Displaying publications 21 - 40 of 113 in total

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  1. Autophagy and GLUT4: The missing pieces
    Elhassan SAM, Candasamy M, Chan EWL, Bhattamisra SK
    Diabetes Metab Syndr, 2018 Nov;12(6):1109-1116.
    PMID: 29843994 DOI: 10.1016/j.dsx.2018.05.020
    BACKGROUND: Autophagy is a process devoted to degrade and recycle cellular components inside mammalian cells through lysosomal system. It plays a main function in the pathophysiology of several diseases. In type 2 diabetes, works demonstrated the dual functions of autophagy in diabetes biology. Studies had approved the role of autophagy in promoting different routes for movement of integral membrane proteins to the plasma membrane. But its role in regulation of GLUT4 trafficking has not been widely observed. In normal conditions, insulin promotes GLUT4 translocation from intracellular membrane compartments to the plasma membrane, while in type 2 diabetes defects occur in this translocation.

    METHOD: Intriguing evidences discussed the contribution of different intracellular compartments in autophagy membrane formation. Furthermore, autophagy serves to mobilise membranes within cells, thereby promoting cytoplasmic components reorganisation. The intent of this review is to focus on the possibility of autophagy to act as a carrier for GLUT4 through regulating GLUT4 endocytosis, intracellular trafficking in different compartments, and translocation to cell membrane.

    RESULTS: The common themes of autophagy and GLUT4 have been highlighted. The review discussed the overlapping of endocytosis mechanism and intracellular compartments, and has shown that autophagy and GLUT4 utilise similar proteins (SNAREs) which are used for exocytosis. On top of that, PI3K and AMPK also control both autophagy and GLUT4.

    CONCLUSION: The control of GLUT4 trafficking through autophagy could be a promising field for treating type 2 diabetes.

    Matched MeSH terms: Phosphatidylinositol 3-Kinases/metabolism
  2. Fisetin induces apoptosis in breast cancer MDA-MB-453 cells through degradation of HER2/neu and via the PI3K/Akt pathway
    Guo G, Zhang W, Dang M, Yan M, Chen Z
    J Biochem Mol Toxicol, 2019 Apr;33(4):e22268.
    PMID: 30431692 DOI: 10.1002/jbt.22268
    Overexpression of human epidermal growth factor receptor 2 (HER2) is observed in breast cancer. The major snag faced by the human population is the development of chemoresistance to HER2 inhibitors by advanced stage breast cancer cells. Moreover, recent researchers focussed on fisetin as an antiproliferative and chemotherapeutic agent. Therefore, this study was intended to analyze the effects of fisetin on HER2/neu-overexpressing breast cancer cell lines. Our results depicted that fisetin induced apoptosis of these cells by various mechanisms, such as inactivation of the receptor, induction of proteasomal degradation, decreasing its half-life, decreasing enolase phosphorylation, and alteration of phosphatidylinositol 3-kinase/Akt signaling.
    Matched MeSH terms: Phosphatidylinositol 3-Kinases/metabolism*
  3. Fulltext The role of autophagy-related proteins in the pathogenesis of neuromyelitis optica spectrum disorders
    Guo HL, Shen XR, Liang XT, Li LZ
    Bioengineered, 2022 Jun;13(6):14329-14338.
    PMID: 36694421 DOI: 10.1080/21655979.2022.2084273
    This study aimed to investigate the expression of autophagy-related proteins in a mouse model of neuromyelitis optica (NMO). Mice were assigned to one of four groups: an animal experimental model group (NMO-EAE group, given with exogenous IL-17A), Interleukin-17 monoclonal antibody intervention group (NMO-EAE_0IL17inb), No exogenous interleukin-17 enhanced immune intervention group (NMO-EAE_0IL17), and a control group. Behavioral scores were assessed in each group, and the protein expressions of sequestosome 1 (P62), Beclin-1, the mammalian target of rapamycin (mTOR), phosphoinositide 3-kinase (PI3K-I), and LC3II/LC3I were detected using Western blotting. In the NMO-EAE_0IL17 group, the expression of Beclin-1 decreased, the LC3II/LC3I ratio was lower, and the expressions of P62, mTOR, and PI3K-I increased; after administration of IL-17A inhibitor into the brain tissue, however, the expression of Beclin-1 increased significantly, along with the LC3II/LC3I ratio, while the expressions of P62, mTOR and PI3K-I protein decreased significantly. In terms of behavioral scores, the scores of optic neuritis and myelitis were more serious, onset occurred earlier and the progress was faster, after the administration of IL-17A. In the mechanism of NMO animal model, IL-17A may regulate autophagy and affect the disease process through the activation of the PI3K-mTOR signaling pathway.
    Matched MeSH terms: Phosphatidylinositol 3-Kinases/metabolism
  4. New emerging targets in osteosarcoma therapy: PTEN and PI3K/Akt crosstalk in carcinogenesis
    Sadrkhanloo M, Paskeh MDA, Hashemi M, Raesi R, Bahonar A, Nakhaee Z, et al.
    Pathol Res Pract, 2023 Nov;251:154902.
    PMID: 37922723 DOI: 10.1016/j.prp.2023.154902
    Osteosarcoma (OS) is a malignant bone carcinoma that affects people in childhood and adulthood. The heterogeneous nature and chromosomal instability represent certain characteristics of OS cells. These cancer cells grow and migrate abnormally, making the prognosis undesirable for patients. Conventional and current treatments fail to completely eradicate tumor cells, so new therapeutics targeting genes may be considered. PI3K/Akt is a regulator of events such as growth, cell death, migration, and differentiation, and its expression changes during cancer progression. PTEN reduces PI3K/Akt expression, and its mutations and depletions have been reported in various tumors. Experimental evidence shows that there is upregulation of PI3K/Akt and downregulation of PTEN in OS. Increasing PTEN expression may suppress PI3K/Akt to minimize tumorigenesis. In addition, PI3K/Akt shows a positive association with growth, metastasis, EMT and metabolism of OS cells and inhibits apoptosis. Importantly, overexpression of PI3K/Akt causes drug resistance and radio-resistance and its level can be modulated by miRNAs, lncRNAs and circRNAs. Silencing PI3K/Akt by compounds and drugs can suppress OS. Here, we review in detail the function of the PTEN/PI3K/Akt in OS, revealing its biological function, function in tumor progression, resistance to therapy, and pharmacological significance.
    Matched MeSH terms: Phosphatidylinositol 3-Kinases/metabolism
  5. Sodium alginate encapsulated iron oxide decorated with thymoquinone nanocomposite induces apoptosis in human breast cancer cells via PI3K-Akt-mTOR pathway
    Alzahrani B, Elderdery AY, Alsrhani A, Alzerwi NAN, Althobiti MM, Elkhalifa AME, et al.
    Int J Biol Macromol, 2023 Jul 31;244:125054.
    PMID: 37245766 DOI: 10.1016/j.ijbiomac.2023.125054
    The present study investigated the cytotoxicity and proapoptotic properties of iron oxide-sodium-alginate-thymoquinone nanocomposites against breast cancer MDA-MB-231 cells in vitro and in silico. This study used chemical synthesis to formulate the nanocomposite. Electron microscopies such as scanning (SEM) and transmission (TEM), Fourier transform infrared (FT-IR), Ultraviolet-Visible, Photoluminescence spectroscopy, selected area (electron) diffraction (SAED), energy dispersive X-ray analysis (EDX), and X-ray diffraction studies (XRD) were used to characterize the synthesized ISAT-NCs and the average size of them was found to be 55 nm. To evaluate the cytotoxic, antiproliferative, and apoptotic potentials of ISAT-NCs on MDA-MB-231 cells, MTT assays, FACS-based cell cycle studies, annexin-V-PI staining, ELISA, and qRT-PCR were used. PI3K-Akt-mTOR receptors and thymoquinone were predicted using in-silico docking studies. Cell proliferation is reduced in MDA-MB-231 cells due to ISAT-NC cytotoxicity. As a result of FACS analysis, ISAT-NCs had nuclear damage, ROS production, and elevated annexin-V levels, which resulted in cell cycle arrest in the S phase. The ISAT-NCs in MDA-MB-231 cells were found to downregulate PI3K-Akt-mTOR regulatory pathways in the presence of inhibitors of PI3K-Akt-mTOR, showing that these regulatory pathways are involved in apoptotic cell death. We also predicted the molecular interaction between thymoquinone and PI3K-Akt-mTOR receptor proteins using in-silico docking studies which also support PI3K-Akt-mTOR signaling inhibition by ISAT-NCs in MDA-MB-231 cells. As a result of this study, we can conclude that ISAT-NCs inhibit the PI3K-Akt-mTOR pathway in breast cancer cell lines, causing apoptotic cell death.
    Matched MeSH terms: Phosphatidylinositol 3-Kinases/metabolism
  6. Fulltext Deciphering the roles of aryl hydrocarbon receptor (AHR) in regulating carcinogenesis
    Chong ZX, Yong CY, Ong AHK, Yeap SK, Ho WY
    Toxicology, 2023 Aug 15;495:153596.
    PMID: 37480978 DOI: 10.1016/j.tox.2023.153596
    Aryl hydrocarbon receptor (AHR) is a ligand-dependent receptor that belongs to the superfamily of basic helix-loop-helix (bHLH) transcription factors. The activation of the canonical AHR signaling pathway is known to induce the expression of cytochrome P450 enzymes, facilitating the detoxification metabolism in the human body. Additionally, AHR could interact with various signaling pathways such as epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT3), hypoxia-inducible factor-1α (HIF-1α), nuclear factor ekappa B (NF-κβ), estrogen receptor (ER), and androgen receptor (AR) signaling pathways. Over the past 30 years, several studies have reported that various chemical, physical, or biological agents, such as tobacco, hydrocarbon compounds, industrial and agricultural chemical wastes, drugs, UV, viruses, and other toxins, could affect AHR expression or activity, promoting cancer development. Thus, it is valuable to overview how these factors regulate AHR-mediated carcinogenesis. Current findings have reported that many compounds could act as AHR ligands to drive the expressions of AHR-target genes, such as CYP1A1, CYP1B1, MMPs, and AXL, and other targets that exert a pro-proliferation or anti-apoptotic effect, like XIAP. Furthermore, some other physical and chemical agents, such as UV and 3-methylcholanthrene, could promote AHR signaling activities, increasing the signaling activities of a few oncogenic pathways, such as the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathways. Understanding how various factors regulate AHR-mediated carcinogenesis processes helps clinicians and scientists plan personalized therapeutic strategies to improve anti-cancer treatment efficacy. As many studies that have reported the roles of AHR in regulating carcinogenesis are preclinical or observational clinical studies that did not explore the detailed mechanisms of how different chemical, physical, or biological agents promote AHR-mediated carcinogenesis processes, future studies should focus on conducting large-scale and functional studies to unravel the underlying mechanism of how AHR interacts with different factors in regulating carcinogenesis processes.
    Matched MeSH terms: Phosphatidylinositol 3-Kinases*
  7. Fulltext NKX3.1 Expression and Molecular Characterization of Secretory Myoepithelial Carcinoma (SMCA): Advancing the Case for a Salivary Mucous Acinar Phenotype
    Patel S, Wald AI, Bastaki JM, Chiosea SI, Singhi AD, Seethala RR
    Head Neck Pathol, 2023 Jun;17(2):467-478.
    PMID: 36746884 DOI: 10.1007/s12105-023-01524-2
    BACKGROUND: Secretory myoepithelial carcinomas (SMCA) are rare, mucinous, signet ring predominant tumors with primitive myoepithelial features. While many mucinous salivary gland tumors have now been molecularly characterized, key drivers in SMCA have yet to be elucidated. Recently, NKX3.1, a homeodomain transcription factor implicated in salivary mucous acinar development was also shown in a subset of salivary mucinous neoplasms, salivary intraductal papillary mucinous neoplasms (SG-IPMN). To date, NKX3.1 expression has not been characterized in other mucinous salivary lesions. Here, we report molecular and extended immunophenotypic findings in SMCA and NKX3.1 expression in the context of other head and neck lesions.

    METHODS: We retrieved 4 previously reported SMCA, performed additional immunohistochemical and targeted next-generation sequencing (NGS). We also investigated the use of NKX3.1 as a marker for SMCA in the context of its prevalence and extent (using H-score) in a mixed cohort of retrospectively and prospectively tested head and neck lesions (n = 223) and non-neoplastic tissues (n = 66).

    RESULTS: NKX3.1 positivity was confirmed in normal mucous acini as well as in mucous acinar class of lesions (5/6, mean H-score: 136.7), including mucinous adenocarcinomas (3/4), SG-IPMN (1/1), and microsecretory adenocarcinoma (MSA) (1/1). All SMCA were positive. Fluorescence in situ hybridization for SS18 rearrangements were negative in all successfully tested cases (0/3). NGS was successful in two cases (cases 3 and 4). Case 3 demonstrated a PTEN c.655C>T p.Q219* mutation and a SEC16A::NOTCH1 fusion while case 4 (clinically aggressive) showed a PTEN c.1026+1G>A p.K342 splice site variant, aTP53 c.524G>A p.R175H mutation and a higher tumor mutation burden (29 per Mb). PTEN immunohistochemical loss was confirmed in both cases and a subset of tumor cells showed strong (extreme) staining for P53 in Case 4.

    CONCLUSION: Despite a partial myoepithelial phenotype, SMCA, along with mucinous adenocarcinomas/SG-IPMN and MSA, provisionally constitute a mucous acinar class of tumors based on morphology and NKX3.1 expression. Like salivary mucinous adenocarcinomas/SG-IPMN, SMCA also show alterations of the PTEN/PI3K/AKT pathway and may show progressive molecular alterations. We document the first extramammary tumor with a SEC16A::NOTCH1 fusion.

    Matched MeSH terms: Phosphatidylinositol 3-Kinases/genetics
  8. The impact of leptin on sperm
    Almabhouh FA, Singh HJ
    Reprod Fertil Dev, 2023 May;35(8):459-468.
    PMID: 37196661 DOI: 10.1071/RD22222
    Despite its important role in numerous physiological functions, including regulation of appetite and body weight, immune function and normal sexual maturation, raised leptin levels could result in significant damaging effects on sperm. The adverse effects of leptin on the male reproductive system result from its direct actions on the reproductive organs and cells instead of the hypothalamus-pituitary-gonadal axis. Binding of leptin to the receptors in the seminiferous tubular cells of the testes increases free radical production and decreases the gene expression and activity of endogenous enzymatic antioxidants. These effects are mediated via the PI3K pathway. The resultant oxidative stress causes significant damage to the seminiferous tubular cells, germ cells and sperm DNA leading to apoptosis, increased sperm DNA fragmentation, decreased sperm count, increased fraction of sperm with abnormal morphology, and decreased seminiferous tubular height and diameter. This review summarises the evidence in the literature on the adverse effects of leptin on sperm, which could underlie the often-reported sperm abnormalities in obese hyperleptinaemic infertile males. Although leptin is necessary for normal reproductive function, its raised levels could be pathologic. There is, therefore, a need to identify the cut-off level in the serum and seminal fluid above which leptin becomes pathological for better management of leptin associated adverse effects on male reproductive function.
    Matched MeSH terms: Phosphatidylinositol 3-Kinases/metabolism
  9. The mTOR signalling pathway in cancer and the potential mTOR inhibitory activities of natural phytochemicals
    Tan HK, Moad AI, Tan ML
    Asian Pac J Cancer Prev, 2014;15(16):6463-75.
    PMID: 25169472
    The mammalian target of rapamycin (mTOR) kinase plays an important role in regulating cell growth and cell cycle progression in response to cellular signals. It is a key regulator of cell proliferation and many upstream activators and downstream effectors of mTOR are known to be deregulated in various types of cancers. Since the mTOR signalling pathway is commonly activated in human cancers, many researchers are actively developing inhibitors that target key components in the pathway and some of these drugs are already on the market. Numerous preclinical investigations have also suggested that some herbs and natural phytochemicals, such as curcumin, resveratrol, timosaponin III, gallic acid, diosgenin, pomegranate, epigallocatechin gallate (EGCC), genistein and 3,3'-diindolylmethane inhibit the mTOR pathway either directly or indirectly. Some of these natural compounds are also in the clinical trial stage. In this review, the potential anti-cancer and chemopreventive activities and the current status of clinical trials of these phytochemicals are discussed.
    Matched MeSH terms: Phosphatidylinositol 3-Kinases/antagonists & inhibitors; Phosphatidylinositol 3-Kinases/metabolism
  10. Increased Expression of Phosphatidylinositol 3-Kinase p110α and Gene Amplification of PIK3CA in Nasopharyngeal Carcinoma
    Yip WK, He PY, Abdullah MA, Yusoff S, Seow HF
    Pathol Oncol Res, 2016 Apr;22(2):413-9.
    PMID: 26581613 DOI: 10.1007/s12253-015-0007-8
    Molecular alterations in PIK3CA oncogene that encodes the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K p110α) are commonly found in human cancers. In this study, we examined the expression of PI3K p110α and PIK3CA gene amplification in 74 nasopharyngeal carcinoma (NPC) cases. Immunohistochemical staining demonstrated overexpression of PI3K p110α protein in 44.6% (33/74) of NPCs and 4.8% (2/42) of the adjacent normal nasopharyngeal mucosa. Copy number of PIK3CA gene was successfully analyzed in 51 of the total NPC cases and 19 non-malignant nasopharynx tissues by quantitative real-time PCR. Using mean + 2(standard deviation) of copy numbers in the non-malignant nasopharynx tissues as a cutoff value, PIK3CA copy number gain was found in 10 of 51 (19.6%) NPC cases. High PI3K p110α expression level was correlated with increased PIK3CA copy number (Spearman's rho =0.324, P = 0.02). PI3K p110α expression and PIK3CA copy number did not associate with Akt phosphorylation, and patient and tumor variables. This study suggests that PI3K p110α overexpression, which is attributed, at least in part, to PIK3CA gene amplification, may contribute to NPC pathogenesis. However, these molecular aberrations may not be responsible for activation of Akt signaling in NPC.
    Matched MeSH terms: Phosphatidylinositol 3-Kinases/genetics*; Phosphatidylinositol 3-Kinases/metabolism*
  11. LY294002, a PI3K pathway inhibitor, prevents leptin-induced adverse effects on spermatozoa in Sprague-Dawley rats
    Md Mokhtar AH, Malik IA, Abd Aziz NAA, Almabhouh FA, Durairajanayagam D, Singh HJ
    Andrologia, 2019 Apr;51(3):e13196.
    PMID: 30456785 DOI: 10.1111/and.13196
    This study examined the effects of PI3K and AMPK signalling pathway inhibitors on leptin-induced adverse effects on rat spermatozoa. Sprague-Dawley rats, aged 14-16 weeks, were randomised into control, leptin-, leptin + dorsomorphin (AMPK inhibitor)-, and leptin+LY294002 (PI3K inhibitor)-treated groups with six rats per group. Leptin was given once daily for 14 days via the intraperitoneal (i.p.) route at a dose of 60 ug kg-1 body weight. Rats in the leptin and inhibitor-treated groups received concurrently either dorsomorphin (5 mg kg-1  day-1 ) or LY294002 (1.2 mg kg-1  day-1 ) i.p. for 14 days. Controls received 0.1 ml of normal saline. Upon completion, sperm count, sperm morphology, seminiferous tubular epithelial height (STEH), seminiferous tubular diameter (STD), 8-hydroxy-2-deoxyguanosine (8-OHdG) and phospho-Akt/total Akt ratio were estimated. Data were analysed using ANOVA. Sperm count, STEH and STD were significantly lower, while the percentage of spermatozoa with abnormal morphology and the level of 8-OHdG were significantly higher in rats treated with leptin and leptin + dorsomorphin when compared to those in controls and LY294002-treated rats. Testicular phospho-Akt/total Akt ratio was significantly higher in leptin and leptin + LY294002-treated rats. In conclusion, LY294002 prevents leptin-induced changes in rat sperm parameters, suggesting the potential role of the PI3K signalling pathway in the adverse effects of leptin on sperm parameters.
    Matched MeSH terms: Phosphatidylinositol 3-Kinases/antagonists & inhibitors*; Phosphatidylinositol 3-Kinases/metabolism
  12. Fulltext Upregulation of Phosphatidylinositol 3-Kinase (PI3K) Enhances Ethylene Biosynthesis and Accelerates Flower Senescence in Transgenic Nicotiana tabacum L
    Dek MSP, Padmanabhan P, Sherif S, Subramanian J, Paliyath AG
    Int J Mol Sci, 2017 Jul 15;18(7).
    PMID: 28714880 DOI: 10.3390/ijms18071533
    Phosphatidylinositol 3-kinase (PI3K) is a key enzyme that phosphorylates phosphatidylinositol at 3'-hydroxyl position of the inositol head group initiating the generation of several phosphorylated phosphatidylinositols, collectively referred to as phosphoinositides. The function of PI3K in plant senescence and ethylene signal transduction process was studied by expression ofSolanum lycopersicumPI3K in transgenicNicotiana tabacum, and delineating its effect on flower senescence. Detached flowers of transgenic tobacco plants with overexpressedSl-PI3K(OX) displayed accelerated senescence and reduced longevity, when compared to the flowers of wild type plants. Flowers from PI3K-overexpressing plants showed enhanced ethylene production and upregulated expression of 1-aminocyclopropane-1-carboxylic acid oxidase 1 (ACO1). Real time polymerase chain reaction (PCR) analysis showed thatPI3Kwas expressed at a higher level in OX flowers than in the control. Seedlings of OX-lines also demonstrated a triple response phenotype with characteristic exaggerated apical hook, shorter hypocotyls and increased sensitivity to 1-aminocyclopropane-1-carboxylate than the control wild type seedlings. In floral tissue from OX-lines,Solanum lycopersicumphosphatidylinositol 3-kinase green fluorescent protein (PI3K-GFP) chimera protein was localized primarily in stomata, potentially in cytoplasm and membrane adjacent to stomatal pores in the guard cells. Immunoblot analysis of PI3K expression in OX lines demonstrated increased protein level compared to the control. Results of the present study suggest that PI3K plays a crucial role in senescence by enhancing ethylene biosynthesis and signaling.
    Matched MeSH terms: Phosphatidylinositol 3-Kinases/genetics*; Phosphatidylinositol 3-Kinases/metabolism
  13. Dual treatments targeting IGF-1R, PI3K, mTORC or MEK synergize to inhibit cell growth, induce apoptosis, and arrest cell cycle at G1 phase in MDA-MB-231 cell line
    Ayub A, Yip WK, Seow HF
    Biomed Pharmacother, 2015 Oct;75:40-50.
    PMID: 26463630 DOI: 10.1016/j.biopha.2015.08.031
    Triple-negative breast cancers (TNBCs) are aggressive cancers that do not benefit from hormonal therapy or therapies that target HER2 receptors. Insulin-like growth factor 1 receptor (IGF-1R), which has been shown to be overexpressed in breast cancer, activates numerous downstream kinases that associate with cell proliferation and survival. This study compared the effects caused by dual treatments targeting IGF-1R, PI3K, mTORC, or MEK with those by single treatments in a TNBC cell line, MDA-MB-231. We used small-molecule kinase inhibitors, namely, NVP-AEW541, NVP-BKM120, KU0063794, and PD0325901 to target IGF-1R, PI3K, mTORC, and MEK, respectively. Combination treatments of PD0325901 with NVP-AEW541, NVP-BKM120 or KU0063794 and NVP-AEW541 with KU0063794 demonstrated a significant synergistic growth inhibition. These dual treatments increased apoptosis and/or cell cycle arrest at G0/G1 phase and enhanced the inhibition of phosphorylation of Akt or downstream molecules of mTORC1, as compared to the single treatments. Our study suggests that targeting multiple kinases in IGF-1R signaling may be a promising therapeutic approach.
    Matched MeSH terms: Phosphatidylinositol 3-Kinases
  14. Prediction of colorectal cancer driver genes from patients’ genome data
    Muhammad-iqmal Abdullah, Nor Azlan Nor Muhammad
    Sains Malaysiana, 2018;47:3095-3105.
    Colorectal cancer refers to the cancer that occurs in the colon and rectum. It has been established as the third most
    common cancer and the forth one in causing worldwide mortality. Cancer caused by the mutation of several genes that
    usually involved in the regulation of cell proliferation, growth and cell death. The mutation that leads to abnormal
    function of genes, either in enabling the genes to gain or loss of function was termed as driver mutation and the genes
    with driver mutation ability was termed as driver genes. The identification of driver genes provides insight on mechanistic
    process of cancer development where this information can be used to further understand their mode of action for causing
    dysregulation in signaling pathways. In this study, two bioinformatic tools, i.e. CGI and iCAGES were used to predict
    potential driver genes from the genome of eight colorectal cancer patients with annotated variants datasets. 44 unique
    driver genes and 21 pathways have been identified; such as p53 signaling, PI3K-AKT, Endocrine resistance, MAPK and
    cell cycle pathways. The identification of these pathways can lead to the identification of potential drugs targeting these
    pathways.
    Matched MeSH terms: Phosphatidylinositol 3-Kinases
  15. Fulltext Inhibitors targeting CDK4/6, PARP and PI3K in breast cancer: a review
    Nur Husna SM, Tan HT, Mohamud R, Dyhl-Polk A, Wong KK
    Ther Adv Med Oncol, 2018;10:1758835918808509.
    PMID: 30542378 DOI: 10.1177/1758835918808509
    Breast cancer is the global leading cause of cancer-related death in women and it represents a major health burden worldwide. One of the promising breast cancer therapeutic avenues is through small molecule inhibitors (SMIs) which have undergone rapid progress with successful clinical trials. Recently, three emerging and vital groups of proteins are targeted by SMIs for breast cancer treatment, namely cyclin-dependent kinase 4 and 6 (CDK4/6), poly (adenosine diphosphate-ribose) polymerase (PARP) and phosphoinositide 3-kinase (PI3K). Several of these inhibitors have been approved for the treatment of breast cancer patients or progressed into late-stage clinical trials. Thus, modeling from these successful clinical trials, as well as their limitations, is pivotal for future development and trials of other inhibitors or therapeutic regimens targeting breast cancer patients. In this review, we discuss eight recently approved or novel SMIs against CDK4/6 (palbociclib, ribociclib and abemaciclib), PARP (olaparib, veliparib and talazoparib), and PI3K (buparlisib and alpelisib). The mechanisms of action, series of clinical trials and limitations are described for each inhibitor.
    Matched MeSH terms: Phosphatidylinositol 3-Kinases
  16. Therapeutic Potential of Albumin Nanoparticles Encapsulated Visnagin in MDA-MB-468 Triple-Negative Breast Cancer Cells
    Alsrhani A, Elderdery AY, Alzahrani B, Alzerwi NAN, Althobiti MM, Rayzah M, et al.
    Molecules, 2023 Apr 04;28(7).
    PMID: 37049991 DOI: 10.3390/molecules28073228
    Breast cancer is among the most recurrent malignancies, and its prevalence is rising. With only a few treatment options available, there is an immediate need to search for better alternatives. In this regard, nanotechnology has been applied to develop potential chemotherapeutic techniques, particularly for cancer therapy. Specifically, albumin-based nanoparticles are a developing platform for the administration of diverse chemotherapy drugs owing to their biocompatibility and non-toxicity. Visnagin, a naturally derived furanochromone, treats cancers, epilepsy, angina, coughs, and inflammatory illnesses. In the current study, the synthesis and characterization of albumin visnagin (AV) nanoparticles (NPs) using a variety of techniques such as transmission electron microscopy, UV-visible, Fourier transform infrared, energy dispersive X-ray composition analysis, field emission scanning electron microscopy, photoluminescence, X-Ray diffraction, and dynamic light scattering analyses have been carried out. The MTT test, dual AO/EB, DCFH-DA, Annexin-V-FITC/PI, Propidium iodide staining techniques as well as analysis of apoptotic proteins, antioxidant enzymes, and PI3K/Akt/mTOR signaling analysis was performed to examine the NPs' efficacy to suppress MDA-MB-468 cell lines. The NPs decreased cell viability increased the amount of ROS in the cells, disrupted membrane integrity, decreased the level of antioxidant enzymes, induced cell cycle arrest, and activated the PI3K/Akt/mTOR signaling cascade, ultimately leading to cell death. Thus, AV NPs possesses huge potential to be employed as a strong anticancer therapy alternative.
    Matched MeSH terms: Phosphatidylinositol 3-Kinases
  17. Molecular target therapeutics of EGF-TKI and downstream signaling pathways in non-small cell lung cancers
    Liu CY, Lin HF, Lai WY, Lin YY, Lin TW, Yang YP, et al.
    J Chin Med Assoc, 2022 Apr 01;85(4):409-413.
    PMID: 35383703 DOI: 10.1097/JCMA.0000000000000703
    Lung carcinoma (LC) is the third most common cancer diagnosis and accounted for the most cancer-related mortality worldwide in 2018. Based on the type of cells from which it originates, LC is commonly classified into non-small cell lung cancers (NSCLC) and small cell lung cancers (SCLC). NSCLC account for the majority of LC and can be further categories into adenocarcinoma, large cell carcinoma, and squamous cell carcinoma. Accurate classification of LC is critical for its adequate treatment and therapeutic outcome. Since NSCLC express more epidermal growth factor receptor (EGFR) with activation mutations, targeted therapy EGFR-tyrosine kinase inhibitors (TKIs) have been considered as primary option of NSCLC patients with activation EGFR mutation. In this review, we present the genetic alterations, reported mutations in EGFR, and TKIs treatment in NSCLC patients with an emphasis on the downstream signaling pathways in NSCLC progression. Among the signaling pathways identified, mitogen activation protein kinase (MAPK), known also as extracellular signal-regulated protein kinase (Erk) pathway, is the most investigated among the related pathways. EGFR activation leads to the autophosphorylation of its kinase domain and subsequent activation of Ras, phosphorylation of Raf and MEK1/2, and the activation of ERK1/2. Phosphatidylinositol 3-kinase (PI3K)/Akt is another signal pathway that regulates cell cycle and has been linked to NSCLC progression. Currently, three generations of EGFR TKIs have been developed as a first-line treatment of NSCLC patients with EGFR activation and mutation in which these treatment options will be further discussed in this review. The Supplementary Appendix for this article is available at http://links.lww.com/JCMA/A138.
    Matched MeSH terms: Phosphatidylinositol 3-Kinases
  18. Fulltext The anticancer mechanism of action of selected polyphenols in triple-negative breast cancer (TNBC)
    Farghadani R, Naidu R
    Biomed Pharmacother, 2023 Sep;165:115170.
    PMID: 37481930 DOI: 10.1016/j.biopha.2023.115170
    Breast cancer is a leadingcause of cancer-related deaths in women globally, with triple-negative breast cancer (TNBC) being an aggressive subtype that lacks targeted therapies and is associated with a poor prognosis. Polyphenols, naturally occurring compounds in plants, have been investigated as a potential therapeutic strategy for TNBC. This review provides an overview of the anticancer effects of polyphenols in TNBC and their mechanisms of action. Several polyphenols, including resveratrol, quercetin, kaempferol, genistein, epigallocatechin-3-gallate, apigenin, fisetin, hesperetin and luteolin, have been shown to inhibit TNBC cell proliferation, induce cell cycle arrest, promote apoptosis, and suppress migration/invasion in preclinical models. The molecular mechanisms underlying their anticancer effects involve the modulation of several signalling pathways, such as PI3K/Akt, MAPK, STATT, and NF-κB pathways. Polyphenols also exhibit synergistic effects with chemotherapy drugs, making them promising candidates for combination therapy. The review also highlights clinical trials investigating the potential use of polyphenols, individually or in combination therapy, against breast cancer. This review deepens the under-standing of the mechanism of action of respective polyphenols and provides valuable insights into the potential use of polyphenols as a therapeutic strategy for TNBC, and lays the groundwork for future research in this area.
    Matched MeSH terms: Phosphatidylinositol 3-Kinases
  19. Fulltext Kaempferol: Paving the path for advanced treatments in aging-related diseases
    Hussain MS, Altamimi ASA, Afzal M, Almalki WH, Kazmi I, Alzarea SI, et al.
    Exp Gerontol, 2024 Apr;188:112389.
    PMID: 38432575 DOI: 10.1016/j.exger.2024.112389
    Aging-related diseases (ARDs) are a major global health concern, and the development of effective therapies is urgently needed. Kaempferol, a flavonoid found in several plants, has emerged as a promising candidate for ameliorating ARDs. This comprehensive review examines Kaempferol's chemical properties, safety profile, and pharmacokinetics, and highlights its potential therapeutic utility against ARDs. Kaempferol's therapeutic potential is underpinned by its distinctive chemical structure, which confers antioxidative and anti-inflammatory properties. Kaempferol counteracts reactive oxygen species (ROS) and modulates crucial cellular pathways, thereby combating oxidative stress and inflammation, hallmarks of ARDs. Kaempferol's low toxicity and wide safety margins, as demonstrated by preclinical and clinical studies, further substantiate its therapeutic potential. Compelling evidence supports Kaempferol's substantial potential in addressing ARDs through several mechanisms, notably anti-inflammatory, antioxidant, and anti-apoptotic actions. Kaempferol exhibits a versatile neuroprotective effect by modulating various proinflammatory signaling pathways, including NF-kB, p38MAPK, AKT, and the β-catenin cascade. Additionally, it hinders the formation and aggregation of beta-amyloid protein and regulates brain-derived neurotrophic factors. In terms of its anticancer potential, kaempferol acts through diverse pathways, inducing apoptosis, arresting the cell cycle at the G2/M phase, suppressing epithelial-mesenchymal transition (EMT)-related markers, and affecting the phosphoinositide 3-kinase/protein kinase B signaling pathways. Subsequent studies should focus on refining dosage regimens, exploring innovative delivery systems, and conducting comprehensive clinical trials to translate these findings into effective therapeutic applications.
    Matched MeSH terms: Phosphatidylinositol 3-Kinases
  20. Dietary Carbohydrate Promotes Cell Survival in Cancer Via the Up-Regulation of Fat Mass and Obesity-Associated Gene Expression Level
    Doaei S, Gholamalizadeh M, Akbari ME, Akbari S, Feradova H, Rahimzadeh G, et al.
    Malays J Med Sci, 2019 Mar;26(2):8-17.
    PMID: 31447604 DOI: 10.21315/mjms2019.26.2.2
    Cancer cells are mainly dependent on glycolysis for their growth and survival. Dietary carbohydrates play a critical role in the growth and proliferation of cancer and a low-carbohydrate diet may help slow down the growth of tumours. However, the exact mechanisms behind this effect are unclear. This review study aimed to investigate the effect of fat mass and obesity-associated (FTO) gene in the association between dietary carbohydrates and cancer. This study was carried out using keywords such as polymorphism and/or cancer and/or dietary carbohydrate and/or FTO gene. PubMed and Science Direct databases were used to collect all related articles published from 1990 to 2018. Recent studies showed that the level of FTO gene expression in cancer cells is dramatically increased and may play a role in the growth of these cells through the regulation of the cellular metabolic pathways, including the phosphoinositide 3-kinases/protein kinaseB (PI3K/AKT) signaling pathway. Dietary carbohydrate may influence the FTO gene expression by eliminating the inhibitory effect of adenosine monophosphate-activated protein kinase (AMPK) on the FTO gene expression. This review summarised what has been recently discovered about the effects of dietary carbohydrate on cancer cells and tried to determine the mediating role of the FTO gene in these effects.
    Matched MeSH terms: Phosphatidylinositol 3-Kinases
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