP2X7 is an ATP-gated ion channel that is highly expressed by leukocytes, such as macrophages. Here, P2X7 has been demonstrated to be involved in the regulation of various cell death pathways; including apoptosis, pyroptosis, necrosis, and autophagy. However, cell death induction via P2X7 is complex and is reliant upon the nature of the stimulus, the duration of the stimulus, and the cell type investigated. Previous reports state that high extracellular ATP concentrations promote osmotic lysis, but whether positive allosteric modulation of P2X7 in the presence of lower concentrations of ATP condemns cells to the same fate is unknown. In this study, we compared cell death induced by high ATP concentrations, to cell death induced by compound K, a recently identified and potent positive allosteric modulator of P2X7. Based on our observations, we propose that high ATP concentrations induce early cell swelling, loss of mitochondrial membrane potential, plasma membrane rupture, and LDH release. Conversely, positive allosteric modulation of P2X7 primarily promotes an intrinsic apoptosis pathway. This was characterised by an increase in mitochondrial Ca2+, accelerated production of mitochondrial ROS, loss of mitochondrial membrane permeability in a Bax-dependent manner, the potential involvement of caspase-1, and caspase-3, and significantly accelerated kinetics of caspase-3 activation. This study highlights the ability of positive allosteric modulators to calibrate P2X7-dependent cell death pathways and may have important implications in modulating the antimicrobial immune response and in the resolution of inflammation.

scholarly journals Liposomal drug delivery system as an effective treatment approach for lung cancer

2020 ◽  
Vol 10 (3-s) ◽  
pp. 367-370
Author(s):  
Kinjal Patel ◽  
Devanshi Patel
Keyword(s):  
Lung Cancer ◽  
Drug Delivery ◽  
Drug Loading ◽  
Chemotherapeutic Agents ◽  
The Body ◽  
Therapeutic Interventions ◽  
Target Delivery ◽  
Liposomal Drug ◽  
Cancer Management ◽  
Important Field

Worldwide, cancer is one of the leading causes of mortality and cancer rates are set to increase at alarming rate globally. There are various types of cancer in which the leading type is the lung cancer.   In recent years lipid-based carriers, such as liposomes, have successfully encapsulated chemotherapeutic agents ameliorating some toxicity issues, while enhancing the overall therapeutic activity in cancer patients. In addition to this, nanomaterials can help to improved half-life in the body, morphology, for increased drug loading and many other ways. The survey discussed in this review will lead the anticancer therapy and cancer management which will provide the platform to the next generation.  Therefore, this critical review includes the therapeutic interventions, liposomes target delivery, active and passive drug loading. Finally, we attempt to summarize the current challenges in nanotherapeutics and provide an outlook on the future of this important field. Keywords: Drug Delivery, Liposomes target Delivery, Nanostructures, Drug loading

scholarly journals Multiple Autonomous Cell Death Suppression Strategies Ensure Cytomegalovirus Fitness

Viruses ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 1707
Author(s):  
Pratyusha Mandal ◽  
Lynsey N. Nagrani ◽  
Liliana Hernandez ◽  
Anita Louise McCormick ◽  
Christopher P. Dillon ◽  
...  
Keyword(s):  
Cell Death ◽  
Murine Cytomegalovirus ◽  
Mammalian Host ◽  
Caspase 8 ◽  
Intrinsic Apoptosis ◽  
Pathogen Invasion ◽  
Cell Death Pathways ◽  
Viral Inhibitor ◽  
Extrinsic Apoptosis ◽  
Infected Cells

Programmed cell death pathways eliminate infected cells and regulate infection-associated inflammation during pathogen invasion. Cytomegaloviruses encode several distinct suppressors that block intrinsic apoptosis, extrinsic apoptosis, and necroptosis, pathways that impact pathogenesis of this ubiquitous herpesvirus. Here, we expanded the understanding of three cell autonomous suppression mechanisms on which murine cytomegalovirus relies: (i) M38.5-encoded viral mitochondrial inhibitor of apoptosis (vMIA), a BAX suppressor that functions in concert with M41.1-encoded viral inhibitor of BAK oligomerization (vIBO), (ii) M36-encoded viral inhibitor of caspase-8 activation (vICA), and (iii) M45-encoded viral inhibitor of RIP/RHIM activation (vIRA). Following infection of bone marrow-derived macrophages, the virus initially deflected receptor-interacting protein kinase (RIPK)3-dependent necroptosis, the most potent of the three cell death pathways. This process remained independent of caspase-8, although suppression of this apoptotic protease enhances necroptosis in most cell types. Second, the virus deflected TNF-mediated extrinsic apoptosis, a pathway dependent on autocrine TNF production by macrophages that proceeds independently of mitochondrial death machinery or RIPK3. Third, cytomegalovirus deflected BCL-2 family protein-dependent mitochondrial cell death through combined TNF-dependent and -independent signaling even in the absence of RIPK1, RIPK3, and caspase-8. Furthermore, each of these cell death pathways dictated a distinct pattern of cytokine and chemokine activation. Therefore, cytomegalovirus employs sequential, non-redundant suppression strategies to specifically modulate the timing and execution of necroptosis, extrinsic apoptosis, and intrinsic apoptosis within infected cells to orchestrate virus control and infection-dependent inflammation. Virus-encoded death suppressors together hold control over an intricate network that upends host defense and supports pathogenesis in the intact mammalian host.

scholarly journals Silymarin and Cancer: A Dual Strategy in Both in Chemoprevention and Chemosensitivity

Molecules ◽  
2020 ◽  
Vol 25 (9) ◽  
pp. 2009 ◽  
Author(s):  
Dominique Delmas ◽  
Jianbo Xiao ◽  
Anne Vejux ◽  
Virginie Aires
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Current Knowledge ◽  
Organic Anion ◽  
Chemotherapeutic Agents ◽  
Normal Cells ◽  
Antiapoptotic Proteins ◽  
Cell Death Pathways ◽  
Anion Transporters ◽  
Atp Binding Cassettes

Silymarin extracted from milk thistle consisting of flavonolignan silybin has shown chemopreventive and chemosensitizing activity against various cancers. The present review summarizes the current knowledge on the potential targets of silymarin against various cancers. Silymarin may play on the system of xenobiotics, metabolizing enzymes (phase I and phase II) to protect normal cells against various toxic molecules or to protect against deleterious effects of chemotherapeutic agents on normal cells. Furthermore, silymarin and its main bioactive compounds inhibit organic anion transporters (OAT) and ATP-binding cassettes (ABC) transporters, thus contributing to counteracting potential chemoresistance. Silymarin and its derivatives play a double role, namely, limiting the progression of cancer cells through different phases of the cycle—thus forcing them to evolve towards a process of cell death—and accumulating cancer cells in a phase of the cell cycle—thus making it possible to target a greater number of tumor cells with a specific anticancer agent. Silymarin exerts a chemopreventive effect by inducing intrinsic and extrinsic pathways and reactivating cell death pathways by modulation of the ratio of proapoptotic/antiapoptotic proteins and synergizing with agonists of death domains receptors. In summary, we highlight how silymarin may act as a chemopreventive agent and a chemosensitizer through multiple pathways.

Hydroxyl Group Difference between Anthraquinone Derivatives Regulate Different Cell Death Pathways via Nucleo-Cytoplasmic Shuttling of p53

2019 ◽  
Vol 19 (2) ◽  
pp. 184-193 ◽  
Author(s):  
Mohd Kamil ◽  
Ejazul Haque ◽  
Snober S. Mir ◽  
Safia Irfan ◽  
Adria Hasan ◽  
...  
Keyword(s):  
Cell Death ◽  
Cellular Localization ◽  
A549 Cells ◽  
Human Lung Cancer ◽  
Hydroxyl Group ◽  
Marker Genes ◽  
Hydroxyl Groups ◽  
P53 Expression ◽  
Cancer Management ◽  
Cell Death Pathways

Background: Despite a number of measures having been taken for cancer management, it is still the second leading cause of death worldwide. p53 is the protein principally being targeted for cancer treatment. Targeting p53 localization may be an effective strategy in chemotherapy as it controls major cell death pathways based on its cellular localization. Anthraquinones are bioactive compounds widely being considered as potential anticancer agents but their mechanism of action is yet to be explored. It has been shown that the number and position of hydroxyl groups within the different anthraquinones like Emodin and Chrysophanol reflects the number of intermolecular hydrogen bonds which affect its activity. Emodin contains an additional OH group at C-3, in comparison to Chrysophanol and may differentially regulate different cell death pathways in cancer cell. Objective: The present study was aimed to investigate the effect of two anthraquinones Emodin and Chrysophanol on induction of different cell death pathways in human lung cancer cells (A549 cell line) and whether single OH group difference between these compounds differentially regulate cell death pathways. Methods: The cytotoxic effect of Emodin and Chrysophanol was determined by the MTT assay. The expression of autophagy and apoptosis marker genes at mRNA and protein level after treatment was checked by the RT-PCR and Western Blot, respectively. For cellular localization of p53 after treatment, we performed immunofluorescence microscopy. Results: We observed that both compounds depicted a dose-dependent cytotoxic response in A549 cells which was in concurrence with the markers associated with oxidative stress such as an increase in ROS generation, decrease in MMP and DNA damage. We also observed that both compounds up-regulated the p53 expression where Emodin causes nuclear p53 localization, which leads to down-regulation in mTOR expression and induces autophagy while Chrysophanol inhibits p53 translocation into nucleus, up-regulates mTOR expression and inhibits autophagy. Conclusion: From this study, it may be concluded that the structural difference of single hydroxyl group may switch the mechanism from one pathway to another which could be useful in the future to improve anticancer treatment and help in the development of new selective therapies.

scholarly journals Necroptosis in Pulmonary Diseases: A New Therapeutic Target

2021 ◽  
Vol 12 ◽  
Author(s):  
Lingling Wang ◽  
Ling Zhou ◽  
Yuhao Zhou ◽  
Lu Liu ◽  
Weiling Jiang ◽  
...  
Keyword(s):  
Cell Death ◽  
Plasma Membranes ◽  
Inflammatory Responses ◽  
Neurological Diseases ◽  
Kinase Domain ◽  
The Body ◽  
Interacting Protein ◽  
Membrane Rupture ◽  
Regulated Cell Death ◽  
Scientific Attention

In the past decades, apoptosis has been the most well-studied regulated cell death (RCD) that has essential functions in tissue homeostasis throughout life. However, a novel form of RCD called necroptosis, which requires receptor-interacting protein kinase-3 (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL), has recently been receiving increasing scientific attention. The phosphorylation of RIPK3 enables the recruitment and phosphorylation of MLKL, which oligomerizes and translocates to the plasma membranes, ultimately leading to plasma membrane rupture and cell death. Although apoptosis elicits no inflammatory responses, necroptosis triggers inflammation or causes an innate immune response to protect the body through the release of damage-associated molecular patterns (DAMPs). Increasing evidence now suggests that necroptosis is implicated in the pathogenesis of several human diseases such as systemic inflammation, respiratory diseases, cardiovascular diseases, neurodegenerative diseases, neurological diseases, and cancer. This review summarizes the emerging insights of necroptosis and its contribution toward the pathogenesis of lung diseases.

scholarly journals Subamolide B Isolated from Medicinal PlantCinnamomum subaveniumInduces Cytotoxicity in Human Cutaneous Squamous Cell Carcinoma Cells through Mitochondrial and CHOP-Dependent Cell Death Pathways

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Shu-Yi Yang ◽  
Hui-Min Wang ◽  
Tai-Wen Wu ◽  
Yi-Ju Chen ◽  
Jeng-Jer Shieh ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Death ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Ectopic Expression ◽  
Chemotherapeutic Agents ◽  
Cutaneous Squamous Cell Carcinoma ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Cell Death Pathways

Subamolide B is a butanolide isolated fromCinnamomum subavenium, a medicinal plant traditionally used to treat various ailments including carcinomatous swelling. We herein reported for the first time that subamolide B potently induced cytotoxicity against diverse human skin cancer cell lines while sparing nonmalignant cells. Mechanistic studies on human cutaneous squamous cell carcinoma (SCC) cell line SCC12 highlighted the involvement of apoptosis in subamolide B-induced cytotoxicity, as evidenced by the activation of caspases-8, -9, -4, and -3, the increase in annexin V-positive population, and the partial restoration of cell viability by cotreatment with the pan-caspase inhibitor z-VAD-fmk. Additionally, subamolide B evoked cell death pathways mediated by FasL/Fas, mitochondria, and endoplasmic reticulum (ER) stress, as supported by subamolide B-induced FasL upregulation, BCL-2 suppression/cytosolic release of cytochrome c, and UPR activation/CHOP upregulation, respectively. Noteworthy, ectopic expression of c-FLIPLor dominant-negative mutant of FADD failed to impair subamolide B-induced cytotoxicity, whereas BCL-2 overexpression or CHOP depletion greatly rescued subamolide B-stimulated cells. Collectively, these results underscored the central role of mitochondrial and CHOP-mediated cell death pathways in subamolide B-induced cytotoxicity. Our findings further implicate the potential of subamolide B for cutaneous SCC therapy or as a lead compound for developing novel chemotherapeutic agents.

Mitochondrial metabolic reprogramming controls the induction of immunogenic cell death and efficacy of chemotherapy in bladder cancer

2021 ◽  
Vol 13 (575) ◽  
pp. eaba6110
Author(s):  
Bianca Oresta ◽  
Chiara Pozzi ◽  
Daniele Braga ◽  
Rodolfo Hurle ◽  
Massimo Lazzeri ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Cell Death ◽  
Complex I ◽  
Dendritic Cell Maturation ◽  
Chemotherapeutic Agents ◽  
Metabolic Reprogramming ◽  
Immunogenic Cell Death ◽  
Treatment Schedule ◽  
Cancer Management

Although chemotherapeutic agents have been used for decades, the mechanisms of action, mechanisms of resistance, and the best treatment schedule remain elusive. Mitomycin C (MMC) is the gold standard treatment for non–muscle-invasive bladder cancer (NMIBC). However, it is effective only in a subset of patients, suggesting that, aside from cytotoxicity, other mechanisms could be involved in mediating the success of the treatment. Here, we showed that MMC promotes immunogenic cell death (ICD) and in vivo tumor protection. MMC-induced ICD relied on metabolic reprogramming of tumor cells toward increased oxidative phosphorylation. This favored increased mitochondrial permeability leading to the cytoplasmic release of mitochondrial DNA, which activated the inflammasome for efficient IL-1β (interleukin-1β) secretion that promoted dendritic cell maturation. Resistance to ICD was associated with mitochondrial dysfunction related to low abundance of complex I of the respiratory chain. Analysis of complex I in patient tumors indicated that low abundance of this mitochondrial complex was associated with recurrence incidence after chemotherapy in patients with NMIBC. The identification of mitochondria-mediated ICD as a mechanism of action of MMC offers opportunities to optimize bladder cancer management and provides potential markers of treatment efficacy that could be used for patient stratification.

scholarly journals The caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Mingxia Jiang ◽  
Ling Qi ◽  
Lisha Li ◽  
Yanjing Li
Keyword(s):  
Cell Death ◽  
Tumor Cell ◽  
Caspase 3 ◽  
Suppressor Gene ◽  
Signal Pathway ◽  
Cell Swelling ◽  
Tumor Cell Death ◽  
Cell Death Pathways ◽  
Apoptotic Pathways ◽  
New Strategies

Abstract Apoptosis has long been recognized as a mechanism that kills the cancer cells by cytotoxic drugs. In recent years, studies have proved that pyroptosis can also shrink tumors and inhibit cells proliferation. Both apoptosis and pyroptosis are caspase-dependent programmed cell death pathways. Cysteinyl aspartate specific proteinase-3 (Caspase-3) is a common key protein in the apoptosis and pyroptosis pathways, and when activated, the expression level of tumor suppressor gene Gasdermin E (GSDME) determines the mechanism of tumor cell death. When GSDME is highly expressed, the active caspase-3 cuts it and releases the N-terminal domain to punch holes in the cell membrane, resulting in cell swelling, rupture, and death. When the expression of GSDME is low, it will lead to the classical mechanism of tumor cell death, which is apoptosis. More interestingly, researchers have found that GSDME can also be located upstream of caspase-3, connecting extrinsic, and intrinsic apoptotic pathways. Then, promoting caspase-3 activation, and forming a self-amplifying feed-forward loop. GSDME-mediated pyroptosis is correlated with the side effects of chemotherapy and anti-tumor immunity. This article mainly reviews the caspase-3/GSDME signal pathway as a switch between apoptosis and pyroptosis in cancer, to provide new strategies and targets for cancer treatment.

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