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Nucleic Acids as Therapeutic Targets and Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
VAL101 is an example of a GeneICETM-based BCL-2 inhibitor in development with Valirx Plc. BCL-2 is known to inhibit apoptosis, a process which normally prevents cancer initiation and development. Considered to be an “oncogene”, it has been shown to be associated with most cancers and is thought to be overexpressed in up to 80% of leukemias and breast cancers, and 90% of prostate cancers. Therefore, inhibition of Bcl-2 should block tumor development and has been the goal of many drug development programs culminating, for example, in agents such as venetoclax (VenclextaTM) (see Chapter 6).
Human Bcl-2 Antisense Therapy for Lymphomas
Published in Eric Wickstrom, Clinical Trials of Genetic Therapy with Antisense DNA and DNA Vectors, 2020
Finbarr E. Cotter, Andrew Webb, Paul Clarke, David Cunningham
The use of new drugs, different chemotherapy combinations and high dose chemotherapy with bone marrow or peripheral stem cell rescue have had a minimal impact on patient survival. Bcl-2 expression appears to be a major factor in failure of cure with chemotherapy. As already outlined, overexpression of the bcl-2 gene results in resistance to programmed cell death (apoptosis) (Hockenbery et al., 1990) leading, to chemoresistance (Miyashita and Reed, 1992). Two recent studies have examined the prognostic significance of Bcl-2 protein overexpression in patients with diffuse, large Β cell lymphoma. In both these studies, multivariate analyses confirmed the importance of Bcl-2 expression as an independent prognostic marker (Hermine et al., 1996; Hill et al., 1996).
Apoptosis of Biliary Epithelial Cells
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
Natalie J. Török, Gregory J. Gores
The members of the Bcl-2 family of proteins play major role in regulation of apoptosis. Bcl-2, the prototype of this family is known to inhibit apoptosis by preventing cytochrome-c release from the mitochondria thereby preventing caspase 3 activation. Bcl-2 was shown to be expressed by bile ductules and small bile duct epithelium, but not large bile duct epithelium.20,21 Expression of Bax, Mcl-1 and Bcl-XL was also detected in cholangiocytes isolated from normal livers and immortalized by SV-40.22 However, expression of Bak, Bcl-XS was not detected.
The role of autophagy in acute myeloid leukemia development
Published in Expert Review of Anticancer Therapy, 2023
Martyna Bednarczyk, Karolina Kociszewska, Olga Grosicka, Sebastian Grosicki
Proteins from the Bcl-2 and Bcl-XL group, involved in apoptosis, also participate in autophagy by acting as its’ inhibitors. In some cell types of these proteins bind to Beclin 1, lowering its affinity for PI3K III. The role of these proteins in autophagy is related to the fact that the Bcl-2/Bcl-XL-Beclin 1-PI3K complex has a lower kinase activity than the complex without the attached Bcl-2 or Bcl-XL proteins. Interactions between Beclin1 and the above-mentioned proteins are regulated by their phosphorylation status. The DAPK-1 kinase (Death-associated protein kinase 1) phosphorylates Beclin1, while the JNK1 kinase (c-Jun N-terminal kinases) phosphorylates the Bcl-2 protein. These proteins then become disconnected, inducing autophagy. In addition, the phosphorylated protein Bcl-2 combines with the pro-apoptotic protein Bax, inhibiting apoptosis [23]. Figure 2 shows involved of autophagy in cancer development.
Multifunctional icariin and tanshinone IIA co-delivery liposomes with potential application for Alzheimer’s disease
Published in Drug Delivery, 2022
Jiao Wang, Liang Kong, Rui-Bo Guo, Si-Yu He, Xin-Ze Liu, Lu Zhang, Yang Liu, Yang Yu, Xue-Tao Li, Lan Cheng
As we all know, Aβ1–42 induces oxidative stress and neuroinflammation that results in DNA damage and caspase-dependent neuronal apoptosis, which plays a crucial part in neurodegeneration (Fang et al., 2018). Hence, alleviating the apoptosis may be a possible treatment for AD. The mitochondrial pathway is the main process of inducing apoptosis, mainly mediated by Bcl-2 family and caspase. The Bcl-2 family consists of pro-apoptotic proteins (Bax, Bad, and Bak) and anti-apoptotic proteins (Bcl-2 and Bcl-XL) (Pahrudin Arrozi et al., 2020). Bax can increase mitochondrial permeability, release pro-apoptotic factors, and inhibit anti-apoptotic Bcl-2 family proteins to trigger caspase signaling, leading to neuronal apoptosis (Lu et al., 2021). In order to evaluate the inhibitory effect of varying formulations on nerve cell apoptosis in vivo, the paraffin sections of brain tissue treated with free ICA/TSIIA, ICA/TSIIA liposomes or Ang2-ICA/TSIIA liposomes were stained by immunohistochemistry. The expression of Bax and caspase-3 was significantly increased, while Bcl-2 is not expressed or at a low level in the hippocampus and cortex of APP/PS1 mice. After Ang2-ICA/TSIIA liposomes treatment, the expression of Bax and caspase-3 was significantly decreased, while the expression of Bcl-2 was significantly increased (Figure 8(A–C)). These results indicated that Ang2-ICA/TSIIA liposomes could inhibit neuronal apoptosis in AD mice.
Design, synthesis, molecular modeling and biological evaluation of novel Benzoxazole-Benzamide conjugates via a 2-Thioacetamido linker as potential anti-proliferative agents, VEGFR-2 inhibitors and apoptotic inducers
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Ibrahim H. Eissa, Radwan El-Haggar, Mohammed A. Dahab, Marwa F. Ahmed, Hazem A. Mahdy, Reem I. Alsantali, Alaa Elwan, Nicolas Masurier, Samar S. Fatahala
Apoptosis, a mechanism of programmed cell death in multicellular organisms, is a chain of biochemical reactions that results in specific cell changes and cell death18. One of the main pathways of cell apoptosis induction is the mitochondria-dependent apoptotic pathway which is regulated by the B-cell lymphoma-2 (Bcl-2) protein family19,20. The Bcl-2 different family members could express opposite functions; some are pro-apoptotic proteins such as Bac and Bax, the two nuclear-encoded proteins that promote cell apoptosis, while others are anti-apoptotic proteins, such as Bcl-2 and Bcl-xL that inhibit cell apoptosis9. In this concern, it was reported that many cancer cells are characterised by the anti-apoptotic Bcl-2 protein overexpression that leads to apoptosis prevention as well as drug resistance21,22. Therefore, the production of Bcl-2 proteins inhibitors has become a significant target for introducing promising anti-cancer agents23,24.