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Anti-Cancer Agents from Natural Sources
Published in Rohit Dutt, Anil K. Sharma, Raj K. Keservani, Vandana Garg, Promising Drug Molecules of Natural Origin, 2020
Debasish Bandyopadhyay, Felipe Gonzalez
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.
In Silico approach of soursop leaf for prediction of anticancer molecular target therapy
Published in Ade Gafar Abdullah, Isma Widiaty, Cep Ubad Abdullah, Medical Technology and Environmental Health, 2020
M.K. Dewi, Y. Kharisma, L. Yuniarti
Intrinsic pathway (mitochondria) occurs due to mitochondrial permeability that releases proapoptotic molecules into the cytosol. Growth factors and other signals can stimulate the formation of Bcl2 and Bcl-XL antiapoptotic proteins, which are present in the mitochondrial membrane and cytoplasm to prevent apoptosis. When cells are stressed, antiapoptosis is replaced by Bak and Bax proapoptosis which forms the channel through which cytochrome c and other mitochondrial proteins exit into the cytosol. Cytochrome c binds to the Apaf-1 protein and activates the caspase 9. Caspase 9 activates the exclusionary caspases 3, 6, and 7. Caspase, Bax, and Bid are proapoptotic proteins (Green 2006).
Cell death after irradiation: How, when and why cells die
Published in Michael C. Joiner, Albert J. van der Kogel, 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.
Overexpression of NDRG2 promotes the therapeutic effect of pazopanib on ovarian cancer
Published in Journal of Receptors and Signal Transduction, 2021
Ying Cui, Guihua Shen, Linlin Ma, Qiubo Lv
Caspase-9 is a key regulator in the intrinsic pathway involved under multiple stimuli, including chemotherapies, stress agents, and radiation. Dysfunction of caspase-9 activation leads to the development of degenerative disease and cancer. Activation of caspase-9 requires the binding with APAF-1 [44]. APAF-1 is known to bind with caspase-9 through CARD domains, which provides an indispensable complementary interface for activation of caspase-9 [45]. A previous study found that activation of caspase-9 and caspase-3 are present at the end stage of the disease, suggesting that activation of caspases might contribute to the apoptosis of cells [46], this result showed that caspase-9 is required for the maintaining of cellular homeostasis via regulation of apoptosis. Other studies showed that activated caspase-9 further induce the cleave of caspase-3, which binds with the apoptosome and performs as an executor of the apoptosis process [47].
Co-delivery of quercetin and caffeic-acid phenethyl ester by polymeric nanoparticles for improved antitumor efficacy in colon cancer cells
Published in Journal of Microencapsulation, 2021
Reyhan Dilsu Colpan, Aysegul Erdemir
In order to confirm QuCaNP-3 induced of apoptosis on protein level we further determined cleaved-caspase-9 and caspase-3 expressions by western blotting (Figure 6(b)). Upon apoptotic stimulation cytochrome-c interacts with pro-caspase 9 and Apaf-1. Then this complex processes dimeric pro-caspase 9 into a large (37 kDa) and small (10 kDa) two subunits. While caspase-9 does not need to be cleaved to be active, apoptotic cell death is always accompanied by an autocatalytic cleavage and downstream effector caspase dependent cleavage of caspase-9 (Twiddy and Cain 2007). After activation, caspase-9 can directly cleave and active caspase-3 and 7. After 48 h treatment with free quercetin-CAPE and QuCaNP-3, cleaved caspase-9 expression was detected on QuCaNP-3 treated cells. Furthermore, caspase-3 expression levels were found to be higher on QuCaNP-3 treated cells than free quercetin-CAPE. Taken together, apoptosis of HT-29 cells could possibly be promoted by activation of intrinsic apoptosis pathway by QuCaNP-3 nanoparticles.
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.