Displaying publications 81 - 100 of 165 in total

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  1. Fulltext Mitochondrial DNA mutations in Malaysian female breast cancer patients
    Omasanggar R, Yu CY, Ang GY, Emran NA, Kitan N, Baghawi A, et al.
    PLoS One, 2020;15(5):e0233461.
    PMID: 32442190 DOI: 10.1371/journal.pone.0233461
    Cancer development has been ascribed with diverse genetic variations which are identified in both mitochondrial and nuclear genomes. Mitochondrial DNA (mtDNA) alterations have been detected in several tumours which include lung, colorectal, renal, pancreatic and breast cancer. Several studies have explored the breast tumour-specific mtDNA alteration mainly in Western population. This study aims to identify mtDNA alterations of 20 breast cancer patients in Malaysia by next generation sequencing analysis. Twenty matched tumours with corresponding normal breast tissues were obtained from female breast cancer patients who underwent mastectomy. Total DNA was extracted from all samples and the entire mtDNA (16.6kb) was amplified using long range PCR amplification. The amplified PCR products were sequenced using mtDNA next-generation sequencing (NGS) on an Illumina Miseq platform. Sequencing involves the entire mtDNA (16.6kb) from all pairs of samples with high-coverage (~ 9,544 reads per base). MtDNA variants were called and annotated using mtDNA-Server, a web server. A total of 18 of 20 patients had at least one somatic mtDNA mutation in their tumour samples. Overall, 65 somatic mutations were identified, with 30 novel mutations. The majority (59%) of the somatic mutations were in the coding region, whereas only 11% of the mutations occurred in the D-loop. Notably, somatic mutations in protein-coding regions were non-synonymous (49%) in which 15.4% of them are potentially deleterious. A total of 753 germline mutations were identified and four of which were novel mutations. Compared to somatic alterations, less than 1% of germline missense mutations are harmful. The findings of this study may enhance the current knowledge of mtDNA alterations in breast cancer. To date, the catalogue of mutations identified in this study is the first evidence of mtDNA alterations in Malaysian female breast cancer patients.
    Matched MeSH terms: Breast Neoplasms/metabolism
  2. Fulltext Exceedingly Higher co-loading of Curcumin and Paclitaxel onto Polymer-functionalized Reduced Graphene Oxide for Highly Potent Synergistic Anticancer Treatment
    Muthoosamy K, Abubakar IB, Bai RG, Loh HS, Manickam S
    Sci Rep, 2016 Sep 06;6:32808.
    PMID: 27597657 DOI: 10.1038/srep32808
    Metastasis of lung carcinoma to breast and vice versa accounts for one of the vast majority of cancer deaths. Synergistic treatments are proven to be the effective method to inhibit malignant cell proliferation. It is highly advantageous to use the minimum amount of a potent toxic drug, such as paclitaxel (Ptx) in ng/ml together with a natural and safe anticancer drug, curcumin (Cur) to reduce the systemic toxicity. However, both Cur and Ptx suffer from poor bioavailability. Herein, a drug delivery cargo was engineered by functionalizing reduced graphene oxide (G) with an amphiphilic polymer, PF-127 (P) by hydrophobic assembly. The drugs were loaded via pi-pi interactions, resulting in a nano-sized GP-Cur-Ptx of 140 nm. A remarkably high Cur loading of 678 wt.% was achieved, the highest thus far compared to any other Cur nanoformulations. Based on cell proliferation assay, GP-Cur-Ptx is a synergistic treatment (CI breast, MDA-MB-231 (IC50 = 1.450 μg/ml) cancer cells. These positive findings are further confirmed by increased reactive oxygen species, mitochondrial membrane potential depletion and cell apoptosis. The same dose treated on normal MRC-5 cells shows that the system is biocompatible and cancerous cell-specific.
    Matched MeSH terms: Breast Neoplasms/metabolism
  3. Expression of DDR1 and DVL1 in invasive ductal and lobular breast carcinoma does not correlate with histological type, grade and hormone receptor status
    Ameli F, Rose IM, Masir N
    Asian Pac J Cancer Prev, 2015;16(6):2385-90.
    PMID: 25824769
    BACKGROUND: Invasive ductal (IDC) and lobular (ILC) carcinomas are the common histological types of breast carcinoma which are difficult to distinguish when poorly differentiated. Discoidin domain receptor (DDR1) and Drosophila dishevelled protein (DVL1) were recently suggested to differentiate IDC from ILC.

    OBJECTIVES: To assess the expression of DDR1 and DVL1 and their association with histological type, grading and hormonal status of IDC and ILC.

    MATERIALS AND METHODS: This cross sectional study was conducted on IDC and ILC breast tumours. Tumours were immunohistochemically stained for (DDR1) and (DVL1) as well as estrogen receptor (ER), progesterone receptor (PR) and C-erbB2 receptor. Demographic data including age and ethnicity were obtained from patient records.

    RESULTS: A total of 51 cases (30 IDCs and 21 ILCs) were assessed. DDR1 and DVL1 expression was not significantly associated with histological type (p=0.57 and p=0.66 respectively). There was no association between DDR1 and DVL1 expression and tumour grade (p=0.32 and p=1.00 respectively), ER (p=0.62 and 0.50 respectively), PR (p=0.38 and p=0.63 respectively) and C-erbB2 expression (p=0.19 and p=0.33 respectively) in IDC. There was no association between DDR1 and DVL1 expression and tumour grade (p=0.52 and p=0.33 respectively), ER (p=0.06 and p=0.76 respectively), PR (p=0.61 and p=0.43 respectively) and C-erbB2 expression (p=0.58 and p=0.76 respectively) in ILC.

    CONCLUSIONS: This study revealed that DDR1 and DVL1 are present in both IDC and ILC regardless of the tumour differentiation. More studies are needed to assess the potential of these two proteins in distinguishing IDC from ILC in breast tumours.

    Matched MeSH terms: Breast Neoplasms/metabolism
  4. Microwave-assisted synthesis of sec/tert-butyl 2-arylbenzimidazoles and their unexpected antiproliferative activity towards ER negative breast cancer cells
    Abdul Rahim AS, Salhimi SM, Arumugam N, Pin LC, Yee NS, Muttiah NN, et al.
    J Enzyme Inhib Med Chem, 2013 Dec;28(6):1255-60.
    PMID: 23061895 DOI: 10.3109/14756366.2012.729828
    A new series of N-sec/tert-butyl 2-arylbenzimidazole derivatives was synthesised in 85-96% yields within 2-3.5 min by condensing ethyl 3-amino-4-butylamino benzoate with various substituted metabisulfite adducts of benzaldehyde under focused microwave irradiation. The benzimidazole analogues were characterised using (1)H NMR, (13)C NMR, high resolution MS and melting points. Evaluation of antiproliferative activity of the benzimidazole analogues against MCF-7 and MDA-MB-231 revealed several compounds with unexpected selective inhibitions of MDA-MB-231 in micromolar range. All analogues were found inactive towards MCF-7. The most potent inhibition against MDA-MB-231 human breast cancer cell line came from the unsubstituted 2-phenylbenzimidazole 10a.
    Matched MeSH terms: Breast Neoplasms/metabolism
  5. MicroRNAs as Biomarker for Breast Cancer
    Aggarwal T, Wadhwa R, Gupta R, Paudel KR, Collet T, Chellappan DK, et al.
    Endocr Metab Immune Disord Drug Targets, 2020;20(10):1597-1610.
    PMID: 32342824 DOI: 10.2174/1871530320666200428113051
    Regardless of advances in detection and treatment, breast cancer affects about 1.5 million women all over the world. Since the last decade, genome-wide association studies (GWAS) have been extensively conducted for breast cancer to define the role of miRNA as a tool for diagnosis, prognosis and therapeutics. MicroRNAs are small, non-coding RNAs that are associated with the regulation of key cellular processes such as cell multiplication, differentiation, and death. They cause a disturbance in the cell physiology by interfering directly with the translation and stability of a targeted gene transcript. MicroRNAs (miRNAs) constitute a large family of non-coding RNAs, which regulate target gene expression and protein levels that affect several human diseases and are suggested as the novel markers or therapeutic targets, including breast cancer. MicroRNA (miRNA) alterations are not only associated with metastasis, tumor genesis but also used as biomarkers for breast cancer diagnosis or prognosis. These are explained in detail in the following review. This review will also provide an impetus to study the role of microRNAs in breast cancer.
    Matched MeSH terms: Breast Neoplasms/metabolism*
  6. Ezrin is Significantly Overexpressed in Luminal A, Luminal B, and HER2 Subtype Breast Cancer
    Jais MH, Md Zin RR, Muhd Hanapi NA, Md Ali SA
    Appl Immunohistochem Mol Morphol, 2017 01;25(1):44-48.
    PMID: 26469327
    Ezrin, a membrane-linking protein, has been shown to play an important role in the carcinogenesis of infiltrating breast ductal carcinoma and its strong expression has been used to predict poor prognosis in patients with breast carcinoma. In this study, we compared ezrin protein distribution pattern in benign breast disease and breast cancer molecular subtypes and evaluated their association with clinicopathologic variables. A total of 376 breast cases (142 benign and 234 malignant cases) were studied. Immunohistochemical analysis for ezrin was performed and its expression was observed in terms of its distribution, intensity, and proportion of cells reactive for ezrin. Ezrin was expressed in all benign cases and 91.7% of malignant cases. Apical staining was positively associated with benign breast disease, whereas membranous and cytoplasmic staining were more frequently observed in malignant cases, specifically of hormone receptor-positive subtypes (luminal A and luminal B). Ezrin was significantly overexpressed in luminal A, luminal B, and HER2 subtypes. Reduced ezrin expression was significantly associated with triple-negative breast cancer molecular subtype. No significant association was demonstrated between ezrin expression and Her2 gene amplification, tumor grading, or staging.
    Matched MeSH terms: Breast Neoplasms/metabolism*
  7. Fulltext The Molecular Targets and Anti-Invasive Effects of 2,6-bis-(4-hydroxyl-3methoxybenzylidine) cyclohexanone or BHMC in MDA-MB-231 Human Breast Cancer Cells
    Harun SNA, Israf DA, Tham CL, Lam KW, Cheema MS, Md Hashim NF
    Molecules, 2018 Apr 10;23(4).
    PMID: 29642589 DOI: 10.3390/molecules23040865
    In order to metastasize, tumor cells need to migrate and invade the surrounding tissues. It is important to identify compound(s) capable of disrupting the metastasis of invasive cancer cells, especially for hindering invadopodia formation, so as to provide anti-metastasis targeted therapy. Invadopodia are thought to be specialized actin-rich protrusions formed by highly invasive cancer cells to degrade the extracellular matrix (ECM). A curcuminoid analogue known as 2,6-bis-(4-hydroxy-3-methoxybenzylidine)cyclohexanone or BHMC has shown good potential in inhibiting inflammation and hyperalgesia. It also possesses an anti-tumor effects on 4T1 murine breast cancer cells in vivo. However, there is still a lack of empirical evidence on how BHMC works in preventing human breast cancer invasion. In this study, we investigated the effect of BHMC on MDA-MB-231 breast cancer cells and its underlying mechanism of action to prevent breast cancer invasion, especially during the formation of invadopodia. All MDA-MB-231 cells, which were exposed to the non-cytotoxic concentrations of BHMC, expressed the proliferating cell nuclear antigen (PCNA), which indicate that the anti-proliferative effects of BHMC did not interfere in the subsequent experiments. By using a scratch migration assay, transwell migration and invasion assays, we determined that BHMC reduces the percentage of migration and invasion of MDA-MB-231 cells. The gelatin degradation assay showed that BHMC reduced the number of cells with invadopodia. Analysis of the proteins involved in the invasion showed that there is a significant reduction in the expressions of Rho guanine nucleotide exchange factor 7 (β-PIX), matrix metalloproteinase-9 (MMP-9), and membrane type 1 matrix metalloproteinase (MT1-MMP) in the presence of BHMC treatment at 12.5 µM. Therefore, it can be postulated that BHMC at 12.5 µM is the optimal concentration for preventing breast cancer invasion.
    Matched MeSH terms: Breast Neoplasms/metabolism*
  8. Fulltext Oxidative stress-mediated apoptosis induced by ethanolic mango seed extract in cultured estrogen receptor positive breast cancer MCF-7 cells
    Abdullah AS, Mohammed AS, Rasedee A, Mirghani ME
    Int J Mol Sci, 2015;16(2):3528-36.
    PMID: 25664859 DOI: 10.3390/ijms16023528
    Breast cancer has become a global health issue requiring huge expenditures for care and treatment of patients. There is a need to discover newer cost-effective alternatives for current therapeutic regimes. Mango kernel is a waste product with potential as a source of anti-cancer phytochemicals, especially since it is non-toxic towards normal breast cell lines at concentrations for which it induces cell death in breast cancer cells. In this study, the anti-cancer effect of mango kernel extract was determined on estrogen receptor-positive human breast carcinoma (MCF-7) cells. The MCF-7 cells were cultured and treated with 5, 10 and 50 μg/mL of mango kernel extract for 12 and 24 h. In response to treatment, there were time- and dose-dependent increases in oxidative stress markers and pro-apoptotic factors; Bcl-2-like protein 4 (BAX), p53, cytochrome c and caspases (7, 8 and 9) in the MCF-7 cells treated with the extract. At the same time, there were decreases in pro-survival markers (Bcl-2 and glutathione) as the result of the treatments. The changes induced in the MCF-7 cells by mango kernel extract treatment suggest that the extract can induce cancer cell apoptosis, likely via the activation of oxidative stress. These findings need to be evaluated further to determine whether mango kernel extract can be developed as an anti-breast cancer agent.
    Matched MeSH terms: Breast Neoplasms/metabolism*
  9. Subcellular localization of leptin and leptin receptor in breast cancer detected in an electron microscopic study
    Al-Shibli SM, Amjad NM, Al-Kubaisi MK, Mizan S
    Biochem Biophys Res Commun, 2017 Jan 22;482(4):1102-1106.
    PMID: 27914811 DOI: 10.1016/j.bbrc.2016.11.165
    Leptin (LEP) and leptin receptor (LEPR) have long been found associated with breast cancer. So far no high-resolution method such as electron microscopy has been used to investigate the subcellular localization of leptin and leptin receptor in breast cancer. We collected cancer and non-cancer breast tissues from 51 women with invasive ductal breast cancer. Leptin and leptin receptor in the tissues were estimated using immunohistochemistry (IHC). LEP and LEPR were localized at subcellular level by immunocytochemistry (ICC) using ultra-fine gold particle conjugated antibody, and visualized with transmission electron microscopy (TEM). IHC showed high presence of LEP and LEPR in 65% and 67% respectively of the breast cancer samples, 100% and 0% respectively of the adipose tissue samples, and no high presence in the non-cancer breast tissue samples. On TEM views both LEP and LEPR were found highly concentrated within the nucleus of the cancer cells, indicating that nucleus is the principal seat of action. However, presence of high concentration of LEP does not necessarily prove its over-expression, as often concluded, because LEP could be internalized from outside by LEPR in the cells. In contrast, LEPR is definitely over-expressed in the ductal breast cancer cells. Therefore, we hypothesize that over-expression of LEPR, rather than that of LEP has a fundamental role in breast carcinogenesis in particular, and probably for LEP-LEPR associated tumors in general.
    Matched MeSH terms: Breast Neoplasms/metabolism*
  10. Fulltext Survival analysis of Malaysian women with breast cancer: results from the University of Malaya Medical Centre
    Mohd Taib NA, Yip CH, Mohamed I
    Asian Pac J Cancer Prev, 2008 Apr-Jun;9(2):197-202.
    PMID: 18712958
    BACKGROUND: Breast cancer is the commonest cancer amongst Malaysian women but local survival data are scarce. The present study was therefore conducted to assess overall survival and prognostic factors in Malaysian breast cancer patients.

    METHODS: The research sample was a prospective cohort of 413 patients diagnosed with breast cancer in the University of Malaya Medical Centre between 1993 to 1997. Survival data were obtained from the National Registry of Birth and Deaths in December 2000. The clinico-pathological variables studied were age, ethnic group, stage, tumour size, lymph node status, oestrogen receptor status and grade. The data were analysed utilizing Splus statistical software. The important prognostic factors were identified by fitting the Cox's proportional hazard model to the data set. Survival probabilities were estimated using the Kaplan-Meier method and differences were compared by the log-rank test.

    RESULTS: The overall 5-year survival was 59.1%. The Cox's proportional hazard model identified stage, lymph node status, size and grade as factors that correlated with prognosis. Age was not a significant prognostic factor. The Cox regression model by stepwise selection showed stage, nodal status and grade of tumour to be independent prognostic factors, whereas ethnicity, age and ER status were not.

    INTERPRETATION: The overall survival in our centre was low. Recognizing factors that affect prognosis of breast cancer patients in Malaysia may improve delivery of health care to at-risk groups by strategizing interventions as survival depends on early detection and effective treatment.
    Matched MeSH terms: Breast Neoplasms/metabolism
  11. Fulltext (6E,10E) Isopolycerasoidol and (6E,10E) Isopolycerasoidol Methyl Ester, Prenylated Benzopyran Derivatives from Pseuduvaria monticola Induce Mitochondrial-Mediated Apoptosis in Human Breast Adenocarcinoma Cells
    Taha H, Looi CY, Arya A, Wong WF, Yap LF, Hasanpourghadi M, et al.
    PLoS One, 2015;10(5):e0126126.
    PMID: 25946039 DOI: 10.1371/journal.pone.0126126
    Phytochemicals from Pseuduvaria species have been reported to display a wide range of biological activities. In the present study, a known benzopyran derivative, (6E,10E) isopolycerasoidol (1), and a new benzopyran derivative, (6E,10E) isopolycerasoidol methyl ester (2), were isolated from a methanol extract of Pseuduvaria monticola leaves. The structures of the isolated compounds were elucidated by spectroscopic methods including 1D and 2D NMR, IR, UV, and LCMS-QTOF, and by comparison with previously published data. The anti-proliferative and cytotoxic effects of these compounds on human breast cancer cell-lines (MCF-7 and MDA-MB-231) and a human normal breast epithelial cell line (MCF-10A) were investigated. MTT results revealed both (1) and (2) were efficient in reducing cell viability of breast cancer cells. Flow cytometry analysis demonstrated that (1) and (2) induced cell death via apoptosis, as demonstrated by an increase in phosphotidylserine exposure. Both compounds elevated ROS production, leading to reduced mitochondrial membrane potential and increased plasma membrane permeability in breast cancer cells. These effects occurred concomitantly with a dose-dependent activation of caspase 3/7 and 9, a down-regulation of the anti-apoptotic gene BCL2 and the accumulation of p38 MAPK in the nucleus. Taken together, our data demonstrate that (1) and (2) induce intrinsic mitochondrial-mediated apoptosis in human breast cancer cells, which provides the first pharmacological evidence for their future development as anticancer agents.
    Matched MeSH terms: Breast Neoplasms/metabolism
  12. Fulltext Human CD3+ T-Cells with the Anti-ERBB2 Chimeric Antigen Receptor Exhibit Efficient Targeting and Induce Apoptosis in ERBB2 Overexpressing Breast Cancer Cells
    Munisvaradass R, Kumar S, Govindasamy C, Alnumair KS, Mok PL
    Int J Mol Sci, 2017 Sep 08;18(9).
    PMID: 28885562 DOI: 10.3390/ijms18091797
    Breast cancer is a common malignancy among women. The innate and adaptive immune responses failed to be activated owing to immune modulation in the tumour microenvironment. Decades of scientific study links the overexpression of human epidermal growth factor receptor 2 (ERBB2) antigen with aggressive tumours. The Chimeric Antigen Receptor (CAR) coding for specific tumour-associated antigens could initiate intrinsic T-cell signalling, inducing T-cell activation, and cytotoxic activity without the need for major histocompatibility complex recognition. This renders CAR as a potentially universal immunotherapeutic option. Herein, we aimed to establish CAR in CD3+ T-cells, isolated from human peripheral blood mononucleated cells that could subsequently target and induce apoptosis in the ERBB2 overexpressing human breast cancer cell line, SKBR3. Constructed CAR was inserted into a lentiviral plasmid containing a green fluorescent protein tag and produced as lentiviral particles that were used to transduce activated T-cells. Transduced CAR-T cells were then primed with SKBR3 cells to evaluate their functionality. Results showed increased apoptosis in SKBR3 cells co-cultured with CAR-T cells compared to the control (non-transduced T-cells). This study demonstrates that CAR introduction helps overcome the innate limitations of native T-cells leading to cancer cell apoptosis. We recommend future studies should focus on in vivo cytotoxicity of CAR-T cells against ERBB2 expressing tumours.
    Matched MeSH terms: Breast Neoplasms/metabolism*
  13. Differential effects of two-pore channel protein 1 and 2 silencing in MDA-MB-468 breast cancer cells
    Jahidin AH, Stewart TA, Thompson EW, Roberts-Thomson SJ, Monteith GR
    Biochem Biophys Res Commun, 2016 Sep 02;477(4):731-736.
    PMID: 27353380 DOI: 10.1016/j.bbrc.2016.06.127
    Two-pore channel proteins, TPC1 and TPC2, are calcium permeable ion channels found localized to the membranes of endolysosomal calcium stores. There is increasing interest in the role of TPC-mediated intracellular signaling in various pathologies; however their role in breast cancer has not been extensively evaluated. TPC1 and TPC2 mRNA was present in all non-tumorigenic and tumorigenic breast cell lines assessed. Silencing of TPC2 but not TPC1 attenuated epidermal growth factor-induced vimentin expression in MDA-MB-468 breast cancer cells. This effect was not due to a general inhibition of epithelial to mesenchymal transition (EMT) as TPC2 silencing had no effect on epidermal growth factor (EGF)-induced changes on E-cadherin expression. TPC1 and TPC2 were also shown to differentially regulate cyclopiazonic acid (CPA)-mediated changes in cytosolic free Ca(2+). These findings indicate potential differential regulation of signaling processes by TPC1 and TPC2 in breast cancer cells.
    Matched MeSH terms: Breast Neoplasms/metabolism*
  14. Cytology of mucinous carcinoma of breast: a report of 28 cases with histological correlation
    Jayaram G, Swain M, Chew MT, Yip CH, Moosa F
    Malays J Pathol, 2000 Dec;22(2):65-71.
    PMID: 16329537
    Pure mucinous carcinoma (MC) of the breast is a relatively uncommon variant of breast carcinoma with distinctive histological and cytological features. In this study we have analysed fine needle aspiration (FNA) cytological material from 28 cases of MC of breast and correlated the cytomorphological features with histopathology. The 28 patients consisted of 27 females and one male patient. 14 patients were Chinese, 10 were Indian and four were Malay. Their ages ranged from 38 to 90 with a mean at 52 years. The left breast was involved in 17 and the right in 11 cases. The duration of the lump varied from two weeks to 10 years. The cytological picture was characterized by abundant extracellular mucin giving a "sea of mucin" or "whirlpools of mucin" effect, in which were seen floating clusters of tumour cells with relatively bland cytological features. Myxo-vascular fragments were seen in 12 cases. Dissociated tumour cells showed a plasmacytoid appearance with eccentric nuclei. In four cases, the mucin was scanty in amount and the cellularity was high while in two cases, the cellularity was very low. Psammoma bodies were seen in cytological smears in one case. Histological study of excision or mastectomy specimens confirmed all 28 cases to be pure MC. Knowledge of the distinctive cytomorphological appearance of MC would enable correct identification of these lesions as malignant and prompt treatment that could further enhance the survival of these prognostically good breast cancers.
    Matched MeSH terms: Breast Neoplasms/metabolism
  15. A novel synthetic analogue of ω-3 17,18-epoxyeicosatetraenoic acid activates TNF receptor-1/ASK1/JNK signaling to promote apoptosis in human breast cancer cells
    Dyari HRE, Rawling T, Chen Y, Sudarmana W, Bourget K, Dwyer JM, et al.
    FASEB J, 2017 12;31(12):5246-5257.
    PMID: 28798154 DOI: 10.1096/fj.201700033R
    A saturated analog of the cytochrome P450-mediated ω-3-17,18-epoxide of ω-3-eicosapentaenoic acid (C20E) activated apoptosis in human triple-negative MDA-MB-231 breast cancer cells. This study evaluated the apoptotic mechanism of C20E. Increased cytosolic cytochrome c expression and altered expression of pro- and antiapoptotic B-cell lymphoma-2 proteins indicated activation of the mitochondrial pathway. Caspase-3 activation by C20E was prevented by pharmacological inhibition and silencing of the JNK and p38 MAP kinases (MAPK), upstream MAPK kinases MKK4 and MKK7, and the upstream MAPK kinase kinase apoptosis signal-regulating kinase 1 (ASK1). Silencing of the death receptor TNF receptor 1 (TNFR1), but not Fas, DR4, or DR5, and the adapters TRADD and TNF receptor-associated factor 2, but not Fas-associated death domain, prevented C20E-mediated apoptosis. B-cell lymphoma-2 homology 3-interacting domain death agonist (Bid) cleavage by JNK/p38 MAPK linked the extrinsic and mitochondrial pathways of apoptosis. In further studies, an antibody against the extracellular domain of TNFR1 prevented apoptosis by TNF-α but not C20E. These findings suggest that C20E acts intracellularly at TNFR1 to activate ASK1-MKK4/7-JNK/p38 MAPK signaling and to promote Bid-dependent mitochondrial disruption and apoptosis. Inin vivostudies, tumors isolated from C20E-treated nu/nu mice carrying MDA-MB-231 xenografts showed increased TUNEL staining and decreased Ki67 staining, reflecting increased apoptosis and decreased proliferation, respectively. ω-3-Epoxy fatty acids like C20E could be incorporated into treatments for triple-negative breast cancers.-Dyari, H. R. E., Rawling, T., Chen, Y., Sudarmana, W., Bourget, K., Dwyer, J. M., Allison, S. E., Murray, M. A novel synthetic analogue of ω-3 17,18-epoxyeicosatetraenoic acid activates TNF receptor-1/ASK1/JNK signaling to promote apoptosis in human breast cancer cells.
    Matched MeSH terms: Breast Neoplasms/metabolism*
  16. Fulltext Evaluation of cytotoxic and chemotherapeutic properties of boldine in breast cancer using in vitro and in vivo models
    Paydar M, Kamalidehghan B, Wong YL, Wong WF, Looi CY, Mustafa MR
    Drug Des Devel Ther, 2014;8:719-33.
    PMID: 24944509 DOI: 10.2147/DDDT.S58178
    To date, plants have been the major source of anticancer drugs. Boldine is a natural alkaloid commonly found in the leaves and bark of Peumus boldus. In this study, we found that boldine potently inhibited the viability of the human invasive breast cancer cell lines, MDA-MB-231 (48-hour IC₅₀ 46.5±3.1 μg/mL) and MDA-MB-468 (48-hour IC₅₀ 50.8±2.7 μg/mL). Boldine had a cytotoxic effect and induced apoptosis in breast cancer cells as indicated by a higher amount of lactate dehydrogenase released, membrane permeability, and DNA fragmentation. In addition, we demonstrated that boldine induced cell cycle arrest at G2/M phase. The anticancer mechanism is associated with disruption of the mitochondrial membrane potential and release of cytochrome c in MDA-MB-231. Boldine selectively induced activation of caspase-9 and caspase-3/7, but not caspase-8. We also found that boldine could inhibit nuclear factor kappa B activation, a key molecule in tumor progression and metastasis. In addition, protein array and Western blotting analysis showed that treatment with boldine resulted in downregulation of Bcl-2 and heat shock protein 70 and upregulation of Bax in the MDA-MB-231 cell line. An acute toxicity study in rats revealed that boldine at a dose of 100 mg/kg body weight was well tolerated. Moreover, intraperitoneal injection of boldine (50 or 100 mg/kg) significantly reduced tumor size in an animal model of breast cancer. Our results suggest that boldine is a potentially useful agent for the treatment of breast cancer.
    Matched MeSH terms: Breast Neoplasms/metabolism
  17. Modulation of oncogenic transcription factors by bioactive natural products in breast cancer
    Hasanpourghadi M, Pandurangan AK, Mustafa MR
    Pharmacol Res, 2018 02;128:376-388.
    PMID: 28923544 DOI: 10.1016/j.phrs.2017.09.009
    Carcinogenesis, a multi-step phenomenon, characterized by alterations at genetic level and affecting the main intracellular pathways controlling cell growth and development. There are growing number of evidences linking oncogenes to the induction of malignancies, especially breast cancer. Modulations of oncogenes lead to gain-of-function signals in the cells and contribute to the tumorigenic phenotype. These signals yield a large number of proteins that cause cell growth and inhibit apoptosis. Transcription factors such as STAT, p53, NF-κB, c-JUN and FOXM1, are proteins that are conserved among species, accumulate in the nucleus, bind to DNA and regulate the specific genes targets. Oncogenic transcription factors resulting from the mutation or overexpression following aberrant gene expression relay the signals in the nucleus and disrupt the transcription pattern. Activation of oncogenic transcription factors is associated with control of cell cycle, apoptosis, migration and cell differentiation. Among different cancer types, breast cancer is one of top ten cancers worldwide. There are different subtypes of breast cancer cell-lines such as non-aggressive MCF-7 and aggressive and metastatic MDA-MB-231 cells, which are identified with distinct molecular profile and different levels of oncogenic transcription factor. For instance, MDA-MB-231 carries mutated and overexpressed p53 with its abnormal, uncontrolled downstream signalling pathway that account for resistance to several anticancer drugs compared to MCF-7 cells with wild-type p53. Appropriate enough, inhibition of oncogenic transcription factors has become a potential target in discovery and development of anti-tumour drugs against breast cancer. Plants produce diverse amount of organic metabolites. Universally, these metabolites with biological activities are known as "natural products". The chemical structure and function of natural products have been studied since 1850s. Investigating these properties leaded to recognition of their molecular effects as anticancer drugs. Numerous natural products extracted from plants, fruits, mushrooms and mycelia, show potential inhibitory effects against several oncogenic transcription factors in breast cancer. Natural compounds that target oncogenic transcription factors have increased the number of candidate therapeutic agents. This review summarizes the current findings of natural products in targeting specific oncogenic transcription factors in breast cancer.
    Matched MeSH terms: Breast Neoplasms/metabolism*
  18. 1'S-1'-acetoxyeugenol acetate: a novel phenylpropanoid from Alpinia conchigera enhances the apoptotic effects of paclitaxel in MCF-7 cells through NF-κB inactivation
    In LL, Azmi MN, Ibrahim H, Awang K, Nagoor NH
    Anticancer Drugs, 2011 Jun;22(5):424-34.
    PMID: 21346553 DOI: 10.1097/CAD.0b013e328343cbe6
    In this study, the apoptotic mechanism and combinatorial chemotherapeutic effects of the cytotoxic phenylpropanoid compound 1'S-1'-acetoxyeugenol acetate (AEA), extracted from rhizomes of the Malaysian ethnomedicinal plant Alpinia conchigera Griff. (Zingiberaceae), on MCF-7 human breast cancer cells were investigated for the first time. Data from cytotoxic and apoptotic assays such as live and dead and poly-(ADP-ribose) polymerase cleavage assays indicated that AEA was able to induce apoptosis in MCF-7 cells, but not in normal human mammary epithelial cells. A microarray global gene expression analysis of MCF-7 cells, treated with AEA, suggested that the induction of tumor cell death through apoptosis was modulated through dysregulation of the nuclear factor-kappaB (NF-κB) pathway, as shown by the reduced expression of various κB-regulated gene targets. Consequent to this, western blot analysis of proteins corresponding to the NF-κB pathway indicated that AEA inhibited phosphorylation levels of the inhibitor of κB-kinase complex, resulting in the elimination of apoptotic resistance originating from NF-κB activation. This AEA-based apoptotic modulation was elucidated for the first time in this study, and gave rise to the proposal of an NF-κB model termed the 'Switching/Alternating Model.' In addition to this, AEA was also found to synergistically enhance the proapoptotic effects of paclitaxel, when used in combination with MCF-7 cells, presumably by a chemosensitizing role. Therefore, it was concluded that AEA isolated from the Malaysian tropical ginger (A. conchigera) served as a very promising candidate for further in-vivo development in animal models and in subsequent clinical trials involving patients with breast-related malignancies.
    Matched MeSH terms: Breast Neoplasms/metabolism
  19. Fulltext Inactivation of nuclear factor κB by MIP-based drug combinations augments cell death of breast cancer cells
    Subramaniam M, Liew SK, In L, Awang K, Ahmed N, Nagoor NH
    Drug Des Devel Ther, 2018;12:1053-1063.
    PMID: 29750018 DOI: 10.2147/DDDT.S141925
    Background: Drug combination therapy to treat cancer is a strategic approach to increase successful treatment rate. Optimizing combination regimens is vital to increase therapeutic efficacy with minimal side effects.

    Materials and methods: In the present study, we evaluated the in vitro cytotoxicity of double and triple combinations consisting of 1'S-1'-acetoxychavicol acetate (ACA), Mycobacterium indicus pranii (MIP) and cisplatin (CDDP) against 14 various human cancer cell lines to address the need for more effective therapy. Our data show synergistic effects in MCF-7 cells treated with MIP:ACA, MIP:CDDP and MIP:ACA:CDDP combinations. The type of interaction between MIP, ACA and CDDP was evaluated based on combination index being <0.8 for synergistic effect. Identifying the mechanism of cell death based on previous studies involved intrinsic apoptosis and nuclear factor kappa B (NF-κB) and tested in Western blot analysis. Inactivation of NF-κB was confirmed by p65 and IκBα, while intrinsic apoptosis pathway activation was confirmed by caspase-9 and Apaf-1 expression.

    Results: All combinations confirmed intrinsic apoptosis activation and NF-κB inactivation.

    Conclusion: Double and triple combination regimens that target induction of the same death mechanism with reduced dosage of each drug could potentially be clinically beneficial in reducing dose-related toxicities.

    Matched MeSH terms: Breast Neoplasms/metabolism
  20. Fulltext Anti-Cancer Effects of Synergistic Drug-Bacterium Combinations on Induced Breast Cancer in BALB/c Mice
    Subramaniam M, Arshad NM, Mun KS, Malagobadan S, Awang K, Nagoor NH
    Biomolecules, 2019 10 18;9(10).
    PMID: 31635311 DOI: 10.3390/biom9100626
    Cancer development and progression are extremely complex due to the alteration of various genes and pathways. In most cases, multiple agents are required to control cancer progression. The purpose of this study is to investigate, using a mouse model, the synergistic interactions of anti-cancer agents, 1'-S-1'-acetoxychavicol acetate (ACA), Mycobacterium indicus pranii (MIP), and cisplatin (CDDP) in double and triple combinations to treat chemo-sensitize and immune-sensitize breast cancer. Changes in tumor volume and body weight were monitored. Organs were harvested and stained using hematoxylin-eosin for histopathological assessment. Milliplex enzyme-linked immunosorbent assay (ELISA) was performed to determine cytokine levels, while immunohistochemistry (IHC) was conducted on tumor biopsies to verify systemic drug effects. In vivo mouse models showed tumor regression with maintenance of regular body weight for all the different treatment regimens. IHC results provided conclusive evidence indicating that combination regimens were able to down-regulate nuclear factor kappa-B activation and reduce the expression of its regulated pro-inflammatory proteins. Reduction of pro-inflammatory cytokines (e.g., IL-6, TNF-α, and IFN-ɣ) levels were observed when using the triple combination, which indicated that the synergistic drug combination was able to significantly control cancer progression. In conclusion, ACA, MIP, and CDDP together serve as promising candidates for further development and for subsequent clinical trials against estrogen-sensitive breast cancer.
    Matched MeSH terms: Breast Neoplasms/metabolism
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