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1.
Molecular mechanisms of natural compounds in cell death induction and sensitization to chemotherapeutic drugs in lung cancer.
Wattanathamsan, O, Hayakawa, Y, Pongrakhananon, V
Phytotherapy research : PTR. 2019;(10):2531-2547
Abstract
Cancer remains one of the leading causes of death worldwide, especially lung cancer. Chemotherapeutic drugs are commonly used for lung cancer treatment; nonetheless, undesirable side effects and drug resistance remain major challenges for therapeutic success. Therefore, harmless and effective treatments against lung cancer are urgently required. The use of natural phytochemical products, in single or combinatorial therapy, is an emerging strategy for prevention and cure of cancer because of the various remarkable anticancer properties of these compounds. Cell death, which primarily occurs via apoptosis and nonapoptotic mechanisms (necrosis, autophagy, and cellular senescence), is one of the antineoplastic effects of natural compounds. In this review, we highlight representative plant-derived compounds with cancer chemopreventive and sensitizing effects in combination with chemotherapeutic drugs with various cell death-inducing mechanisms. Relevant molecular mechanisms implicated in the pharmacological effects of these natural compounds are discussed. Overall, this review provides a reference and new perspective for application of phytochemical agents as potential anti-lung cancer drugs for further cancer drug research and development.
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2.
Nitric oxide is a suppressor of aluminum-induced mitochondria and caspase-like protease-dependent programmed cell death in plants.
He, H, He, LF
Plant signaling & behavior. 2019;(9):1640566
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Abstract
Aluminum (Al) promotes programmed cell death (PCD) in plants. Although a lot of knowledge about the mechanisms of Al tolerance has been learned, how Al-induced PCD is regulated by nitric oxide (NO) is poorly understood. Mitochondrion is the regulatory center for PCD. We found that Al reduced the level of mitochondrial NO/H2O2, promoted the opening of mitochondrial permeability transition pore, decreased mitochondrial inner membrane potential (∆ψm), and increased caspase-like protease activity. NO-specific scavenger cPTIO enhanced these effects that were reversed by NO donor sodium nitroprusside. Our data suggest that NO suppresses Al-induced PCD by improving mitochondrial physiological properties.
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3.
MicroRNAs play an essential role in autophagy regulation in various disease phenotypes.
Zhao, Y, Wang, Z, Zhang, W, Zhang, L
BioFactors (Oxford, England). 2019;(6):844-856
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Abstract
Autophagy is a highly conserved catabolic process and fundamental biological process in eukaryotic cells. It recycles intracellular components to provide nutrients during starvation and maintains quality control of organelles and proteins. In addition, autophagy is a well-organized homeostatic cellular process that is responsible for the removal of damaged organelles and intracellular pathogens. Moreover, it also modulates the innate and adaptive immune systems. Micro ribonucleic acids (microRNAs) are a mature class of post-transcriptional modulators that are widely expressed in tissues and organs. And, it can suppress gene expression by targeting messenger RNAs for translational repression or, at a lesser extent, degradation. Research indicates that microRNAs regulate autophagy through different pathways, playing an essential role in the treatment of various diseases. It is an important regulator of fundamental cellular processes such as proliferation, autophagy, and cell apoptosis. In this review article, we first review the current knowledge of autophagy and the function of microRNAs. Then, we summarize the mechanism of autophagy and the signaling pathways related to autophagy by citing at least the main proteins involved in the different phases of the process. Second, we introduce other members of RNA and report some examples in various pathologies. Finally, we review the current literature regarding microRNA-based therapies for cancer, atherosclerosis, cardiac disease, tuberculosis, and viral diseases. MicroRNAs can cause autophagy upregulation or downregulation by targeting genes or affecting autophagy-related signaling pathways. Therefore, the microRNAs have a huge potential in autophagy regulation, and it is the function as diagnostic and prognostic markers.
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Effects of novel antidiabetes agents on apoptotic processes in diabetes and malignancy: Implications for lowering tissue damage.
Yaribeygi, H, Lhaf, F, Sathyapalan, T, Sahebkar, A
Life sciences. 2019;:116538
Abstract
Apoptosis is a complicated process that involves activation of a series of intracellular signaling. Tissue injuries from diabetes mellitus mostly occur as a consequence of higher rate of apoptosis process due to activation of a series of molecular mechanisms. Several classes of anti-hyperglycaemic agents have been developed which could potentially modulate the apoptotic process resulting in fewer tissue damages. Novel types of anti-hyperglycaemic medications such as sodium glucose cotransporters-2 inhibitors, glucagon like peptide-1 receptor agonists and dipeptidyl peptidase 4 inhibitors have shown to provide potent anti-hyperglycaemic effects, but their influences on diabetes-induced apoptotic injuries is largely unknown. Therefore, in the current study, we reviewed the published data about the possible effects of these anti-hyperglycaemic agents on apoptosis in diabetic milieu as well as in cancer cells.
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Autoimmune epithelitis (Sjögren's syndrome); the impact of metabolic status of glandular epithelial cells on auto-immunogenicity.
Katsiougiannis, S, Tenta, R, Skopouli, FN
Journal of autoimmunity. 2019;:102335
Abstract
It is well established that distinct cell metabolic alterations strongly contribute to the modulation of innate and adaptive immune responses. In the past decade the term immunometabolism has been introduced to describe the intracellular metabolic shifts of immune cells that lead to alterations of their functions. The pathogenesis of Sjögren's syndrome (SS), also referred to as autoimmune epithelitis, is not completely understood, but strong evidence supports the central role of the salivary glandular epithelial cells which are the target cells in the initiation of the autoimmune responses. Moreover, the altered epithelial functional phenotype, observed in the salivary gland lesion, may explain their disturbed secretory as well as immunoregulatory functions. From an immunometabolic perspective we have focused our studies on the endoplasmic reticulum (ER) of the salivary gland epithelial cells (SGEC) and the implication of its altered functions in the immunogenicity of these cells in SS. We showed that ER of SGEC in SS patients in situ is stressed and extensively dilated. Using salivary gland cell cultures, we studied in vitro the effect of ER stress on the metabolic behavior and viability of the cells. ER stress induced by thapsigargin increased spliced X-box binding protein-1 (XBP-1, transcription factor that increases the transcription of UPR target genes) levels in a time-dependent manner followed by autophagy and resulted to cell apoptosis. In apoptotic cells, we observed that the autoantigens Ro52 and La were redistributed in apoptotic blebs. During the induction of ER stress autophagy rescued the cells from apoptosis acting as a protective mechanism. We have also shown that adiponectin, a multifunctional hormone, is upregulated in the SGEC of SS patients acting in an autocrine or paracrine manner in the same cells. Adiponectin through activation of AMPK, the major sensor for cell energy demands, protected SGEC from apoptosis. Our results in combination with the work of others indicate that any effort of cell adaptation to ER stress may up regulate a proinflammatory milieu. This enhances the notion that metabolic alterations of the targeted epithelial cells in SS, independently of the cause, may induce an immunogenic phenotype. Therefore, SGEC have the potential to directly regulate susceptibility to and/or severity of autoimmune responses. Since adiponectin plays a vital role in the viability of SGEC through phosphorylation of AMPK, therapeutic interventions using PPAR agonists that upregulate adiponectin and concomitantly modify the energy metabolism, may be promising candidates for therapeutic intervention in SS.
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Silymarin antiproliferative and apoptotic effects: Insights into its clinical impact in various types of cancer.
Hosseinabadi, T, Lorigooini, Z, Tabarzad, M, Salehi, B, Rodrigues, CF, Martins, N, Sharifi-Rad, J
Phytotherapy research : PTR. 2019;(11):2849-2861
Abstract
Silymarin is a complex extract isolated from the plant Silybum marianum, widely known for its prominent antioxidant and hepatoprotective effects, although increasing evidences have reported extraordinary antiproliferative and apoptotic abilities. As a result, several signaling pathways involved in cell cycle control, cell proliferation, and cell death have been deconvoluted as critical mechanisms. In this regard, cyclin and cyclin-dependent pathways have been the most studied ones. Following that, apoptotic pathways, such as p53, Akt, STAT-3, Ras, and caspases pathways, have been extensively studied, although other mechanisms involved in inflammation and angiogenesis have also been highlighted as silymarin-likely targets in cancer therapy. Therefore, the main challenge of this review is to discuss the diverse molecular mechanisms for silymarin antiproliferative and apoptotic effects; most of them largely studied in various types of cancers so far. Clinical trials and combination therapies related to silymarin application in cancer prevention and treatment are presented as well.
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Ferroptosis-Induced Endoplasmic Reticulum Stress: Cross-talk between Ferroptosis and Apoptosis.
Lee, YS, Lee, DH, Choudry, HA, Bartlett, DL, Lee, YJ
Molecular cancer research : MCR. 2018;(7):1073-1076
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Abstract
Since its discovery in 2012, ferroptosis has been well characterized by the accumulation of lipid peroxides due to the failure of glutathione-dependent antioxidant defenses. It is known as an iron-dependent form of programmed cell death, which is distinct from other forms of cell death such as apoptosis and necrosis. Nonetheless, little is known about the ferroptotic agent-induced endoplasmic reticulum (ER) stress response and its role in cell death. Recent studies reveal that the ferroptotic agent-induced ER stress response plays an important role in the cross-talk between ferroptosis and other types of cell death. Ferroptotic agents induce the unfolded protein response and subsequently ER stress-mediated activation of the PERK-eIF2α-ATF4-CHOP pathway. CHOP (C/EBP homologous protein) signaling pathway-mediated p53-independent PUMA (p53 upregulated modulator of apoptosis) expression is involved in the synergistic interaction between ferroptosis and apoptosis. This review highlights the recent literature on ferroptotic and apoptotic agent interactions through the ER stress-mediated PERK-eIF2α-ATF4-CHOP-PUMA pathway and implicates combined treatment to effectively enhance tumoricidal efficacy as a novel therapeutic strategy for cancer. Mol Cancer Res; 16(7); 1073-6. ©2018 AACR.
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Betulinic acid as apoptosis activator: Molecular mechanisms, mathematical modeling and chemical modifications.
Kumar, P, Bhadauria, AS, Singh, AK, Saha, S
Life sciences. 2018;:24-33
Abstract
A natural product betulinic acid (BA) has gained a huge significance in the recent years for its strong cytotoxicity. Surprisingly, in spite of being an interesting cancer protecting agent on a variety of tumor cells, the normal cells and tissues are rarely affected by BA. Betulinic acid and analogues (BAs) generally exert through the mechanisms that provokes an event of direct cell death and bypass the resistance to normal chemotherapeutics. Although the major mechanism associated with its ability to induce direct cell death is mitochondrial apoptosis, there are several other mechanisms explored recently. Importantly, mathematical modeling of apoptosis has been an important tool to explore the precise mechanism involved in mitochondrial apoptosis. Thus, this review is an endeavor to sum up the molecular mechanisms underlying the action of BA and future directions to apply mathematical modeling technique to better understand the precise mechanism of BA-induced apoptosis. The last section of the review encompasses the plausible structural modifications and formulations to enhance the therapeutic efficacy of BA.
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Amygdalin from Apricot Kernels Induces Apoptosis and Causes Cell Cycle Arrest in Cancer Cells: An Updated Review.
Saleem, M, Asif, J, Asif, M, Saleem, U
Anti-cancer agents in medicinal chemistry. 2018;(12):1650-1655
Abstract
BACKGROUND Amygdalin is a cyanogenic glycoside which is described as a naturally occurring anticancer agent. Current review highlights apoptosis-inducing attributes of amygdalin towards different cancers and its potential application as an anti-cancer agent in cancer therapy. METHOD Data about amygdalin was retrieved from all major scientific databases i.e., PubMed, ScienceDirect, Google Scholar, Scopus and Medline by using combination of keywords like amygdalin, apoptosis, laetrile, vitamin B- 17, pro-apoptotic proteins, anti-apoptotic proteins, hydrogen cyanide, mechanism of action of amygdalin and amygdalin therapy on humans. However, no specific time frame was followed for collection of data. RESULTS Data collected from already published articles revealed that apoptosis is a central process activated by amygdalin in cancer cells. It is suggested to stimulate apoptotic process by upregulating expression of Bax (proapoptotic protein) and caspase-3 and downregulating expression of Bcl-2 (anti-apoptotic protein). It also promotes arrest of cell cycle in G0/G1 phase and decrease number of cells entering S and G2/M phases. Thus, it is proposed to enhance deceleration of cell cycle by blocking cell proliferation and growth. CONCLUSION The current review epitomizes published information and provides complete interpretations about all known anti-cancer mechanisms of amygdalin, possible role of naturally occurring amygdalin in fight against cancer and mistaken belief about cyanide toxicity causing potential of amygdalin. However, well-planned clinical trials are still needed to be conducted to prove effectiveness of this substance in vivo and to get approval for human use.
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10.
Reactive oxygen species modulate itraconazole-induced apoptosis via mitochondrial disruption in Candida albicans.
Lee, W, Lee, DG
Free radical research. 2018;(1):39-50
Abstract
Itraconazole (ITC), a well-known fungistatic agent, has potent fungicidal activity against Candida albicans. However, its mechanism of fungicidal activity has not been elucidated yet, and we aimed to identify the mechanism of ITC against C. albicans. ITC caused cell shrinkage via potassium leakage through the ion channel. Since shrunken cells could indicate apoptosis, we investigated apoptotic features. Annexin V-FITC and TUNEL assays indicated that fungicidal activity of ITC was involved in apoptosis. Subsequently, we confirmed an intracellular factor that could cause apoptosis. ITC treatment caused reactive oxygen species (ROS) accumulation. To confirm whether ROS is related with ITC-triggered cell death, cell viability was examined using the ROS scavenger N-acetylcysteine (NAC). NAC pretreatment recovered ITC-induced cell death, indicating that antifungal activity of ITC is associated with ROS, which is also confirmed by impaired glutathione-related antioxidant system and oxidized intracellular lipids. Moreover, ITC-induced mitochondrial dysfunction, in turn, triggered cytochrome c release and metacaspase activation, leading to apoptosis. Unlike the only ITC-treatment group, cells with NAC pretreatment did not show significant damage to mitochondria, and attenuated apoptotic features. Therefore, our results suggest that ITC induces apoptosis as fungicidal mechanism, and intracellular ROS is major factor to trigger the apoptosis by ITC in C. albicans.