Anti-Cancer Agents from Natural Sources
Rohit Dutt, Anil K. Sharma, Raj K. Keservani, Vandana Garg in Promising Drug Molecules of Natural Origin, 2020
Cytolethal distending toxins (CDTs) are a type of heterotrimeric toxins, produced by specific gram-negative mucocutaneous bacteria (Jinadasa et al., 2011). CDTs are AB-type toxins with DNase potential, which allows them to penetrate the targeted cell’s DNA (Guerra et al., 2011). They are primarily composed of cdtA, cdtB, and cdtC subunits. Because of this reason, it has been studied constantly to fully understand the mechanistic pathways in cancer cells. Bachran et al. (2014) extracted CdtB from Haemophilus ducreyi and fused it to the N-terminal 255 amino acids of Bacillus anthracis toxin lethal factor (LFn) to determine its (LFnCdtB) anti-malignant character. LFnCdtB showed its ability to inhibit proliferation of several human cancerous cells by arresting cell cycle in the G2/M phase, followed by apoptosis. In LLC model, the cytotoxicity was moderate to low. Further study on A549 adenocarcinoma was reported by Yaghoobi et al. (2016). A combined formulation of pcDNA3.1, an expression vector and cdtB derived from Aggregatibacter actinomycetemcomitans was applied in A549 cells. Apoptosis was noted through caspase-9 activation. Cells evaluated with pcDNA3.1 alone demonstrated 16.5%cell death whereas the cells evaluated with pcDNA3.1/cdtB demonstrated about four-fold higher (63.4%) rate of cell death through apoptosis. Morphological changes were also observed by chromatin condensation, which changed the shape of cancer cells. Growth and proliferation were notably inhibited in a time-dependent manner when pcDNA3.1/cdtB combination was used.
Cell death after irradiation: How, when and why cells die
Michael C. Joiner, Albert J. van der Kogel in Basic Clinical Radiobiology, 2018
Apoptosis that initiates from caspase 9 is termed the intrinsic pathway because it is activated within the cell in response to various forms of cell damage. The activation of caspase 9 is controlled in large part by the balance of pro- and anti-apoptotic proteins that reside in or near the mitochondria. Under normal conditions this balance is in favour of the anti-apoptotic factors (such as BCL2), and activation of caspase 9 is prevented. Conditions that alter this balance lead to release of cytochrome C and other molecules from the mitochondria into the cytoplasm resulting in formation of a structure known as the apoptosome, and subsequently activation of caspase 9. After irradiation, this balance can be tipped in favour of apoptosis due in part to p53 activation and induction of pro-apoptotic proteins such as BAX and PUMA.
Neurological Activities of Seaweeds and their Extracts
Leonel Pereira in Therapeutic and Nutritional Uses of Algae, 2018
A common pathological hallmark of various neurodegenerative diseases is the loss of subsets of neurons (Mattson 2000). Neurodegeneration of these neural subsets may be a consequence of various forms of neural cell death, including necrosis and apoptosis (Bains and Shaw 1997). A study carried out by Jhamandas et al. (2005) successfully showed that fucoidan (see Fig. 2.1, Chapter 2) isolated from Fucus vesiculosus, could protect cholinergic neuronal death in rats induced by Aß1-42. Fucoidan pretreatment blocked the activation of caspase-9 and caspase-3. Caspase-9 and caspase-3 have been suggested to mediate the terminal stages of neuronal apoptosis (Cowan et al. 2001). Caspase-9 and caspase-3 are two of several central components of the machinery responsible for apoptosis. Therefore, the ability of fucoidan to block the activation of caspase-9 and caspase-3 suggest that inhibition of neuronal death by fucoidan mainly occurs through apoptotic inhibition. In neurodegenerative diseases, apoptosis might be pathogenic, and targeting this process might mitigate neurodegenerative diseases (Vila and Przedborski 2003).
Neuronal protective effect of Songling Xuemaikang capsules alone and in combination with carbamazepine on epilepsy in kainic acid-kindled rats
Published in Pharmaceutical Biology, 2019
Haiyan Yang, Rui Zhang, Chen Jia, Mengyu Chen, Wen Yin, Liming Wei, Haisheng Jiao
Studies in recent years have found that the PI3K/Akt signal pathway has a certain relationship with hippocampal hypoxic-ischaemic brain injuries caused by chronic epilepsy (Kitagawa et al. 1999). The activation of the PI3K/Akt signal transduction pathways in cells downstream of its signal cascade reaction may be the key to resisting apoptosis (Zheng et al. 2013). Akt could be activated via phosphorylation at site 308 of threonine and site 473 of serine and then exert its inhibitory or activation effects on downstream proteins NF-κB, Bad and caspase, thus promoting cell survival (Shultz et al. 2010). Caspase-9 is the initiator and central part of the cell apoptosis pathway. Akt can phosphorylate and deactivate caspase-9, ultimately blocking cell apoptosis. Consistently, our study confirmed that compared with treatment with CBZ or SXC alone, the administration of CBZ together with SXC increased the expression of p-Akt and inhibited the expression of caspase-9 to significantly control the process of apoptosis and protect neuronal cells. The results indicated that the mechanism of action may be related to activation of the PI3K/Akt signal pathway, phosphorylation of Akt proteins and inhibition of caspase-9 mitochondrial apoptosis, thus ultimately resisting cell apoptosis and exerting neuronal protective effect.
Cytotoxic Activity and Initiation of Apoptosis via Intrinsic Pathway in Jurkat Cells by Leaf Extract of Zanthoxylum rhetsa DC
Published in Nutrition and Cancer, 2021
Rashmi Mallya, Milind J. Bhitre
Cytochrome C, an electron carrier protein present in mitochondrial membrane, is one of the key signaling molecules of apoptosis. Inhibition of anti-apoptotic proteins or stimulation of pro-apoptotic proteins of Bcl2 family causes alteration of mitochondrial potential and release of cytochrome C into the cytosol which activates caspase 9. Caspase 9 leads to activation of proteins caspase 3 and 7, resulting in apoptosis (25). Caspases or aspartate-specific cysteine proteases play a key role in cell survival and apoptosis. They are divided into inflammatory caspases and apoptotic caspases. Apoptotic caspase is further divided into initiator caspase (caspase 2, 8, 9, 10) and effector caspase (caspase 3, 6, 7). Caspase 3 is the major effector caspase in various mammalian cells including leukemia cells. Initiator caspases are activated by caspase 3 by a feedback amplification loop and result in incremental caspase stimulation. This causes activation of executioner caspase which leads to DNA fragmentation and cell death. The degree of sensitivity of cancer cells to apoptosis induced by various anticancer drugs is regulated by caspase 3 (26). Thus, mechanistic studies conducted in the present study indicated that methanol extract of leaf induced apoptosis in Jurkat cells by stimulation of intrinsic pathway.
Royal jelly arranges apoptotic and oxidative stress pathways and reduces damage to liver tissues of rats by down-regulation of Bcl-2, GSK3 and NF-κB and up-regulation of caspase and Nrf-2 protein signalling pathways
Published in Biomarkers, 2023
Abdullah Aslan, Ozlem Gok, Seda Beyaz, Gozde Parlak, Muhammed Ismail Can, Ramazan Gundogdu, Serpil Baspinar, Ibrahim Hanifi Ozercan, Akif Evren Parlak
Apoptosis is a gene-regulated event involved in various cellular processes such as chromatin condensation, cell contraction and DNA damage. The two main families of proteins, including the caspase 3, 8, and 9 enzymes and the cysteine proteases called the Bcl-2 family play significant roles in apoptosis. caspase 3, 8 and 9 enzymes are effective in the apoptotic process of the liver. As one of the most significant member of the caspase family, caspase-3 is responsible for the biochemical mechanism of apoptosis leading to chromatin condensation, DNA fragmentation and apoptotic bodies. Members of the Bcl-2 protein family, which have anti-apoptotic or pro-apoptotic effects, may prevent the apoptotic activity by blocking the release of cytochrome-c from mitochondria (Karadeniz et al. 2011, Aslan et al. 2022b). Pro-apoptotic proteins such as Bax, commonly found in mitochondria and endoplasmic reticulum, promote apoptosis (Cao et al. 2013, Almeer et al.2019). ATP with the addition of a complex called apoptosome leads to the conversion of inactive procaspase 9to active caspase-9 and activation of other effector caspases. Following its activation, caspase-9 initiates the caspase cascade, significantly activating procaspase 3 and procaspase 7. Caspase-3 then continues to activate the terminating procaspase 6 and procaspase 2. Caspase-6 continues to divide and activate procaspase-8 and procaspase-10, initiating the remaining caspase cascade leading to irreversible cell suicide (Atagun et al. 2011, Aslan et al. 2022a).