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Small-Molecule Targeted Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
The BCL-2 family of proteins can either inhibit or promote apoptosis, and members are characterized by the BCL-2 homologous domains BH1, BH2, BH3, and BH4. The combinations of the different domains in the proteins determine their roles in the apoptosis process. Members of the family that inhibit apoptosis include BCL-2 itself, BCL-XL, and BCL-w, which possess all four of the domains. BCL-2 is the most well known of the antiapoptotic proteins, and is classified as an oncogene. Studies have shown that the BCL-2 oncogene may inhibit apoptosis in two ways, either by disrupting the channels that allow pro-apoptotic factors to leave the mitochondria or by directly controlling the activation of caspases. Over-expression of the pro-survival BCL-2 family members (e.g., BCL-2, BCL-XL, and MCL-1) is often associated with tumor maintenance, progression, and chemoresistance.
Modulation of Classical Multidrug Resistance and Drug Resistance in General
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
Most anticancer drugs and ionizing radiation exert their therapeutic effects by activating apoptosis or programmed cell death. The expression of proteins involved in apoptosis is a major determinant of sensitivity to therapies (10,11,13–15,93–95). In addition to Bcl-2, which is oncogenic in many B-cell lymphomas, by chromosomal translocations, Bcl-xl and Mcl-1 are also anti-apoptotic proteins that can confer resistance to therapies (11,95). Inhibitors of these proteins are being investigated in hematologic cancers. Oblimersen, an antisense phosphorothioate drug targeting the Bcl-2 gene, has shown some activity when combined with fludarabine in chronic lymphocytic leukemias, with remission rates of 7% versus 17% (96). Small molecule inhibitors of the BH3 domain shared by the Bcl-2, Bcl-xl, and Mcl-1 proteins are being studied in lymphomas and multiple myeloma (97–100).
Microalgae and Cyanobacteria as a Potential Source of Anticancer Compounds
Published in Gokare A. Ravishankar, Ranga Rao Ambati, Handbook of Algal Technologies and Phytochemicals, 2019
In another study, Kim et al. (2014) found stigmasterol isolated from Navicula incerta showed potent apoptotic effect against HepG2 liver cancer cells. The compound was found to up-regulate the expression of proapoptotic genes (Bax, p53) but down-regulate the expression of antiapoptotic genes including Bcl-2. In addition, flowcytometric analysis revealed that the HepG2 cells were arrested at G2/M phase. In another study, Samarakoon et al. (2014) found that a novel fatty alcohol ester, nonyl 8-acetoxy-6-methyloctanoate (NAMC), isolated from Phaeodactylum tricornutum, showed strong suppression of the growth of HL-60 (human promyelocyticleukaemia) cells. The compound induced apoptosis by activating Bax and suppressing Bcl-xL and by up-regulating other inducers of apoptosis, particularly caspase-3 and p53.
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.
Potentiality of raloxifene loaded melittin functionalized lipidic nanovesicles against pancreatic cancer cells
Published in Drug Delivery, 2022
Usama A. Fahmy, Shaimaa M. Badr-Eldin, Hibah M. Aldawsari, Nabil A. Alhakamy, Osama A. A. Ahmed, Mohamed F. Radwan, Basma G. Eid, Shaban R. M. Sayed, Gamal A. El Sherbiny, Walaa Abualsunun
Bcl-2 and Bcl-xL are one apoptotic protein and have been associated with cell survival of tumor cells via blocking the mechanism of programmed cell death. It was further reported that overexpressed Bcl2 was associated with proliferation and Myc-induced angiogenesis (Wong, 2011; Iqubal et al., 2020). On the other hand, Bax is a pro-apoptotic protein related to the induction of apoptosis, which coordinates with caspases leading to the death of tumor cells. Thus, an increased level of Bcl-2 is associated with anti-oncogenic activity, whereas an increased level of Bax is associated with pro-oncogenic activity. In the current study, when we checked the anticancer potential of RLX-raw, plain formula, and optimized RLX-PL-MEL showed reduced expression of Bcl-2 and increased expression of Bax in the PANC1 cells and hence confirmed the enhanced pro-apoptotic and anticancer potential of RLX-PL-MEL.
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
It is well known that the anti-apoptotic proteins Bcl-2 and Bcl-xL are mainly overexpressed in various types of cancer, causing survival of cancer cells and/or drug resistance7–9. Therefore, inhibition of these proteins expression leads to cancer cell death and has been used as a strategy for anticancer drug development23. In this study, the impact of compounds 1 and 11 on Bcl-2 and Bcl-xL expression in HCT-116 and MCF-7 cancer cell lines was examined using Western blot analysis and all the data were normalised to β-actin (Figure 9). The presented results revealed that benzoxazoles 1 and 11 inhibited Bcl-2 and Bcl-xL expression in both HCT-116 and MCF-7 cancer cell lines in a corresponding manner to their cytotoxic activity and their apoptosis induction ability.