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European Journal of Pharmacology Jun 2024Cancer often involves the overactivation of RAS/RAF/MEK/ERK (MAPK) and PI3K-Akt-mTOR pathways due to mutations in genes like RAS, RAF, PTEN, and PIK3CA. Various... (Review)
Review
Cancer often involves the overactivation of RAS/RAF/MEK/ERK (MAPK) and PI3K-Akt-mTOR pathways due to mutations in genes like RAS, RAF, PTEN, and PIK3CA. Various strategies are employed to address the overactivation of these pathways, among which targeted therapy emerges as a promising approach. Directly targeting specific proteins, leads to encouraging results in cancer treatment. For instance, RTK inhibitors such as imatinib and afatinib selectively target these receptors, hindering ligand binding and reducing signaling initiation. These inhibitors have shown potent efficacy against Non-Small Cell Lung Cancer. Other inhibitors, like lonafarnib targeting Farnesyltransferase and GGTI 2418 targeting geranylgeranyl Transferase, disrupt post-translational modifications of proteins. Additionally, inhibition of proteins like SOS, SH2 domain, and Ras demonstrate promising anti-tumor activity both in vivo and in vitro. Targeting downstream components with RAF inhibitors such as vemurafenib, dabrafenib, and sorafenib, along with MEK inhibitors like trametinib and binimetinib, has shown promising outcomes in treating cancers with BRAF-V600E mutations, including myeloma, colorectal, and thyroid cancers. Furthermore, inhibitors of PI3K (e.g., apitolisib, copanlisib), AKT (e.g., ipatasertib, perifosine), and mTOR (e.g., sirolimus, temsirolimus) exhibit promising efficacy against various cancers such as Invasive Breast Cancer, Lymphoma, Neoplasms, and hematological malignancies. This review offers an overview of small molecule inhibitors targeting specific proteins within the RAS upstream and downstream signaling pathways in cancer.
PubMed: 38866361
DOI: 10.1016/j.ejphar.2024.176727 -
Inflammopharmacology May 2024Inflammatory bowel diseases (IBDs) are prevalent and debilitating diseases with limited clinical treatment strategies. Mesenchymal stem cell (MSCs) are pluripotent stem...
Inflammatory bowel diseases (IBDs) are prevalent and debilitating diseases with limited clinical treatment strategies. Mesenchymal stem cell (MSCs) are pluripotent stem cells with self-renewal capability and multiple immunomodulatory effects, which make them a promising therapeutic approach for IBDs. Thus, optimization of MSCs regimes is crucial for their further clinical application. Wogonin, a flavonoid-like compound with extensive immunomodulatory and adjuvant effects, has been investigated as a potential pretreatment for MSCs in IBD treatment. In this study, we employed the DSS-induced acute colitis mouse model to compare the therapeutic effectiveness of MSCs in pretreated with or without wogonin and further explore the underlying mechanism. Compared to untreated MSCs, MSC (pretreated with wogonin) showed greater effectiveness in the treatment of colitis. Further experiments revealed that wogonin treatment activated the AKT signaling pathway, resulting in higher cellular glycolysis. Inhibition of AKT phosphorylation by perifosine not only decreased glycolysis but impaired the therapeutic efficiency of MSC. Consistent with these results, qPCR data indicated that wogonin treatment induced the expression of immunomodulatory molecules IL-10, IDO, and AGR1, which were reduced by perifosine. Together, our data demonstrated that wogonin preconditioning strategy further augmented the therapeutic efficacy of MSCs via promoting glycolysis, which should be a promising strategy for optimizing MSCs therapy in IBDs.
PubMed: 38753221
DOI: 10.1007/s10787-024-01491-2 -
Cytotechnology Feb 2024Blocking the CXCL12/CXCR4 axis can alter the biological functions of leukaemia cells. We hypothesise that interleukin (IL)-8 and IL-6 play an important role in this...
Blocking the CXCL12/CXCR4 axis can alter the biological functions of leukaemia cells. We hypothesise that interleukin (IL)-8 and IL-6 play an important role in this process. To test this hypothesis, we established a co-culture model of leukaemia cells and bone marrow stromal cells. Treatment of cells with AMD3100, a CXCR4 antagonist, and G-CSF blocked the CXCL12/CXCR4 axis, inducing biological changes in the leukaemia cells and altering IL-8 and IL-6 levels. Subsequently, after stimulating the CXCL12/CXCR4 axis, specific pathway blockers were employed to assess the role of four candidate signalling pathways in this process. ELISA results confirmed that MG-132 (10 μm) inhibits IL-8 expression and that the NF-κB signalling pathway contributes to this effect. Moreover, treatment with Perifosine, an AKT inhibitor, inhibited IL-6 expression. In addition, changes in the NF-κB signalling pathway inhibited IL-8 expression. Treatment with SP600125, a Jun N-terminal kinase inhibitor, and Perifosine also inhibited IL-8 expression; however, this effect occurred later. IL-6 expression was also lower in the Perifosine group; hence, inhibiting the PI3K/AKT signalling pathway can reduce IL-6 expression. This process requires the participation of multiple signalling pathways to regulate IL-8 and IL-6 expression. Therefore, the associated mechanism is likely to be highly intricate, with potential cross-effects that may impact leukaemia pathogenesis. IL-6 and IL-8 are physiologically regulated by the CXCL12/CXCR4 axis, while the NF-κB and JNK/AP-1 pathways are required for IL-8 expression in T-cell acute lymphoblastic leukaemia. Accordingly, by upregulating IL-8, the bone marrow microenvironment and CXCL12/CXCR4 axis may contribute to T-cell acute lymphoblastic leukaemia pathogenesis.
PubMed: 38304623
DOI: 10.1007/s10616-023-00600-3 -
International Journal of Biological... Mar 2024Rehmannia glutinosa polysaccharide (RGP) has been reported to exhibit anti-anxiety effects, yet the underlying mechanism remains unclear. Chronic constant light (CCL)...
Neuroprotective effects of Rehmannia glutinosa polysaccharide on chronic constant light (CCL)-induced oxidative stress and autophagic cell death via the AKT/mTOR pathway in mouse hippocampus and HT-22 cells.
Rehmannia glutinosa polysaccharide (RGP) has been reported to exhibit anti-anxiety effects, yet the underlying mechanism remains unclear. Chronic constant light (CCL) induced cognitive dysfunction associated with oxidative stress in mice has been reported. Here, the neuroprotective effect of RGP on hippocampal neuron damage in CCL-treated mice was investigated. In vivo study, mice were subjected to CCL for 4 weeks and/or oral administration of 100, 200 and 400 mg/kg RGP every other day. In vitro experiment, hippocampal neuron cells (HT-22) was exposed to LED light and/or supplemented with 62.5, 125 and 250 μg/mL RGP. Mice exposed to CCL showed impaired cognitive and depressive-like behavior in the hippocampus, which were reversed by RGP. Meanwhile, RGP reversed light-induced oxidative stress and autophagy both in mice and hippocampal neuron cells (HT-22). Furthermore, compared with Light-exposed group, RGP treatment activated the AKT/mTOR pathway. Importantly, the AKT inhibitor Perifosine significantly weakened the neuroprotective of RGP on Light-induced oxidative stress and autophagy in HT-22 cells by inhibiting AKT/mTOR pathway and increasing the content of autophagy-related protein. Our data demonstrated, for the first time, that oxidative stress and the AKT/mTOR pathway plays a critical role in Light-induced apoptosis and autophagic cell death in mice and HT-22 cells.
Topics: Animals; Mice; Proto-Oncogene Proteins c-akt; Rehmannia; Neuroprotective Agents; Autophagic Cell Death; Polysaccharides; TOR Serine-Threonine Kinases; Oxidative Stress; Autophagy; Hippocampus
PubMed: 38286367
DOI: 10.1016/j.ijbiomac.2024.129813 -
Particle and Fibre Toxicology Jan 2024As the demand and application of engineered nanomaterials have increased, their potential toxicity to the central nervous system has drawn increasing attention....
BACKGROUND
As the demand and application of engineered nanomaterials have increased, their potential toxicity to the central nervous system has drawn increasing attention. Tunneling nanotubes (TNTs) are novel cell-cell communication that plays a crucial role in pathology and physiology. However, the relationship between TNTs and nanomaterials neurotoxicity remains unclear. Here, three types of commonly used engineered nanomaterials, namely cobalt nanoparticles (CoNPs), titanium dioxide nanoparticles (TiONPs), and multi-walled carbon nanotubes (MWCNTs), were selected to address this limitation.
RESULTS
After the complete characterization of the nanomaterials, the induction of TNTs formation with all of the nanomaterials was observed using high-content screening system and confocal microscopy in both primary astrocytes and U251 cells. It was further revealed that TNT formation protected against nanomaterial-induced neurotoxicity due to cell apoptosis and disrupted ATP production. We then determined the mechanism underlying the protective role of TNTs. Since oxidative stress is a common mechanism in nanotoxicity, we first observed a significant increase in total and mitochondrial reactive oxygen species (namely ROS, mtROS), causing mitochondrial damage. Moreover, pretreatment of U251 cells with either the ROS scavenger N-acetylcysteine or the mtROS scavenger mitoquinone attenuated nanomaterial-induced neurotoxicity and TNTs generation, suggesting a central role of ROS in nanomaterials-induced TNTs formation. Furthermore, a vigorous downstream pathway of ROS, the PI3K/AKT/mTOR pathway, was found to be actively involved in nanomaterials-promoted TNTs development, which was abolished by LY294002, Perifosine and Rapamycin, inhibitors of PI3K, AKT, and mTOR, respectively. Finally, western blot analysis demonstrated that ROS and mtROS scavengers suppressed the PI3K/AKT/mTOR pathway, which abrogated TNTs formation.
CONCLUSION
Despite their biophysical properties, various types of nanomaterials promote TNTs formation and mitochondrial transfer, preventing cell apoptosis and disrupting ATP production induced by nanomaterials. ROS/mtROS and the activation of the downstream PI3K/AKT/mTOR pathway are common mechanisms to regulate TNTs formation and mitochondrial transfer. Our study reveals that engineered nanomaterials share the same molecular mechanism of TNTs formation and intercellular mitochondrial transfer, and the proposed adverse outcome pathway contributes to a better understanding of the intercellular protection mechanism against nanomaterials-induced neurotoxicity.
Topics: Proto-Oncogene Proteins c-akt; Reactive Oxygen Species; Phosphatidylinositol 3-Kinases; Nanotubes, Carbon; TOR Serine-Threonine Kinases; Neuroglia; Adenosine Triphosphate; Apoptosis; Cell Membrane Structures; Nanotubes
PubMed: 38225661
DOI: 10.1186/s12989-024-00562-0 -
Biology Nov 2023Alkylphospholipids (APLs) have been studied as anticancer drugs that interfere with biological membranes without targeting DNA. Although their mechanism of action is not...
Alkylphospholipids (APLs) have been studied as anticancer drugs that interfere with biological membranes without targeting DNA. Although their mechanism of action is not fully elucidated yet, it is known that they disrupt the intracellular trafficking of cholesterol and its metabolism. Here, we analyzed whether APLs could also interfere with mitochondrial function. For this purpose, we used HT29 colorectal cancer cells, derived from a primary tumor, and SW620 colorectal cancer cells, derived from a metastasis site. After treatment with the APLs miltefosine and perifosine, we analyzed various mitochondrial parameters, including mitochondrial mass, cardiolipin content, mitochondrial membrane potential, HO production, the levels of oxidative phosphorylation (OXPHOS) complexes, metabolic enzymes activity, the oxygen consumption rate, and the levels of apoptosis and autophagy markers. APLs, especially perifosine, increased mitochondrial mass while OXPHOS complexes levels were decreased without affecting the total oxygen consumption rate. Additionally, we observed an increase in pyruvate dehydrogenase (PDH) and isocitrate dehydrogenase (IDH) levels and a decrease in lactate dehydrogenase (LDH) activity, suggesting a metabolic rewiring induced by perifosine. These alterations led to higher mitochondrial membrane potential, which was potentiated by decreased uncoupling protein 2 (UCP2) levels and increased reactive oxygen species (ROS) production. Consequently, perifosine induced an imbalance in mitochondrial function, resulting in higher ROS production that ultimately impacted cellular viability.
PubMed: 38132283
DOI: 10.3390/biology12121457 -
Molecular Psychiatry Nov 2023PTEN germline mutations account for ~0.2-1% of all autism spectrum disorder (ASD) cases, as well as ~17% of ASD patients with macrocephaly, making it one of the top...
PTEN germline mutations account for ~0.2-1% of all autism spectrum disorder (ASD) cases, as well as ~17% of ASD patients with macrocephaly, making it one of the top ASD-associated risk genes. Individuals with germline PTEN mutations receive the molecular diagnosis of PTEN Hamartoma Tumor Syndrome (PHTS), an inherited cancer predisposition syndrome, about 20-23% of whom are diagnosed with ASD. We generated forebrain organoid cultures from gene-edited isogenic human induced pluripotent stem cells (hiPSCs) harboring a PTEN (ASD) or PTEN (cancer) mutant allele to model how these mutations interrupt neurodevelopmental processes. Here, we show that the PTEN allele disrupts early neuroectoderm formation during the first several days of organoid generation, and results in deficient electrophysiology. While organoids generated from PTEN hiPSCs remained morphologically similar to wild-type organoids during this early stage in development, we observed disrupted neuronal differentiation, radial glia positioning, and cortical layering in both PTEN-mutant organoids at the later stage of 72+ days of development. Perifosine, an AKT inhibitor, reduced over-activated AKT and partially corrected the abnormalities in cellular organization observed in PTEN organoids. Single cell RNAseq analyses on early-stage organoids revealed that genes related to neural cell fate were decreased in PTEN mutant organoids, and AKT inhibition was capable of upregulating gene signatures related to neuronal cell fate and CNS maturation pathways. These findings demonstrate that different PTEN missense mutations can have a profound impact on neurodevelopment at diverse stages which in turn may predispose PHTS individuals to ASD. Further study will shed light on ways to mitigate pathological impact of PTEN mutants on neurodevelopment by stage-specific manipulation of downstream PTEN signaling components.
PubMed: 38030818
DOI: 10.1038/s41380-023-02325-3 -
Acta Pharmaceutica Sinica. B Oct 2023It is discovered that activated caspase-3 tends to induce apoptosis in gasdermin E (GSDME)-deficient cells, but pyroptosis in GSDME-sufficient cells. The high GSDME...
It is discovered that activated caspase-3 tends to induce apoptosis in gasdermin E (GSDME)-deficient cells, but pyroptosis in GSDME-sufficient cells. The high GSDME expression and apoptosis resistance of pancreatic ductal adenocarcinoma (PDAC) cells shed light on another attractive strategy for PDAC treatment by promoting pyroptosis. Here we report a hGLuc-hGSDME-PCA system for high-throughput screening of potential GSDME activators against PDAC. This screening system neatly quantifies the oligomerization of GSDME-N to characterize whether pyroptosis occurs under the stimulation of chemotherapy drugs. Based on this system, ponatinib and perifosine are screened out from the FDA-approved anti-cancer drug library containing 106 compounds. Concretely, they exhibit the most potent luminescent activity and cause drastic pyroptosis in PDAC cells. Further, we demonstrate that perifosine suppresses pancreatic cancer by promoting pyroptosis caspase-3/GSDME pathway both and . Collectively, this study reveals the great significance of hGLuc-hGSDME-PCA in identifying compounds triggering GSDME-dependent pyroptosis and developing promising therapeutic agents for PDAC.
PubMed: 37799380
DOI: 10.1016/j.apsb.2023.07.018 -
ACS Omega Aug 2023Non-small cell lung carcinoma (NSCLC) is the most common cancer globally. Phytochemicals and small molecule inhibitors significantly prevent varying types of cancers,... (Review)
Review
Non-small cell lung carcinoma (NSCLC) is the most common cancer globally. Phytochemicals and small molecule inhibitors significantly prevent varying types of cancers, including NSCLC. These therapeutic molecules serve as important sources for new drugs that interfere with cellular proliferation, apoptosis, metastasis, and angiogenesis by regulating signaling pathways. These molecules affect several cellular signaling cascades, including p53, NF-κB, STAT3, RAS, MAPK/ERK, Wnt, and AKT/PI3K, and are thus implicated in the therapeutic management of cancers. This review aims to describe the bioactive compounds and small-molecule inhibitors, their anticancer action, and targeting cellular signaling cascades in NSCLC. We highlighted the therapeutic potential of Epigallocatechin gallate (EGCG), Perifosine, ABT-737, Thymoquinine, Quercetin, Venetoclax, Gefitinib, and Genistein. These compounds are implicated in the therapeutic management of NSCLC. This review further offers deeper mechanistic insights into different signaling pathways that could be targeted for NSCLC therapy by phytochemicals and small-molecule inhibitors.
PubMed: 37546685
DOI: 10.1021/acsomega.3c02424 -
Einstein (Sao Paulo, Brazil) 2023To determine the role of the AKT pathway in the regulating of natural Killer-induced apoptosis of acute myeloid leukemia cells and to characterize the associated...
OBJECTIVE
To determine the role of the AKT pathway in the regulating of natural Killer-induced apoptosis of acute myeloid leukemia cells and to characterize the associated molecular mechanisms.
METHODS
BALB/c nude mice were injected with HL60 cells to induce a xenogenic model of subcutaneous leukemic tumors. Mice were treated with perifosine, and their spleens were analyzed using biometry, histopathology, and immunohistochemistry. Gene expression analysis in leukemia cells was performed by real-time PCR. Protein analysis of leukemia and natural Killer cells was performed by flow cytometry. AKT inhibition in HL60 cells, followed by co-culture with natural Killer cells was performed to assess cytotoxicity. Apoptosis rate was quantified using flow cytometry.
RESULTS
Perifosine treatment caused a reduction in leukemic infiltration in the spleens of BALB/c nude mice. In vitro , AKT inhibition reduced HL60 resistance to natural Killer-induced apoptosis. AKT inhibition suppressed the immune checkpoint proteins PD-L1, galectin-9, and CD122 in HL60 cells, but did not change the expression of their co-receptors PD1, Tim3, and CD96 on the natural Killer cell surface. In addition, the death receptors DR4, TNFR1, and FAS were overexpressed by AKT inhibition, thus increasing the susceptibility of HL60 cells to the extrinsic pathway of apoptosis.
CONCLUSION
The AKT pathway is involved in resistance to natural Killer-induced apoptosis in HL60 cells by regulating the expression of immune suppressor receptors. These findings highlight the importance of AKT in contributing to immune evasion mechanisms in acute myeloid leukemia and suggests the potential of AKT inhibition as an adjunct to immunotherapy.
Topics: Animals; Mice; Humans; Immune Checkpoint Proteins; HL-60 Cells; Mice, Nude; Proto-Oncogene Proteins c-akt; Leukemia, Myeloid, Acute
PubMed: 37341216
DOI: 10.31744/einstein_journal/2023AO0171