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Chemopreventive Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Apoptosis, also known as Programmed Cell Death, is induced in cells in response to physiological or pathological changes in order to eliminate aged cells, or those with extensive genetic mutations that might pose a risk of transforming into cancer cells if not eradicated. There are two predominant apoptotic pathways, the first being the intrinsic/mitochondrial pathway which is regulated by the Bcl protein family. This initially results in various stimuli which trigger increased mitochondrial membrane permeability to release apoptogenic factors, leading to membrane disruption and mitochondrial dysfunction. This results in activation of apoptogenic proteases including caspase-3 and -9, and also the expression of Death Receptors (i.e., DR4 and DR5) on the cell surface. Caspase enzymes also play vital regulatory roles in cell protein turnover via several activating and deactivating mechanisms, with nine different caspases involved in apoptotic pathways. The extrinsic apoptotic pathway is stimulated via binding of a ligand from the TNF superfamily to a Death Receptor on the cell surface. Once bound, the ligand undergoes trimerization which stimulates recruitment of adaptor proteins to their cytosolic Death Domains, such as FasL/FasR, TNFα/TNFR1, and TRAIL/TRAILR1 or TRAILR2.
Anthocyanins and Their Health Benefits
Published in Robert E.C. Wildman, Richard S. Bruno, Handbook of Nutraceuticals and Functional Foods, 2019
Justin G. Martin, Gary D. Stoner, Jairam K.P. Vanamala
In the extrinsic pathway, apoptosis is induced through the activation of death receptors Fas, TNFR1, DR3, and DR4/DR5. These receptors bind to extrinsic ligands (FasL, TNF-α, Apo3L, and Apo2L) and transduce intracellular signals that lead to cell death. In the case of the Fas/FasL, signaling pathway trimerization is induced. Fas trimerization activates caspase-8 through the adapter protein FADD. Caspase-8 stimulates apoptosis through two cascades: (1) it can directly cleave and activate caspase-3, or (2) it can act through Bid and Bc I-2 family proteins to cause the mitochondrial membrane to become depolarized and activate apoptosis via caspase-3.1,84,91 Some ACNs can induce apoptosis through this extrinsic pathway. For example, ACNs from Vitis coignetiae Pulliat induced apoptosis in human leukemia cells by activating caspase-8 and down-regulating Bcl-2 pathways.88
Nutraceutical’s Role in Proliferation and Prevention of Gynecological Cancers
Published in Sheeba Varghese Gupta, Yashwant V. Pathak, Advances in Nutraceutical Applications in Cancer, 2019
Aaishwarya B. Deshmukh, Jayvadan K. Patel, Bharat Mishra
In murine studies, inhibition of triple-negative breast cancer (TNBC) cell lines HCC1806 and HCC1937 was brought about by a synthetic analogue of oridonin (obtained from Rabdosia rubescens), CYD-6-28. CYD-6-28 induces cleavage of p21, Erk, PARP, caspase-3, -7, -8, and arrest of cell cycle at G2/M-phase and causes apoptosis mediated by death receptor 5 (DR5). CYD-6-28 is also shown to have the potential to inhibit Akt, cyclin D1, FLIPL, STAT3, and XIAP. Phaleria macrocarpa (Scheff.), one of the Indonesian traditional medicine, has lavonoid, lavonol, saponin, phenol, and terpenoid as its derivatives. Methanol extracts of P. macrocarpa have strong cytotoxic effect, which is comparable to standard gallic acid. Gallic acid is proven to be cytotoxic to the transformed cell lines of breast, cervix, esophageal, colon, brain, and gastric cancers. Through induction of ROS, the ethanolic extract obtained from mango seed may be apoptotic to the MCF-7 cells. Lavone, chloroform-extracted luteolin from Eclipta alba (Bhringraj), showed selective activation of intrinsic apoptosis, caspase-9 inhibition, sensitization of heat shock protein 60 (Hsp60), a proapoptotic molecular chaperone, and downregulation of antiapoptotic protein XIAP in MDA-MB-231 and MCF-7 cells [71].
Targeting depletion of myeloid-derived suppressor cells potentiates PD-L1 blockade efficacy in gastric and colon cancers
Published in OncoImmunology, 2022
Yao Tang, Cong Zhou, Qingli Li, Xiaojiao Cheng, Tinglei Huang, Fuli Li, Lina He, Baiweng Zhang, Shuiping Tu
Death receptor 5 (DR5) is one of the receptors of TNF-related apoptosis-inducing ligand (TRAIL) that can induce cell death by transducing the pro-apoptotic signal.13 It is frequently expressed on the surface of cancer cells, making DR5 a desirable target for antitumor therapy.14 Up to now, agonistic antibodies that target DR5 have exhibited excellent antitumor efficacy in various murine tumor models and are being tested in clinical trials for cancer treatment.15,16 Despite its amplification in cancer cells, DR5 was also shown to be highly expressed on MDSCs in tumor-bearing mice, and agonistic anti-DR5 antibodies could specifically eliminate MDSCs in tumor-bearing mice and cancer patients,17,18 providing a rationale to combine these agents with PD-1/PD-L1 blockade therapies. However, to the best of our knowledge, there has not been any published literature demonstrating the combination effects of these agents for gastric and colon cancer therapy in vivo. Moreover, the associated toxicity of this form of combination therapy is unknown.
Elevated soluble death receptor 5 can predict poor prognosis in patients with acute respiratory distress syndrome
Published in Expert Review of Respiratory Medicine, 2022
Jiangyue Qin, Hao Wang, Zhuoyao Lyu, Yue Liao, Ni Zeng, Ke Wang, Yongfang Zhou, Zijian Zeng, Zenglin Liao, Yufang Cao, Junyun He, Tao Wang, Fuqiang Wen
Diffuse alveolar epithelial and capillary endothelial injury form the principal pathogenesis of ARDS [5,6]. The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) receptor 2 [also called the death receptor 5 (DR5)], a member of the TNF superfamily, could be a mediator of apoptosis after binding with TRAIL [7]. More specifically, DR5 was found to be expressed on the alveolar epithelial cells (AECs) [8]. TRAIL released from the alveolar macrophages activates AEC apoptosis in influenza virus-infected mice [9]. This evidence implies that TRAIL and DR5 may be involved in the injury and apoptosis of AECs in the development of various pulmonary disorders. Our previous study showed that circulating TRAIL and soluble DR5 levels, which were increased in patients with chronic obstructive pulmonary disease (COPD), were related to the indicators of inflammation and decline in lung function [10]. Wan et al. found that the levels of soluble DR5 were elevated in the serum of patients with small-cell lung cancer, which acted as an independent predictor of treatment response and overall survival [11]. Lee et al. found the levels of TRAIL were elevated in the bronchoalveolar lavage fluid (BALF) of patients with ARDS [12]. However, the changes in soluble DR5 in patients with ARDS, and the predictive prognostic value of TRAIL and soluble DR5 for ARDS remain unclear.
Co-delivery of doxorubicin and TRAIL plasmid by modified PAMAM dendrimer in colon cancer cells, in vitro and in vivo evaluation
Published in Drug Development and Industrial Pharmacy, 2019
Elham Pishavar, Mohammad Ramezani, Maryam Hashemi
Co-delivery of drug/gene as prospective approach for cancer therapy has recently been demonstrated with many advantages through providing potential synergistic effects of different treatment mechanisms with reduced side effects [7,8]. In this combination therapy, nucleic acids can promote apoptosis, suppress the expression of efflux transporters to overcome MDR and act as immunotherapeutic or anti-angiogenic agent [9]. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), as a key factor in the apoptosis pathway, has attracted considerable attention in cancer therapy due to its ability to bind death receptors 4 and 5 (DR4 and DR5) which are overexpressed on the surface of a range of cancer cells [10]. While TRAIL plasmid induces apoptosis through extrinsic pathway mediated by cell surface death receptors, induced apoptosis by DOX is typically through intrinsic pathway such as hypoxia, severe DNA damage, or other cell stresses [11–13]. In this study, we developed and evaluated a novel nano-system based on PAMAM dendrimer for co-delivery of DOX and TRAIL plasmid to colon cancer cells.