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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.
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.
Leukaemias of Mature B- and T/NK-Cells
Published in Tariq I. Mughal, Precision Haematological Cancer Medicine, 2018
The past two decades have witnessed significant insights into the genetics and molecular biology of CLL with the firm recognition of the stunning complexity of the CLL genome, which exhibits high inter- and intra-clonal heterogeneity. These, in turn, inform better risk stratification methods and identification of new therapeutic targets. It is also of interest that in the initial hypothesis postulated by William Dameshek (Boston) and David Galton (London) in the 1960s, CLL arises as a progressive accumulation of immunologically abnormal B-cells, rather than excessive proliferation, and has also garnered support. The CLL cells typically express high levels of the anti-apoptotic proteins BCL-2 and BCL-xL, and low levels of the pro-apoptotic protein BAX and are therefore resistant to apoptosis. Most cells are quiescent in the G0/G1 phase. Additional insights have been gained in understanding the progression and transformation. Many of these efforts are now translating to the adoption of a risk-based treatment strategy for most patients with CLL who require therapy.
Simultaneous inhibition of Chk1 and Bcl-xL induces apoptosis in vitro and represses tumour growth in an in vivo xenograft model
Published in Journal of Chemotherapy, 2023
Yoshihito Morimoto, Kimihiko Takada, Osamu Takeuchi, Kazuhiro Watanabe, Masayoshi Hirohara, Yutaka Masuda
Regarding the mechanism of the combined effect of simultaneous Chk1 and Bcl-xL knockdown, changes in the expression levels of Bcl-2 and Mcl-1, the pro-apoptotic proteins Bax and Bak, and the BH3-only proteins Bim, Bid, Puma, and Noxa were investigated by western blotting (Figure 6). However, the results varied in each cell line. As a report related to the Chk1 and Bcl-2 families, Zhao et al. demonstrated that LY2603618 (Chk1 inhibitor) enhances venetoclax-induced cell death [19]. The mechanism of the synergistic apoptosis-inducing effect by LY2603618 was shown to be via a decrease in Mcl-1 levels. In our siRNA study, Chk1 knockdown resulted in a decrease in Bcl-2 only in MIA PaCa-2 cells. In addition, Chk1 was reported to bind to and inactivate the BH3-only protein Bad [20], but there is no report showing a direct relationship between Chk1 and the Bcl-2 family. In addition, it was confirmed that the combined knockdown of Chk1 and Bcl-xL in SUIT-2 cells induced the highest level of apoptosis. This may be related to high endogenous Bcl-xL expression in SUIT-2 cells compared with the other cell lines. Therefore, Bcl-xL expression may be a biomarker for co-inhibition of Chk1 and Bcl-xL. It is necessary to investigate the mechanism underlying the synergistic effect of simultaneous Chk1 and Bcl-xL inhibition in more detail and to identify biomarkers that predict the clinical effects.
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.