Newly Synthesized Pyrazolinone Chalcones as Anticancer Agents via Inhibiting the PI3K/Akt/ERK1/2 Signaling Pathway
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ABSTRACT:
SUBMITTER: Noser A
PROVIDER: S-EPMC9330109 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Translation of mRNA is one of the processes adopted by cancer cells to maintain survival via phosphorylated (p)-eIF4E overexpression. Once p-eIF4E binds to the cap structure of mRNA, it advocates a nonstop translation process. In this regard, 15 new-based GMP analogs were synthesized to target eIF4E and restrain its binding to cap mRNA. The compounds were tested against three types of cancer cell lines: Caco-2, HepG-2, MCF-7, and normal kidney cells (Vero cells). Most of the compounds showed high potency against breast cancer cells (MCF-7), characterized by the highest cancer type for overexpression of p-eIF4E. Compound 4b was found to be the most active against three cell lines, colon (Caco-2), hepatic (HepG-2), and breast (MCF-7), with positive IC50 values of 31.40, 27.15, and 21.71 μM, respectively. Then, chitosan-coated niosomes loaded with compound 4b (Cs/4b-NSs) were developed (as kinetically enhanced molecules) to improve the anticancer effects further. The prepared Cs/4b-NSs showed pronounced cytotoxicity compared to the free 4b against Caco2, Hepg2, and MCF-7 with IC50 values of 16.15, 26.66, and 6.90 μM, respectively. Then, the expression of both the phosphorylated and nonphosphorylated western blot techniques was conducted on MCF-7 cells treated with the most active compounds (based on the obtained IC50 values) to determine the total protein expression of both eIF4E and p-eIF4e. Interestingly, the selected most active compounds displayed 35.8-40.7% inhibition of p-eIF4E expression when evaluated on MCF-7 compared to Ribavirin (positive control). CS/4b-NSs showed the best inhibition (40.7%). The findings of the present joint in silico molecular docking, simulation dynamic studies, and experimental investigation suggest the potential use of niosomal nanovesicles as a promising nanocarrier for the targeted delivery of the newly synthesized compound 4b to eukaryotic initiation factor 4E. These outcomes support the possible use of Cs/4b-NSs in targeted cancer therapy.
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Project description:A group of novel trimethoxyphenyl (TMP)-based analogues were synthesized by varying the azalactone ring of 2-(3,4-dimethoxyphenyl)-4-(3,4,5-trimethoxybenzylidene)oxazolone 1 and characterized using NMR spectral data as well as elemental microanalyses. All synthesized compounds were screened for their cytotoxic activity utilizing the hepatocellular carcinoma (HepG2) cell line. Compounds 9, 10 and 11 exhibited good cytotoxic potency with IC50 values ranging from 1.38 to 3.21 μM compared to podophyllotoxin (podo) as a reference compound. In addition, compounds 9, 10 and 11 exhibited potent inhibition of β-tubulin polymerization. DNA flow cytometry analysis of compound 9 shows cell cycle disturbance at the G2/M phase and a significant increase in Annexin-V-positive cells compared with the untreated control. Compound 9 was further studied regarding its apoptotic potential in HepG2 cells; it decreased the level of MMP and Bcl-2 as well as boosted the level of p53 and Bax compared with the control HepG2 cells.
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Project description:Bone loss (osteopenia) is a common complication in human solid tumour. In addition, after surgical treatment of gynaecological tumour, osteoporosis often occurs due to the withdrawal of oestrogen. The major characteristic of osteoporosis is the low bone mass with micro-architectural deteriorated bone tissue. And the main cause is the overactivation of osteoclastogenesis, which is one of the most important therapeutic targets. Inflammation could induce the interaction of RANKL/RANK, which is the promoter of osteoclastogenesis. Triptolide is derived from the traditional Chinese herb lei gong teng, presented multiple biological effects, including anti-cancer, anti-inflammation and immunosuppression. We hypothesized that triptolide could inhibits osteoclastogenesis by suppressing inflammation activation. In this study, we confirmed that triptolide could suppress RANKL-induced osteoclastogenesis in bone marrow mononuclear cells (BMMCs) and RAW264.7 cells and inhibited the osteoclast bone resorption functions. PI3K-AKT-NFATc1 pathway is one of the most important downstream pathways of RANKL-induced osteogenesis. The experiments in vitro indicated that triptolide suppresses the activation of PI3K-AKT-NFATc1 pathway and the target point located at the upstream of AKT because both NFATc1 overexpression and AKT phosphorylation could ameliorate the triptolide suppression effects. The expression of MDM2 was elevated, which demonstrated the MDM-p53-induced cell death might contribute to the osteoclastogenesis suppression. Ovariectomy-induced bone loss and inflammation activation were also found to be ameliorated in the experiments in vivo. In summary, the new effect of anti-cancer drug triptolide was demonstrated to be anti-osteoclastogenesis, and we demonstrated triptolide might be a promising therapy for bone loss caused by tumour.
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Project description:Objective: Calcium dobesilate (CaD), an effective drug for the treatment of diabetic microvascular complications, especially diabetic retinopathy, is widely used in the clinic. Interestingly, several studies have indicated that CaD is therapeutic for diabetic kidney disease (DKD). Recently, evidence has indicated that altered vascular endothelial growth factor (VEGF) expression and decreased autophagy are the main pathological mechanisms of proteinuria. Thus, this study was conducted to explore the effect of CaD on restoring autophagy in DKD and the possible signaling pathway between VEGF and autophagy. Methods: Obese mice with spontaneous diabetes (KK-Ay) and high-fat diet- and streptozotocin-induced diabetic mice (HFD/STZ) were used in this study. Biochemical staining, western blotting, and immunohistochemistry were conducted to determine the angioprotective effect of CaD and the underlying mechanism between autophagy and VEGF/VEGFR. Results: Our results showed that CaD was capable of reducing albuminuria and restoring renal histological changes in KK-Ay and HFD/STZ-induced diabetic mice. CaD restored autophagy by decreasing the protein expression of LC3 II, Atg5, and beclin 1 and increasing the expression of P62. Moreover, CaD reduced the activation of the autophagy-related PI3K/AKT/mTOR pathway possibly via decreasing VEGF and downregulating VEGF receptor 2. Conclusion: Overall, CaD, as a novel potential therapeutic drug for DKD, plays a key role in protecting renal function and restoring autophagy by blocking VEGF/VEGFR2 and inhibiting the PI3K/AKT/mTOR signaling pathway.
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Project description:Dihydroartemisinin (DHA) is the first generation of naturally occurring artemisinin derivatives with antimalarial activity. Recent research showed that this drug also features immunosuppressive and anti-inflammatory properties. Autoimmune thyroiditis (AIT) is a common organ-specific autoimmune disease with no available effective drug treatment. In this study, we investigated effects of DHA on AIT in vitro and in vivo. Results showed that DHA can visibly reduce antithyroglobulin antibody and thyroid peroxidase antibody levels and regulate T helper cells (Th) 1/Th2 imbalance of experimental AIT mice. DHA also dose-dependently suppressed proliferation of lymphocytes induced by lipopolysaccharide and concanavalin A. DHA inhibited binding of C-X-C chemokine ligand 10 (CXCL10) and its receptor (C-X-C motif) receptor 3 (CXCR3), thus inhibiting calcium flow. DHA can also reduce expression levels of PI3-kinase (PI3K), p-PI3K, protein kinase B (AKT), p-AKT, nuclear factor (NF)-?B/p65, and p-NF-?B/p65. In conclusion, DHA may serve as treatment drug for AIT by inhibiting the CXCR3/PI3K/AKT/NF-kB signaling pathway.
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