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Synthetic Compounds vs. Phytochemicals for the Treatment of Human Cutaneous Malignant Melanoma
Published in Namrita Lall, Medicinal Plants for Cosmetics, Health and Diseases, 2022
Jacqueline Maphutha, Namrita Lall
Euplotin C (EC), isolated from Euplotes crassus Dujardin, induced apoptosis in three malignant melanoma cell lines (A375, MeWo and 501 Mel) with 50% minimum inhibitory concentrations (IC50) of 3.53 ± 0.19, 2.68 ± 0.29 and 3.56 ± 0.38 µM, respectively. Western blotting analysis revealed that EC inhibited protein kinase B (p-Akt) by 68% and BRAF by 27% (Carpi et al., 2018). Bornyl cis-4-hydroxycinnamate (BCH), isolated from Piper betle L., reduced the viability of two malignant melanoma cell lines (A375 and A2058) at a concentration of 12 µM. Western blotting analysis revealed that the levels of p-PI3K and p-Akt were significantly reduced at 6 µM. Furthermore, BCH reduced the expression of extracellular signal regulated kinase (ERK), c-Jun N-terminal kinases (JNK) and p38 MAPK (MAPK pathway related proteins) (Yang et al., 2018). Isoangustone A (IA), isolated from Glycyrrhiza glabra L., inhibited the growth of the malignant melanoma cell line (SK-MEL28) by 67%. Through an in vitro PI3K assay and Western blotting, PI3K was significantly inhibited in comparison to the positive control, LY294002. Furthermore, IA inhibited p-Akt and molecular targets in the MAPK pathway (MKK4 and MKK7) (Song et al., 2013).
The Role of MAP Kinases, Phosphatidylinositol 3-Kinase, and Ceramide in LPS-induced Signaling in Macrophages
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Anthony L. DeFranco, Alexander J. Finn, Julie Hambleton, Mary T. Crowley, Mary Lee MacKichan, Steven L. Weinstein
Another signaling pathway activated by LPS includes the lipid kinase phosphatidylinositol 3-kinase (PI 3-kinase) and two downstream serine/threonine protein kinases Akt/PKB and p70S6kinase. In various cell types, this signaling pathway is thought to regulate translation of certain mRNAs and also to regulate apoptotic pathways (53,54). PI 3-kinase phosphorylates various inositol-containing phospholipids, generating second messengers that may work primarily by serving as ligands for pleckstrin homology (PH) domains in signaling proteins. The interaction between PH domains and the products of PI 3-kinase often serves to recruit signaling components to the plasma membrane in an inducible fashion (55,56). LPS has recently been shown to activate PI 3-kinase in monocytes (57) and in the RAW264.7 macrophage cell line (S. L. Weinstein et al., unpublished). We have also found that LPS activates Akt/PKB (A. J. Finn and A. L. DeFranco, unpublished data) and p70S6kinase (S. L. Weinstein et al., unpublished). LPS induced approximately a threefold increase in p70S6kmase activity in an in vitro kinase assay. Two inhibitors of PI 3-kinase, wortmannin and the chemically distinct inhibitor LY294002, blocked activation of p70S6kinase in response to LPS. In addition, the activation of p70S6kinase was inhibited by the immunosuppressant rapamycin, indicating a role for the mTOR protein, the target of rapamycin, in the activation of p70S6kinase.
Farnesyltransferase Inhibitors: Current and Prospective Development for Hematologic Malignancies
Published in Gertjan J. L. Kaspers, Bertrand Coiffier, Michael C. Heinrich, Elihu Estey, Innovative Leukemia and Lymphoma Therapy, 2019
MPDs in addition to CML may also be appropriate disease targets for FTI therapy. This heterogeneous group of disorders includes agnogenic myeloid metaplasia (AMM), polycythemia vera (PV), essential thrombocythemia (ET), and atypical CML and CMML, both of which are considered to be hybrid MPD/ MDS disorders. In AMM, Mesa et al. found that the addition of tipifarnib at low doses (<50 nM) to peripheral blood mononuclear cells results in significant inhibition of both myeloid and megakaryocytic colony formation, with megakaryocytic progenitors being exquisitely sensitive to doses less than 5 nM (57). Such inhibition also occurred in normal controls and patients with other chronic MPDs (PV and ET). Interestingly, similar results were achieved with the PI3K inhibitor LY294002, substantiating the notion that tipifarnib exerts at least part of its effect by suppressing PI3K activity (28). Clinically, tipifarnib given to 34 patient with symptomatic MPDs at a dose of 300 mg BID for 21 of every 28 days yielded significant responses in organomegaly in 33% and in transfusion-requiring anemia in 38%, but without appreciable effect on cytogenetic abnormalities, degree of myelofibrosis, or intramedullary angiogenesis (58).
Combination of paeoniflorin and calycosin-7-glucoside alleviates ischaemic stroke injury via the PI3K/AKT signalling pathway
Published in Pharmaceutical Biology, 2022
Peng-Cheng Wang, Sheng-Xin Wang, Xiang-Li Yan, Ying-Ying He, Min-Chun Wang, Hao-Zhen Zheng, Xu-Guang Shi, Yong-Heng Tan, Li-Sheng Wang
Different pathophysiological processes are involved in IS, including the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway (Zhang et al. 2007; Jie et al. 2015; Peng et al. 2019). Activation of the PI3K/AKT signalling pathway inhibits a number of apoptotic mechanisms and promotes cell cycle progression, thereby promoting cell survival and proliferation (Cao et al. 2019). Moreover, the activated PI3K/AKT pathway significantly reduces brain damage, protecting hippocampal and cortical neurons against hypoxia/reoxygenation-induced apoptosis (Gao et al. 2018; Chen et al. 2019; Li et al. 2019). LY294002 is widely used in the characterization of the phosphatidylinositol kinase signalling pathway, being able to penetrate cells and specifically inhibit PI3K (Wang et al. 2017).
Evidence for a PI3-kinase independent pathway in the regulation of Rap1b activation downstream of the P2Y12 receptor in platelets
Published in Platelets, 2022
Carol Dangelmaier, Satya P Kunapuli
Figures 3A and 3B demonstrate that antagonism of the P2Y12 receptor by AR-C69931MX or the P2Y1 receptor by MRS2179 was sufficient to inhibit 2-MeSADP-induced Rap1 activation. These results indicate that both CalDAG-GEF and C3G activation via P2Y1 receptor stimulation and inhibition of RASA3 by P2Y12 receptor stimulation were necessary for Rap1 activation. However, the pan PI3-kinase inhibitor, LY294002, reduced but did not abolish 2-MeSADP-induced Rap1 activation (Figure 3B and 3D). As shown in Figure 3B and 3C, LY294002 effectively inhibited PI3-kinase activity as there is no phosphorylation of Akt (Ser473), an indicator of PI3-kinase activity. Our data indicate therefore that RASA3 could possibly be blocked by a PI3-kinase insensitive mechanism. This was mimicked in mouse platelets where either P2Y1 or P2Y12 was genetically ablated (Figures 4A and 4B). 2-MeSADP-induced Rap1 activation was abolished in either knockout although the PI3-kinase pathway was still intact in platelets lacking P2Y1 as demonstrated by Akt (Ser473) phosphorylation. Thus, we propose that the P2Y12 receptor can regulate Rap1, possibly through RASA3, in a pathway independent of PI3-kinase (outlined in Figure 5).
Annexin A2 promotes development of retinal neovascularization through PI3K/ AKT signaling pathway
Published in Current Eye Research, 2022
Chenyue Li, Zichang Zhao, Shihong Zhao
LY294002 is a widely used PI3K inhibitor and its controversial effects, especially in the retina, may be influenced by experimental conditions.43 Besides, studies have shown that its great efficacy may also be at the expense of remarkable toxicity. For example, weight loss and dry skin were observed in mice intraperitoneally injected with LY294002 at 100 mg/kg.44 Inhibition of PI3K, an extensive critical factor for normal physiological processes, will undoubtedly and inevitably bring about multifarious toxicity.43 An experimental design that pup mice were intraperitoneally injected in a therapeutic dosage of 0.05 mL LY294002 once a day for successive 5 days from P7 to P10 which either kept mice alive or functioned practically was finally set after repeated efforts. The more accurate function dose and profound toxicity of LY294002 may need further researches.