Displaying publications 21 - 40 of 62 in total

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  1. Phosphoinositide 3-kinase δ inactivation prevents vitreous-induced activation of AKT/MDM2/p53 and migration of retinal pigment epithelial cells
    Han H, Chen N, Huang X, Liu B, Tian J, Lei H
    J Biol Chem, 2019 10 18;294(42):15408-15417.
    PMID: 31467081 DOI: 10.1074/jbc.RA119.010130
    Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases that play a critical role in transmitting signals from cell-surface molecules to intracellular protein effectors. Key PI3Ks include PI3Kα, PI3Kβ, and PI3Kδ, which are regulated by receptors. The signaling pathway comprising the PI3Ks, along with a Ser/Thr kinase (AKT), a proto-oncogene product (mouse double minute (MDM)2), and a tumor suppressor protein (p53), plays an essential role in experimental proliferative vitreoretinopathy (PVR), which is a fibrotic blinding eye disorder. However, which PI3K isoforms are involved in PVR is unknown. A major characteristic of PVR is the formation of epi (or sub)-retinal membranes that consist of extracellular matrix and cells, including retinal pigment epithelium (RPE) cells, glial cells, and macrophages. RPE cells are considered key players in PVR pathogenesis. Using immunoblotting and immunofluorescence analyses, we herein provide the evidence that PI3Kδ is highly expressed in human RPEs when it is primarily expressed in leukocytes. We also found that PI3Kδ inactivation through two approaches, CRISPR/Cas9-mediated depletion and a PI3Kδ-specific inhibitor (idelalisib), not only blocks vitreous-induced activation of AKT and MDM2 but also abrogates a vitreous-stimulated decrease in p53. Furthermore, we demonstrate that PI3Kδ inactivation prevents vitreous-induced proliferation, migration, and contraction of human RPEs. These results suggest that PI3Kδ may represent a potential therapeutic target for RPE-related eye diseases, including PVR.
    Matched MeSH terms: Tumor Suppressor Protein p53/metabolism*
  2. Immunohistochemical localisation of RET and p53 mutant protein of thyroid lesions in a North-Eastern Malaysian population and its prognostic implications
    Omar E, Madhavan M, Othman NH
    Pathology, 2004 Apr;36(2):152-9.
    PMID: 15203751
    To investigate RET and p53 expression in local thyroid lesions, in order to shed light on the pathogenesis of papillary carcinoma and explain the high prevalence of this condition among the nodular hyperplasia (multi-nodular goitre) cases.
    Matched MeSH terms: Tumor Suppressor Protein p53/metabolism*
  3. Ursodeoxycholic acid protects cardiomyocytes against cobalt chloride induced hypoxia by regulating transcriptional mediator of cells stress hypoxia inducible factor 1α and p53 protein
    Mohamed AS, Hanafi NI, Sheikh Abdul Kadir SH, Md Noor J, Abdul Hamid Hasani N, Ab Rahim S, et al.
    Cell Biochem Funct, 2017 Oct;35(7):453-463.
    PMID: 29027248 DOI: 10.1002/cbf.3303
    In hepatocytes, ursodeoxycholic acid (UDCA) activates cell signalling pathways such as p53, intracellular calcium ([Ca2+ ]i ), and sphingosine-1-phosphate (S1P)-receptor via Gαi -coupled-receptor. Recently, UDCA has been shown to protect the heart against hypoxia-reoxygenation injury. However, it is not clear whether UDCA cardioprotection against hypoxia acts through a transcriptional mediator of cells stress, HIF-1α and p53. Therefore, in here, we aimed to investigate whether UDCA could protect cardiomyocytes (CMs) against hypoxia by regulating expression of HIF-1α, p53, [Ca2+ ]i , and S1P-Gαi -coupled-receptor. Cardiomyocytes were isolated from newborn rats (0-2 days), and hypoxia was induced by using cobalt chloride (CoCl2 ). Cardiomyocytes were treated with UDCA and cotreated with either FTY720 (S1P-receptor agonist) or pertussis toxin (PTX; Gαi inhibitor). Cells were subjected for proliferation assay, beating frequency, QuantiGene Plex assay, western blot, immunofluorescence, and calcium imaging. Our findings showed that UDCA counteracted the effects of CoCl2 on cell viability, beating frequency, HIF-1α, and p53 protein expression. We found that these cardioprotection effects of UDCA were similar to FTY720, S1P agonist. Furthermore, we observed that UDCA protects CMs against CoCl2 -induced [Ca2+ ]i dynamic alteration. Pharmacological inhibition of the Gαi -sensitive receptor did not abolish the cardioprotection of UDCA against CoCl2 detrimental effects, except for cell viability and [Ca2+ ]i . Pertussis toxin is partially effective in inhibiting UDCA protection against CoCl2 effects on CM cell viability. Interestingly, PTX fully inhibits UDCA cardioprotection on CoCl2 -induced [Ca2+ ]i dynamic changes. We conclude that UDCA cardioprotection against CoCl2 -induced hypoxia is similar to FTY720, and its actions are not fully mediated by the Gαi -coupled protein sensitive pathways. Ursodeoxycholic acid is the most hydrophilic bile acid and is currently used to treat liver diseases. Recently, UDCA is shown to have a cardioprotection effects; however, the mechanism of UDCA cardioprotection is still poorly understood. The current data generated were the first to show that UDCA is able to inhibit the activation of HIF-1α and p53 protein during CoCl2 -induced hypoxia in cardiomyocytes. This study provides an insight of UDCA mechanism in protecting cardiomyocytes against hypoxia.
    Matched MeSH terms: Tumor Suppressor Protein p53/metabolism*
  4. Novel 5-HT3 receptor antagonist QCM-4 attenuates depressive-like phenotype associated with obesity in high-fat-diet-fed mice
    Kurhe Y, Mahesh R, Devadoss T
    Psychopharmacology (Berl), 2017 Apr;234(7):1165-1179.
    PMID: 28238069 DOI: 10.1007/s00213-017-4558-0
    RATIONALE: Depression associated with obesity remains an interesting area to study the biological mechanisms and novel therapeutic intervention.

    OBJECTIVES: The present study investigates the effect of a novel 5-HT3 receptor antagonist 3-methoxy-N-p-tolylquinoxalin-2-carboxamide (QCM-4) on several pathogenic markers of depression associated with obesity such as plasma insulin resistance, hippocampal cyclic adenosine monophosphate (cAMP), brain-derived neurotrophic factor (BDNF), serotonin (5-HT) concentrations, hippocampal neuronal damage, and p53 protein expression in high-fat-diet (HFD)-fed mice.

    METHODS: Obesity was experimentally induced in mice by feeding with HFD for 14 weeks followed by administration of QCM-4 (1 and 2 mg/kg, p.o.)/standard escitalopram (ESC) (10 mg/kg, p.o.)/vehicle (10 ml/kg, p.o.) for 28 days. Behavioral assays such as sucrose preference test (SPT); forced swim test (FST); elevated plus maze (EPM); biochemical assays including oral glucose tolerance tests (OGTT), insulin, cAMP, BDNF, and 5-HT concentrations; and molecular assays mainly histology and immunohistochemistry (IHC) of p53 protein in the dentate gyrus (DG), CA1, and CA3 regions of hippocampus in HFD fed mice were performed.

    RESULTS: Chronic treatment with QCM-4 in HFD-fed mice reversed the behavioral alterations in SPT, FST, and EPM. QCM-4 showed poor sensitivity for plasma glucose, improved insulin sensitivity, increased hippocampal cAMP, BDNF, and 5-HT concentrations. In the hippocampal DG, CA1, and CA3 regions, QCM-4 treatment improved the neuronal morphology in the histopathology and inhibited p53 protein expression in IHC assay in HFD-fed mice.

    CONCLUSION: QCM-4 attenuated the depressive-like phenotype in HFD-fed mice by improving behavioral, biochemical, and molecular alterations through serotonergic neuromodulation.

    Matched MeSH terms: Tumor Suppressor Protein p53/metabolism
  5. LPS-induced Apoptosis is Partially Mediated by Hydrogen Sulphide in RAW 264.7 Murine Macrophages
    George L, Ramasamy T, Sirajudeen K, Manickam V
    Immunol Invest, 2019 Jul;48(5):451-465.
    PMID: 30689461 DOI: 10.1080/08820139.2019.1566355
    Lipopolysaccharide (LPS) induces apoptosis in murine macrophages through the autocrine secretion of tumor necrosis factor (TNF)-α and nitric oxide (NO). LPS-induced inflammation in murine macrophages is associated with hydrogen sulfide (H2S) production. In this present study, we reported the novel role of H2S in LPS-induced apoptosis and its underlying molecular mechanism specifically at late phases in murine macrophage cells. Stimulation of RAW 264.7 macrophages with LPS resulted in a time- and dose-dependent induction of apoptosis. We observed that the LPS-induced early apoptosis (associated with TNF-α secretion) in macrophages was not inhibited in the presence of H2S inhibitor (DL-propargylglycine), whereas early apoptosis was absent in the presence of TNF receptor antibody. Interestingly, LPS-induced late apoptosis paralleled with H2S production was reduced in the presence of H2S inhibitor but not with TNF receptor antibody. The late apoptotic events mediated by H2S and not the TNF-α induced early apoptosis correlated significantly with the induction of p53 and Bax expression in LPS-induced macrophages. Thus, it is possible that RAW 264.7 murine macrophages treated with LPS mediated early apoptosis through TNF-α and the late apoptotic events through the production of H2S.
    Matched MeSH terms: Tumor Suppressor Protein p53/metabolism
  6. Fulltext Newcastle disease virus degrades HIF-1α through proteasomal pathways independent of VHL and p53
    Abd-Aziz N, Stanbridge EJ, Shafee N
    J Gen Virol, 2016 Dec;97(12):3174-3182.
    PMID: 27902314 DOI: 10.1099/jgv.0.000623
    Newcastle disease virus (NDV) is a candidate agent for oncolytic virotherapy. Despite its potential, the exact mechanism of its oncolysis is still not known. Recently, we reported that NDV exhibited an increased oncolytic activity in hypoxic cancer cells. These types of cells negatively affect therapeutic outcome by overexpressing pro-survival genes under the control of the hypoxia-inducible factor (HIF). HIF-1 is a heterodimeric transcriptional factor consisting of a regulated α (HIF-1α) and a constitutive β subunit (HIF-1β). To investigate the effects of NDV infection on HIF-1α in cancer cells, the osteosarcoma (Saos-2), breast carcinoma (MCF-7), colon carcinoma (HCT116) and fibrosarcoma (HT1080) cell lines were used in the present study. Data obtained showed that a velogenic NDV infection diminished hypoxia-induced HIF-1α accumulation, leading to a decreased activation of its downstream target gene, carbonic anhydrase 9. This NDV-induced downregulation of HIF-1α occurred post-translationally and was partially abrogated by proteasomal inhibition. The process appeared to be independent of the tumour suppressor protein p53. These data revealed a correlation between NDV infection and HIF-1α downregulation, which highlights NDV as a promising agent to eliminate hypoxic cancer cells.
    Matched MeSH terms: Tumor Suppressor Protein p53/metabolism*
  7. Dichloromethane fraction of Moringa oleifera leaf methanolic extract selectively inhibits breast cancer cells (MCF7) by induction of apoptosis via upregulation of Bax, p53 and caspase 8 expressions
    Mohd Fisall UF, Ismail NZ, Adebayo IA, Arsad H
    Mol Biol Rep, 2021 May;48(5):4465-4475.
    PMID: 34086162 DOI: 10.1007/s11033-021-06466-y
    Moringa oleifera is a well-known medicinal plant which has anti-cancer and other biological activities. This research aims to determine the cytotoxic and apoptotic effect of M. oleifera leave extract on the breast cancer (MCF7) cells. The extracts were prepared using hexane, dichloromethane, chloroform and n-butanol by fractionating the crude 80% methanol extract of the plant leaves. The cytotoxic effect of the extracts on MCF7 cells were determined using CellTiter 96® AQueous One Solution Cell Proliferation (MTS) assay. The apoptosis study was conducted using Annexin V-FITC analysis and confirmed by Western blotting using selected proteins, which are p53, Bax, cytochrome c and caspase 8. Our results showed that the dichloromethane (DF-CME-MOL) extract was selectively cytotoxic to MCF7 cells (5 μg/mL) without significantly inhibiting the non-cancerous breast (MCF 10A) cells. It had the highest selectivity index (SI) value of 9.5 among the tested extracts. It also induced early apoptosis and increased the expressions of pro-apoptotic proteins Bax, caspase 8 and p53 in MCF7 cells. Gas chromatography-mass spectrometry analysis (GC-MS) analysis showed that the major compounds found in DF-CME-MOL were benzeneacetonitrile, 4-hydroxy- and benzeneacetic acid, 4-hydroxy-, methyl ester among others that were detected. Thus, DF-CME-MOL extract was found to inhibit the proliferation of MCF7 cells by apoptosis induction, which is likely due to the activities of the detected phytochemical compounds of the extract.
    Matched MeSH terms: Tumor Suppressor Protein p53/metabolism*
  8. Fulltext Induction of Apoptosis in MCF-7 Cells via Oxidative Stress Generation, Mitochondria-Dependent and Caspase-Independent Pathway by Ethyl Acetate Extract of Dillenia suffruticosa and Its Chemical Profile
    Tor YS, Yazan LS, Foo JB, Wibowo A, Ismail N, Cheah YK, et al.
    PLoS One, 2015;10(6):e0127441.
    PMID: 26047480 DOI: 10.1371/journal.pone.0127441
    Dillenia suffruticosa, which is locally known as Simpoh air, has been traditionally used to treat cancerous growth. The ethyl acetate extract of D. suffruticosa (EADs) has been shown to induce apoptosis in MCF-7 breast cancer cells in our previous study. The present study aimed to elucidate the molecular mechanisms involved in EADs-induced apoptosis and to identify the major compounds in the extract. EADs was found to promote oxidative stress in MCF-7 cells that led to cell death because the pre-treatment with antioxidants α-tocopherol and ascorbic acid significantly reduced the cytotoxicity of the extract (P<0.05). DCFH-DA assay revealed that treatment with EADs attenuated the generation of intracellular ROS. Apoptosis induced by EADs was not inhibited by the use of caspase-inhibitor Z-VAD-FMK, suggesting that the cell death is caspase-independent. The use of JC-1 dye reflected that EADs caused disruption in the mitochondrial membrane potential. The related molecular pathways involved in EADs-induced apoptosis were determined by GeXP multiplex system and Western blot analysis. EADs is postulated to induce cell cycle arrest that is p53- and p21-dependent based on the upregulated expression of p53 and p21 (P<0.05). The expression of Bax was upregulated with downregulation of Bcl-2 following treatment with EADs. The elevated Bax/Bcl-2 ratio and the depolarization of mitochondrial membrane potential suggest that EADs-induced apoptosis is mitochondria-dependent. The expression of oxidative stress-related AKT, p-AKT, ERK, and p-ERK was downregulated with upregulation of JNK and p-JNK. The data indicate that induction of oxidative-stress related apoptosis by EADs was mediated by inhibition of AKT and ERK, and activation of JNK. The isolation of compounds in EADs was carried out using column chromatography and elucidated using the nuclear resonance magnetic analysis producing a total of six compounds including 3-epimaslinic acid, kaempferol, kaempferide, protocatechuic acid, gallic acid and β-sitosterol-3-O-β-D-glucopyranoside. The cytotoxicity of the isolated compounds was determined using MTT assay. Gallic acid was found to be most cytotoxic against MCF-7 cell line compared to others, with IC50 of 36 ± 1.7 μg/mL (P<0.05). In summary, EADs generated oxidative stress, induced cell cycle arrest and apoptosis in MCF-7 cells by regulating numerous genes and proteins that are involved in the apoptotic signal transduction pathway. Therefore, EADs has the potential to be developed as an anti-cancer agent against breast cancer.
    Matched MeSH terms: Tumor Suppressor Protein p53/metabolism
  9. Fulltext The molecular mechanism of the anticancer effect of Artonin E in MDA-MB 231 triple negative breast cancer cells
    Etti IC, Abdullah R, Kadir A, Hashim NM, Yeap SK, Imam MU, et al.
    PLoS One, 2017;12(8):e0182357.
    PMID: 28771532 DOI: 10.1371/journal.pone.0182357
    Nature has provided us with a wide spectrum of disease healing phytochemicals like Artonin E, obtained from the root bark of Artocarpus elasticus. This molecule had been predicted to be drug-like, possessing unique medicinal properties. Despite strides made in chemotherapy, prognosis of the heterogenous aggressive triple negative breast cancer is still poor. This study was conducted to investigate the mechanism of inhibition of Artonin E, a prenylated flavonoid on MDA-MB 231 triple negative breast cancer cell, with a view of mitigating the hallmarks displayed by these tumors. The anti-proliferative effect, mode of cell death and the mechanism of apoptosis induction were investigated. Artonin E, was seen to effectively relinquish MDA-MB 231 breast cancer cells of their apoptosis evading capacity, causing a half-maximal growth inhibition at low concentrations (14.3, 13.9 and 9.8 μM) after the tested time points (24, 48 and 72 hours), respectively. The mode of cell death was observed to be apoptosis with defined characteristics. Artonin E was seen to induce the activation of both extrinsic and intrinsic caspases initiators of apoptosis. It also enhanced the release of total reactive oxygen species which polarized the mitochondrial membrane, compounding the release of cytochrome c. Gene expression studies revealed the upregulation of TNF-related apoptosis inducing ligand and proapoptotic genes with down regulation of anti-apoptotic genes and proteins. A G2/M cell cycle arrest was also observed and was attributed to the observed upregulation of p21 independent of the p53 status. Interestingly, livin, a new member of the inhibitors of apoptosis was confirmed to be significantly repressed. In all, Artonin E showed the potential as a promising candidate to combat the aggressive triple negative breast cancer.
    Matched MeSH terms: Tumor Suppressor Protein p53/metabolism
  10. Fulltext Regulation of apoptotic effects by erythrocarpine E, a cytotoxic limonoid from Chisocheton erythrocarpus in HSC-4 human oral cancer cells
    Nagoor NH, Shah Jehan Muttiah N, Lim CS, In LL, Mohamad K, Awang K
    PLoS One, 2011;6(8):e23661.
    PMID: 21858194 DOI: 10.1371/journal.pone.0023661
    The aim of this study was to determine the cytotoxic and apoptotic effects of erythrocarpine E (CEB4), a limonoid extracted from Chisocheton erythrocarpus on human oral squamous cell carcinoma. Based on preliminary dimethyl-2-thiazolyl-2,5-diphenyl-2H-tetrazolium bromide (MTT) assays, CEB4 treated HSC-4 cells demonstrated a cytotoxic effect and inhibited cell proliferation in a time and dose dependent manner with an IC(50) value of 4.0±1.9 µM within 24 h of treatment. CEB4 was also found to have minimal cytotoxic effects on the normal cell line, NHBE with cell viability levels maintained above 80% upon treatment. Annexin V-fluorescein isothiocyanate (FITC), poly-ADP ribose polymerase (PARP) cleavage and DNA fragmentation assay results showed that CEB4 induces apoptosis mediated cell death. Western blotting results demonstrated that the induction of apoptosis by CEB4 appeared to be mediated through regulation of the p53 signalling pathway as there was an increase in p53 phosphorylation levels. CEB4 was also found to up-regulate the pro-apoptotic protein, Bax, while down-regulating the anti-apoptotic protein, Bcl-2, suggesting the involvement of the intrinsic mitochondrial pathway. Reduced levels of initiator procaspase-9 and executioner caspase-3 zymogen were also observed following CEB4 exposure, hence indicating the involvement of cytochrome c mediated apoptosis. These results demonstrate the cytotoxic and apoptotic ability of erythrocarpine E, and suggest its potential development as a cancer chemopreventive agent.
    Matched MeSH terms: Tumor Suppressor Protein p53/metabolism
  11. Fulltext Expression of senescence-associated microRNAs and target genes in cellular aging and modulation by tocotrienol-rich fraction
    Khee SG, Yusof YA, Makpol S
    Oxid Med Cell Longev, 2014;2014:725929.
    PMID: 25132913 DOI: 10.1155/2014/725929
    Emerging evidences highlight the implication of microRNAs as a posttranscriptional regulator in aging. Several senescence-associated microRNAs (SA-miRNAs) are found to be differentially expressed during cellular senescence. However, the role of dietary compounds on SA-miRNAs remains elusive. This study aimed to elucidate the modulatory role of tocotrienol-rich fraction (TRF) on SA-miRNAs (miR-20a, miR-24, miR-34a, miR-106a, and miR-449a) and established target genes of miR-34a (CCND1, CDK4, and SIRT1) during replicative senescence of human diploid fibroblasts (HDFs). Primary cultures of HDFs at young and senescent were incubated with TRF at 0.5 mg/mL. Taqman microRNA assay showed significant upregulation of miR-24 and miR-34a and downregulation of miR-20a and miR-449a in senescent HDFs (P < 0.05). TRF reduced miR-34a expression in senescent HDFs and increased miR-20a expression in young HDFs and increased miR-449a expression in both young and senescent HDFs. Our results also demonstrated that ectopic expression of miR-34a reduced the expression of CDK4 significantly (P < 0.05). TRF inhibited miR-34a expression thus relieved its inhibition on CDK4 gene expression. No significant change was observed on the expression of CCND1, SIRT1, and miR-34a upstream transcriptional regulator, TP53. In conclusion tocotrienol-rich fraction prevented cellular senescence of human diploid fibroblasts via modulation of SA-miRNAs and target genes expression.
    Matched MeSH terms: Tumor Suppressor Protein p53/metabolism
  12. Apoptotic activities of thymoquinone, an active ingredient of black seed (Nigella sativa), in cervical cancer cell lines
    Ichwan SJ, Al-Ani IM, Bilal HG, Suriyah WH, Taher M, Ikeda MA
    Chin J Physiol, 2014 Oct 31;57(5):249-55.
    PMID: 25241984 DOI: 10.4077/CJP.2014.BAB190
    Thymoquinone (TQ) is the main constituent of black seed (Nigella sativa, spp) essential oil which shows promising in vitro and in vivo anti-neoplastic activities in different tumor cell lines. However, to date there are only a few reports regarding the apoptotic effects of TQ on cervical cancer cells. Here, we report that TQ stimulated distinct apoptotic pathways in two human cervical cell lines, Siha and C33A. TQ markedly induced apoptosis as demonstrated by cell cycle analysis in both cell lines. Moreover, quantitative PCR revealed that TQ induced apoptosis in Siha cells through p53-dependent pathway as shown by elevated level of p53-mediated apoptosis target genes, whereas apoptosis in C33A cells was mainly associated with the activation of caspase-3. These results support previous findings on TQ as a potential therapeutic agent for human cervical cancer.
    Matched MeSH terms: Tumor Suppressor Protein p53/metabolism
  13. Expression of p53, bcl-2 and Ki-67 in cervical intraepithelial neoplasia and invasive squamous cell carcinoma of the uterine cervix
    Looi ML, Dali AZ, Ali SA, Ngah WZ, Yusof YA
    Anal. Quant. Cytol. Histol., 2008 Apr;30(2):63-70.
    PMID: 18561741
    To assess the expression of p53, bcl-2 and Ki-67 in the progression of cervical neoplasia.
    Matched MeSH terms: Tumor Suppressor Protein p53/metabolism*
  14. Fulltext p53 and p21/WAF-1 overexpressions in prostatic adenocarcinoma
    Wan Muhaizan WM, Ahmad PK, Phang KS, Arni T
    Malays J Pathol, 2006 Dec;28(2):93-9.
    PMID: 18376798 MyJurnal
    This study was carried out to determine the role of p53 and p21 in the pathogenesis of prostatic adenocarcinoma and their association with tumour grade.
    Matched MeSH terms: Tumor Suppressor Protein p53/metabolism*
  15. Gene expression profiling of p53(+/-) knockout and wild-type mice following diethylstilbestrol administration
    Salleh MN, Ismail P, Abdullah AS, Taufiq-Yap YH, Carmichael P
    IUBMB Life, 2004 Jul;56(7):409-16.
    PMID: 15545218
    Studies with clastogenic carcinogen diethylstilbestrol (DES) resulted in a broad of spectrum of toxic and carcinogenic effects in humans and rodents, but the cellular and molecular mechanism(s) by which it induces cancer is not clear. To identify putative genetic targets for p53 in vivo, we applied the cDNA macroarray gene expression profiles associated with apoptosis by comparing p53+/- knockout mice and wild-type mice on the kidney and uterus of female mice. p53+/- knockout mice and wild-type mice were treated with DES (500 micromole kg(-1)) or vehicle i.p once daily for 4 days. Total RNAs were obtained from kidney and uterus of both control and DES-treated. The signal intensities of individual gene spots on the membrane were quantified and normalized to the expression level of the GAPDH gene as an internal control. Our results demonstrated that 16 genes; bad, bax, bcl-2, bcl-w, bcl-x, caspase-3, caspase-7, caspase-8, c-myc, E124, GADD45, mdm2, NKkappab1, p53, p21, Rb and trail were up-regulated and six genes; caspase-1, caspase-2, DR5, E2F1, FasL and iNOS did not changed in response to DES treatment in wild-type mice compared to p53+/- knockout mice. Most genes are involved in cell cycle regulation, signal transduction, apoptosis, or transcription. The greatest changes were seen in bad, bcl-x, mdm2, p53 and p21 gene expression in wild-type mice compared to p53+/- knockout mice. In comparing p53 and p21 gene expression in wild-type mice and p53+/- knockout mice, there was an 4.4-fold vs. 1.8-fold; 8-fold vs. 5.2-fold for kidney and 16-fold vs. 5.5-fold; 2.1-fold vs. 8.3-fold for uterus samples increase in induction (respectively). RT-PCR and densitometric analysis was used to confirm the biggest changes of p21, p53 and bax genes. Using this approach, we have identified apoptosis associated genes regulated in response to DES and have revealed putative differences between the isogenic parent strain and p53+/- knockout mice, which will contribute to a better understanding of toxicity/carcinogenicity mechanisms in this model.
    Matched MeSH terms: Tumor Suppressor Protein p53/metabolism*
  16. Immunohistochemical analysis of p53 expression in primary breast carcinomas
    Naidu R, Yadav M, Nair S, Kutty KK
    Anticancer Res, 1998 Jan-Feb;18(1A):65-70.
    PMID: 9568057
    Expression of p53 protein was investigated by immunohistochemical techniques in archival cases of 134 primary breast carcinomas comprising 13 comedo ductal carcinoma in situ (DCIS), 105 invasive ductal carcinomas, 7 contained the comedo DCIS component adjacent to the invasive ductal component, 5 invasive lobular carcinomas, three colloid carcinomas and one medullary carcinoma. Overexpression of p53 gene product was studied to determine the association with clinico-pathological parameters and also its relationship to c-erbB2. Overexpression of p53 protein was observed in 31% (4/13) of comedo DCIS, 37% (39/105) of invasive ductal carcinomas, 57% (4/7) of carcinomas containing both the in situ and invasive lesions and all medullary carcinomas. A significant relationship (p < 0.05) was observed between strong immunoreactivity of p53 protein and absence of estrogen receptor, histological grade and c-erbB2 but not with lymph node metastases or age of patient. These observations suggest that overexpression of p53 protein may play an important role in tumor progression from noninvasive to invasive in some breast carcinomas and may have potential as an indicator for poorer prognosis.
    Matched MeSH terms: Tumor Suppressor Protein p53/metabolism*
  17. Fulltext Nutlin-3 sensitizes nasopharyngeal carcinoma cells to cisplatin-induced cytotoxicity
    Voon YL, Ahmad M, Wong PF, Husaini R, Ng WT, Leong CO, et al.
    Oncol Rep, 2015 Oct;34(4):1692-700.
    PMID: 26252575 DOI: 10.3892/or.2015.4177
    The small-molecule inhibitor of p53-Mdm2 interaction, Nutlin-3, is known to be effective against cancers expressing wild-type (wt) p53. p53 mutations are rare in nasopharyngeal carcinoma (NPC), hence targeting disruption of p53-Mdm2 interaction to reactivate p53 may offer a promising therapeutic strategy for NPC. In the present study, the effects of Nutlin-3 alone or in combination with cisplatin, a standard chemotherapeutic agent, were tested on C666-1 cells, an Epstein-Barr virus (EBV)-positive NPC cell line bearing wt p53. Treatment with Nutlin-3 activated the p53 pathway and sensitized NPC cells to the cytotoxic effects of cisplatin. The combined treatment also markedly suppressed soft agar colony growth formation and increased apoptosis of NPC cells. The effect of Nutlin-3 on NPC cells was inhibited by knockdown of p53, suggesting that its effect was p53-dependent. Extended treatment with increasing concentrations of Nutlin-3 did not result in emergence of p53 mutations in the C666-1 cells. Collectively, the present study revealed supportive evidence of the effectiveness of combining cisplatin and Nutlin-3 as a potential therapy against NPC.
    Matched MeSH terms: Tumor Suppressor Protein p53/metabolism
  18. Pereskia bleo Leaves Extract Induces Cell Death via Cell Cycle Arrest and Apoptosis in Cervical Cancer Cells HeLa
    Mohd-Salleh SF, Wan-Ibrahim WS, Ismail N
    Nutr Cancer, 2020;72(5):826-834.
    PMID: 31433251 DOI: 10.1080/01635581.2019.1654530
    Introduction:Pereskia bleo is a leafy and edible plant, locally known as "Pokok Jarum Tujuh Bilah" which has anticancer properties. This study purposed to determine the cytotoxic effects of P. bleo leaves extracts on several well-known cancer cells and elucidate its underlying mechanism in inducing cell death.Methods: Cytotoxic activity on selected cell lines was determined using MTT assay. Mechanism of cell death was investigated through cell cycle and Annexin V assay. Expression of apoptotic proteins was measured by flow cytometry method.Results: Ethyl acetate extract of P. bleo leaves (PBEA) appeared to have the strongest IC50 value (14.37 ± 8.40 μg/ml) and most active against HeLa cells was further studied for apoptosis. The cell cycle investigation by flow cytometry evidenced the increment of PBEA treated HeLa cells in G0/G1 phase and apoptotic event was detected in Annexin V assay. Analysis of apoptotic protein showed pro-apoptotic proteins (Bax, p53 and caspase 3) were triggered where as anti-apoptotic protein Bcl-2 was suppressed in treated HeLa cells.Conclusions: Our findings demonstrated that PBEA treatment induced cell death in HeLa cells by p53-mediated mechanism through arresting cell cycle at G0/G1 phase and mitochondrial-mediated pathway with involvement of pro-apoptotic proteins, anti-apoptotic protein, and caspase 3.
    Matched MeSH terms: Tumor Suppressor Protein p53/metabolism
  19. Fulltext Differential expression of senescence tumour markers and its implications on survival outcomes of breast cancer patients
    Pare R, Soon PS, Shah A, Lee CS
    PLoS One, 2019;14(4):e0214604.
    PMID: 30998679 DOI: 10.1371/journal.pone.0214604
    Breast cancer is a heterogeneous disease displaying different histopathological characteristics, molecular profiling and clinical behavior. This study describes the expression patterns of senescence markers P53, DEC1 and DCR2 and assesses their significance on patient survival as a single or combined marker with P16 or P14 using breast cancer progression series. One thousand and eighty (1080) patients with primary invasive ductal carcinoma, no special type, were recruited through an 11-year retrospective study period. We constructed tissue microarrays of normal, benign hyperplasia, ductal carcinoma in situ and invasive ductal carcinoma from each patient and performed immunohistochemical staining to study the protein expression. Statistical analysis includes Pearson chi-square, Kaplan-Meier log ran test and Cox proportional hazard regression were undertaken to determine the associations and predict the survival outcomes. P53, DEC1 and DCR2 expression correlated significantly with normal, benign, premalignant and malignant tissues with (p<0.05). The expression profile of these genes increases from normal to benign to premalignant and plateaued from premalignant to malignant phenotype. There is a significant association between P53 protein expression and age, grade, staging, lymphovascular invasion, estrogen receptor, progesterone receptor and HER2 whereas DCR2 protein expression significantly correlated with tumour grade, hormone receptors status and HER2 (p<0.05 respectively). P53 overexpression correlated with increased risk of relapse (p = 0.002) specifically in patients who did not receive hormone therapy (p = 0.005) or chemotherapy (p<0.0001). The combination of P53+/P16+ is significantly correlated with poor overall and disease-free survival, whereas a combination of P53+/P14+ is associated with worse outcome in disease-free survival (p<0.05 respectively). P53 overexpression appears to be a univariate predictor of poor disease-free survival. The expression profiles of DEC1 and DCR2 do not appear to correlate with patient survival outcomes. The combination of P53 with P16, rather P53 expression alone, appears to provide more useful clinical information on patient survival outcomes in breast cancer.
    Matched MeSH terms: Tumor Suppressor Protein p53/metabolism
  20. Eurycoma longifolia, A Potential Phytomedicine for the Treatment of Cancer: Evidence of p53-mediated Apoptosis in Cancerous Cells
    Thu HE, Hussain Z, Mohamed IN, Shuid AN
    Curr Drug Targets, 2018;19(10):1109-1126.
    PMID: 28721818 DOI: 10.2174/1389450118666170718151913
    BACKGROUND: Eurycoma longifolia is a well-documented herbal medicine that has gained widespread recognition due to its versatile pharmacological activities including anticancer, antimalarial, antimicrobial, antioxidant, aphrodisiac, anti-inflammatory, anxiolytic, anti-diabetic, antirheumatism and anti-ulcer. Plethora of in vitro and in vivo studies evidenced their excellent antiproliferative and anticancer efficacy against various types of human cancers.

    OBJECTIVE: This review was aimed to critically analyze the therapeutic viability and anticancer efficacy of Eurycoma longifolia in the treatment of cancer and also to propose its molecular and translational mechanism of cytotoxicity against cancerous cells.

    RESULTS: Among a range of medicinally active compounds isolated from various parts (roots, stem, bark and leaves) of Eurycoma longifolia, 16 compounds have shown promising anti-proliferative and anticancer efficacies. Eurycomanone, one of the most active medicinal compounds of Eurycoma longifolia, displayed a strong dose-dependent anticancer efficacy against lung carcinoma (A-549 cells) and breast cancer (MCF-7 cells); however, showed moderate efficacy against gastric (MGC-803 cells) and intestinal carcinomas (HT-29 cells). The prime mode of cytotoxicity of Eurycoma longifolia and its medicinal compounds is the induction of apoptosis (programmed cell death) via the up-regulation of the expression of p53 (tumor suppressor protein) and pro-apoptotic protein (Bax) and downregulation of the expression of anti-apoptotic protein (Bcl-2). A remarkable alleviation in the mRNA expression of various cancer-associated biomarkers including heterogeneous nuclear ribonucleoprotein (hnRNP), prohibitin (PHB), annexin-1 (ANX1) and endoplasmic reticulum protein-28 (ERp28) has also been evidenced.

    CONCLUSION: Eurycoma longifolia and its medicinal constituents exhibit promising anticancer efficacy and thus can be considered as potential complementary therapy for the treatment of various types of human cancers.

    Matched MeSH terms: Tumor Suppressor Protein p53/metabolism*
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