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Nuclear Factor Kappa-B: Bridging Inflammation and Cancer
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Mohammad Aslam Khan, Girijesh Kumar Patel, Haseeb Zubair, Nikhil Tyagi, Shafquat Azim, Seema Singh, Aamir Ahmad, Ajay Pratap Singh
Inhibition of NF-κB activation could be achieved by inhibiting kinase activity of IKK with the specific inhibitors of IKKα and/or IKKβ. Irreversible inhibitors, BAY 11-7082 and BAY 11-7085, block phosphorylation of IκBα, suppress proteasomal degradation of IκBα and inhibit NF-κB translocation to the nucleus. In vitro study suggested that BAY 11-7082 treatment blocks NF-κB activation and induces mitochondrial mediated apoptosis. Treatment with BAY 11-7082 downregulated the expression of cyclin A and CDK-2 and induced cell cycle arrest [155]. Another study suggested that BAY 11-7082 induces robust cell death in primary adult leukemic T cells, as compared to normal peripheral blood mononuclear cells (PBMCs), by inhibiting the activation of NF-κB [156]. BAY 11-7085 treatment potentiates the efficacy of cisplatin in ovarian cancer by downregulating the expression of X-linked inhibitor of apoptosis protein (XIAP) and suppressing tumor cell invasiveness [157]. Pham and colleagues suggested that BAY 11-7082 treatment blocked constitutive activation of NF-κB, and induced apoptosis in non-Hodgkin mantle cell lymphoma by downregulating expression of Bcl-XL and Bfl/A1 [158]. In pre-clinical study, it has been shown that colon cancer cells-bearing mice treated with BAY 11-7085 fail to develop tumor, as compared to vehicle treated mice [159]. Co-administration of BAY11-7085 with histone deacetylase inhibitor, suberoylanilide hydroxamic acid (SAHA), reduces NF-κB in non-small cell lung cancer cells and induces enhanced apoptosis, as compared to single treatment [160].
Chemopreventive Agents
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Mangostin and a variety of other xanthones from the mangosteen tree have been investigated for biological properties, and a number of in vitro studies have suggested that some possess antioxidant, anti-inflammatory, antibacterial, antiproliferative, pro-apoptotic, and anticarcinogenic activities. Mangostin itself has been evaluated in vitro in several tumor cell lines, and has been shown to produce a number of different effects. For example, in the murine mammary adenocarcinoma cell line BJMC3879 it inhibited cell growth, enhanced apoptosis, activated caspase-3, caused cytochrome C release from mitochondria, and induced cell-cycle arrest. It was also shown to inhibit proliferation in malignant glioblastoma, prostate carcinoma, and colorectal adenocarcinoma, and carcinoma cell lines.
Garlic
Published in Robert E.C. Wildman, Richard S. Bruno, Handbook of Nutraceuticals and Functional Foods, 2019
Sharon A. Ross, Craig S. Charron
Evidence indicates that garlic constituents (i.e., DADS, DATS, S-allylmercaptocysteine [SAMC], ajoene) have the ability to suppress proliferation of several different cancer cells by blocking cell-cycle progression and/or causing apoptosis (also known as programmed cell death).134–136 Several mechanisms have been cited for the effect of garlic constituents on cell cycle arrest, including reduced Cdk1/cyclin B kinase activity, activation of extracellular signal-regulated kinases (ERK1/2), or induction of phosphorylated checkpoint kinase-1.134,137,138 Knowles and Milner139 showed that the DADS-mediated suppression of Cdk1 kinase activity during cell-cycle arrest in G2/M was not due to direct interaction with the protein, but was associated with (a) a temporal and dose-dependent increase in cyclin B1 protein level, (b) a reduction in the level of Cdk1–cyclin B1 complex formation, (c) inactivating hyperphosphorylation of Cdk1, and (d) a decrease in Cdc25C protein level. The evidence suggests a complex and coordinated interaction of many factors for the observed DADS-induced cell-cycle arrest. Furthermore, gene expression analysis suggested that alterations in DNA repair and cellular adhesion factors may also be involved in the G2/M block following DADS exposure.140
Patented therapeutic approaches targeting LRP/LR for cancer treatment
Published in Expert Opinion on Therapeutic Patents, 2019
Leila Vania, Gavin Morris, Tyrone C Otgaar, Monique J Bignoux, Martin Bernert, Jessica Burns, Anne Gabathuse, Elvira Singh, Eloise Ferreira, Stefan F T Weiss
As mentioned above, targeting proteins involved in enhancing LRP/LR’s tumourigenic function may be a potential therapy against cancer. It is known that LRP/LR has several roles within the nucleus including maintaining nuclear structures. The receptor is also found to play a role in importing and anchoring the E3 protein-ubiquitin ligase RNF8, to nucleosomes in the nucleolus [177]. Studies have shown that RNF8 plays a central role in the DNA damage response to double stranded breaks (DSBs) [110]. In the absence of DNA damage, RNF8 is localized to the nucleosome. In the event of DNA damage, the DNA-damage repair enzyme BRCA1 (breast cancer susceptibility protein 1) translocates to nucleosomes bound by RNF8, which is stabilized by LRP/LR [177] (Figure 7). During the DNA damage response, RNF8 and BRCA1 are then released into the nucleoplasm where they coordinate DSB DNA damage response (DDR). Therefore, disrupting the interaction between LRP/LR and RNF8 in the cytosol, may result in an impaired DNA repair response in tumorigenic cells. Consequently, this may lead to DNA-damage induced cell-cycle arrest and apoptosis, ultimately aiding as a therapeutic approach for the treatment of cancer.
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
Similarly, the results revealed that, for MCF-7 cancer cell line, the percentage of cells in the G2/M phase was significantly increased from 16.53% to 29.62% for compound 1 and 25.24% for compound 11. In addition, the percentage of MCF-7 cells at G1 phase decreased from 55.14% in control to 40.66% and 43.84% after incubation with compounds 1 and 11, respectively (Figure 6). These results indicated that compounds 1 and 11 induced cell cycle arrest at G2/M phase. Finally, the upsurge of cell populations in the pre-G1 phase along with the G2-M phase arrest were significant evidence that compounds 1 and 11 induced apoptosis in both HCT-116 and MCF-7 cancer cell lines.
Anti-psoriasis activities of hydroxytyrosol on HaCaT cells under psoriatic inflammation in vitro
Published in Immunopharmacology and Immunotoxicology, 2023
Caifeng Chen, Li Chen, Jun Zhou, Renhui Cai, Zhenjie Ye, Danqun Zhang
Our study found that the proliferation of psoriatic HaCaT cells is significantly reduced by HT in a dose-dependent manner via MTT assay and 100 μM was the minimal inhibitory concentration. In addition, compared to the control, cell cycle analysis demonstrated that 100 μM HT for 48 h induced cell cycle arrest in the G1 stage. In accordance with our study, HT inhibits cell proliferation in a number of tumor cell lines [30–32]. Moreover, it was found that HT could induce apoptosis and G1/S cell cycle arrest in human colorectal cancer cells [32].