Publications by authors named "Nik Soriani Yaacob"

42 Publications

Hypomethylating Agents and Immunotherapy: Therapeutic Synergism in Acute Myeloid Leukemia and Myelodysplastic Syndromes.

Front Oncol 2021 25;11:624742. Epub 2021 Feb 25.

Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.

Decitabine and guadecitabine are hypomethylating agents (HMAs) that exert inhibitory effects against cancer cells. This includes stimulation of anti-tumor immunity in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) patients. Treatment of AML and MDS patients with the HMAs confers upregulation of cancer/testis antigens (CTAs) expression including the highly immunogenic CTA NY-ESO-1. This leads to activation of CD4 and CD8 T cells for elimination of cancer cells, and it establishes the feasibility to combine cancer vaccine with HMAs to enhance vaccine immunogenicity. Moreover, decitabine and guadecitabine induce the expression of immune checkpoint molecules in AML cells. In this review, the accumulating knowledge on the immunopotentiating properties of decitabine and guadecitabine in AML and MDS patients are presented and discussed. In summary, combination of decitabine or guadecitabine with NY-ESO-1 vaccine enhances vaccine immunogenicity in AML patients. T cells from AML patients stimulated with dendritic cell (DC)/AML fusion vaccine and guadecitabine display increased capacity to lyse AML cells. Moreover, decitabine enhances NK cell-mediated cytotoxicity or CD123-specific chimeric antigen receptor-engineered T cells antileukemic activities against AML. Furthermore, combination of either HMAs with immune checkpoint blockade (ICB) therapy may circumvent their resistance. Finally, clinical trials of either HMAs combined with cancer vaccines, NK cell infusion or ICB therapy in relapsed/refractory AML and high-risk MDS patients are currently underway, highlighting the promising efficacy of HMAs and immunotherapy synergy against these malignancies.
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http://dx.doi.org/10.3389/fonc.2021.624742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947882PMC
February 2021

Health-Related Quality of Life and Family Functioning of Primary Caregivers of Children with Cerebral Palsy in Malaysia.

Int J Environ Res Public Health 2021 02 28;18(5). Epub 2021 Feb 28.

Cerebral Palsy Research Cluster, Universiti Sains Malaysia, Kubang Kerian 16150, Kelantan, Malaysia.

Caregiving for children with cerebral palsy (CP) has proved to negatively impact on the physical and psychological well-being of their primary caregivers. The aim of the current study was to examine the overall impact of caregiving for children with CP on the primary caregivers' health-related quality of life (HRQOL) and family functioning, and to identify potential factors associated with primary caregivers' HRQOL and family functioning. The cross-sectional study involved a total of 159 primary caregivers of children with CP with a mean age of 42.8 ± 8.4 years. Demographic data and information on the physical and leisure activities of the primary caregivers were collected, and their quality of life (QOL) was measured based on the self-reported Pediatric Quality of Life Inventory Family Impact Module (PedsQL FIM). Primary caregivers in the current study have shown good HRQOL and family functioning, with scores of 82.4 and 85.3 out of 100, respectively. Through multiple linear regression analyses, the mother's level of education, family monthly income, sleeping problems in children with CP, and the existence of children with other types of disability have been identified as factors contributing to HRQOL and family functioning. The findings help set out the course for stakeholders to establish action to enhance the QOL of primary caregivers.
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http://dx.doi.org/10.3390/ijerph18052351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957778PMC
February 2021

2-Methoxy-1,4-Naphthoquinone (MNQ) Inhibits Glucose Uptake and Lactate Production in Triple-Negative Breast Cancer Cells.

Asian Pac J Cancer Prev 2021 Feb 1;22(S1):59-65. Epub 2021 Feb 1.

Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia.

Objective: The persistent activation of aerobic glycolysis in cancer cells results in accumulation of lactate and other metabolic intermediates that contribute to tumorigenesis. Increased glycolysis is frequently dysregulated in triple-negative breast cancer (TNBC), which promotes tumor growth and immune escape. This study was conducted to investigate the effect of 2-methoxy-1, 4-naphthoquinone (MNQ), compound extracted from Impatiens balsamina on glycolytic activities in human breast adenocarcinoma, MDA-MB-231 cells.

Methods: Initially, MTT proliferation assay was used to test the cell viability with various doses of MNQ (5-100 µM). As the half maximal inhibitory concentration (IC50) was obtained, glucose uptake and lactate assays of the cells were tested with IC50 dose of MNQ. The treated cells were also subjected to gene and protein analysis of glycolysis-related molecules (GLUT1 and Akt).

Results: The results showed that MNQ decreased the percentage of MDA-MB-231 cell viability in a dose-dependent manner with the IC50 value of 29 µM. The percentage of glucose uptake into the cells and lactate production decreased significantly after treatment with MNQ as compared to untreated cells. Remarkably, the expressions of GLUT1 and Akt molecules decreased in MNQ-treated cells, suggesting that the inhibition of glycolysis by MNQ is GLUT1-dependent and possibly mediated by the Akt signaling pathway.

Conclusion: Our findings indicate the ability of MNQ to inhibit the glycolytic activities as well as glycolysis-related molecules in MDA-MB-231 cells, suggesting the potential of MNQ to be further developed as an effective anticancer agent against TNBC cells.
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http://dx.doi.org/10.31557/APJCP.2021.22.S1.59DOI Listing
February 2021

Strobilanthes crispus bioactive subfraction inhibits tumor progression and improves hematological and morphological parameters in mouse mammary carcinoma model.

J Ethnopharmacol 2021 Mar 28;267:113522. Epub 2020 Oct 28.

Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, Kelantan, Malaysia. Electronic address:

Ethnopharmacological Relevance: Locally known as 'pecah batu', 'bayam karang', 'keci beling' or 'batu jin', the Malaysian medicinal herb, Strobilanthes crispus (S. crispus), is traditionally used by the local communities as alternative or adjuvant remedy for cancer and other ailments and to boost the immune system. S. crispus has demonstrated multiple anticancer therapeutic potential in vitro and in vivo. A pharmacologically active fraction of S. crispus has been identified and termed as F3. Major constituents profiled in F3 include lutein and β-sitosterol.

Aim Of The Study: In this study, the effects of F3, lutein and β-sitosterol on tumor development and metastasis were investigated in 4T1-induced mouse mammary carcinoma model.

Materials And Methods: Tumor-bearing mice were fed with F3 (100 mg/kg/day), lutein (50 mg/kg/day) and β-sitosterol (50 mg/kg/day) for 30 days (n = 5 each group). Tumor physical growth parameters, animal body weight and development of secondary tumors were investigated. The safety profile of F3 was assessed using hematological and histomorphological changes on the major organs in normal control mice (NM).

Results: Our findings revealed significant reduction of physical tumor growth parameters in all tumor-bearing mice treated with F3 (TM-F3), lutein (TM-L) or β-sitosterol (TM-β) as compared with the untreated group (TM). Statistically significant reduction in body weight was observed in TM compared to the NM or treated (TM-F3, TM-L and TM-β) groups. Histomorphological examination of tissue sections from the F3-treated group showed normal features of the vital organs (i.e., liver, kidneys, lungs and spleen) which were similar to those of NM. Administration of F3 to NM mice (NM-F3) did not cause significant changes in full blood count values.

Conclusion: F3 significantly reduced the total tumor burden and prevented secondary tumor development in metastatic breast cancer without significant toxicities in 4T1-induced mouse mammary carcinoma model. The current study provides further support for therapeutic development of F3 with further pharmacokinetics studies.
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http://dx.doi.org/10.1016/j.jep.2020.113522DOI Listing
March 2021

Oral health and nutritional status of children with cerebral palsy in northeastern peninsular Malaysia.

Spec Care Dentist 2020 Jan 27;40(1):62-70. Epub 2019 Nov 27.

Cerebral Palsy Research Cluster, Universiti Sains Malaysia, Kelantan, Malaysia.

Aims: To investigate the oral health and nutritional status of children with cerebral palsy (CP).

Methods And Results: Oral health assessment included dental caries and dental plaque maturity scores (DPMS) while the nutritional assessment included children's height-for-age Z-score (HAZ), body mass index-for-age Z-score (BAZ), mid-upper-arm circumference (MUAC), nutrient intake, cariogenic food frequency (CFF) and daily sugar exposure (DSE). Ninety-three CP children were recruited. The prevalence of caries was 81.7% (95% CI: 72.7%-88.3%). The median (IQR) of the DMFT and dft scores were 0.5(4.0) and 3.0(8.0), respectively. Most of the participants had acid-producing plaque (90.3%), severely stunted (81.4%), and 45% were severely thin with acute malnutrition. Intakes of calcium, iron, zinc, vitamin A, vitamin D and total fat were below 77% of the Recommended Nutrient Intakes for Malaysian children (RNI 2017). Nine types of cariogenic foods/drinks were consumed moderately, and DSE indicated that 45% of the children were at moderate risk of dental caries.

Conclusion: Untreated dental caries, severe stunting and thinness were prevalent, and cariogenic foods/drinks were consumed moderately suggesting a moderate risk of caries. Therefore, controlling cariogenic food intake is crucial, but monitoring daily nutrient intake is needed for the optimum growth of children with CP.
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http://dx.doi.org/10.1111/scd.12436DOI Listing
January 2020

Reinventing the Honey Industry: Opportunities of the Stingless Bee.

Malays J Med Sci 2018 Jul 30;25(4):1-5. Epub 2018 Aug 30.

Integrative Medicine Unit, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian Kelantan, Malaysia.

Honey is uniquely produced by honeybees ( sp.) and stingless bees ( sp.) and exhibits tremendous medicinal properties such as antimicrobial, anticarcinogen and antioxidant. However, it has not been included as a mainstream approach to disease management and has been disregarded in the modern pharmaceutical era. The stingless bee, which is known locally as in Malaysia, is an important species that is well adapted for tropical countries and has emerged as an alternative source of honey. The reinventing honey quality (RHQ) project was introduced in 2012 to empower growth in the stingless bee industry, which has a direct impact on the production of high-quality honey. The objectives of the project include transforming the industry into a sustainable source of income for beekeepers, while simultaneously catalysing bee conservation activities for plant and crop pollination, thus becoming a new medium for targeting socio-economies and ecology.
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http://dx.doi.org/10.21315/mjms2018.25.4.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6422541PMC
July 2018

The oncogenic roles of TRPM ion channels in cancer.

J Cell Physiol 2019 Feb 2. Epub 2019 Feb 2.

Department of Immunology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Kelantan, Malaysia.

Transient receptor potential (TRP) proteins are a diverse family of ion channels present in multiple types of tissues. They function as gatekeepers for responses to sensory stimuli including temperature, vision, taste, and pain through their activities in conducting ion fluxes. The TRPM (melastatin) subfamily consists of eight members (i.e., TRPM1-8), which collectively regulate fluxes of various types of cations such as K , Na , Ca , and Mg . Growing evidence in the past two decades indicates that TRPM ion channels, their isoforms, or long noncoding RNAs encoded within the locus may be oncogenes involved in the regulation of cancer cell growth, proliferation, autophagy, invasion, and epithelial-mesenchymal transition, and their significant association with poor clinical outcomes of cancer patients. In this review, we describe and discuss recent findings implicating TRPM channels in different malignancies, their functions, mechanisms, and signaling pathways involved in cancers, as well as summarizing their normal physiological functions and the availability of ion channel pharmacological inhibitors.
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http://dx.doi.org/10.1002/jcp.28168DOI Listing
February 2019

Strobilanthes crispus inhibits migration, invasion and metastasis in breast cancer.

J Ethnopharmacol 2019 Apr 28;233:13-21. Epub 2018 Dec 28.

Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia. Electronic address:

Ethnopharmacological Relevance: Strobilanthes crispus (L.) Blume, locally known in Malaysia as "Pecah kaca" or "Jin batu", has been traditionally used for treatment of various ailments including cancer. We previously demonstrated that a standardized bioactive subfraction of S. crispus, termed as F3, possessed potent anticancer effects in both in vitro and in vivo breast cancer models.

Aim Of The Study: To investigate the potential of F3 from S. crispus to prevent metastasis in breast cancer.

Materials And Methods: The antimetastatic effects of F3 were first investigated on murine 4T1 and human MDA-MB-231 breast cancer cell (BCC) lines using cell proliferation, wound healing and invasion assays. A 4T1-induced mouse mammary carcinoma model was then used to determine the expression of metastasis tumor markers, epithelial (E)-cadherin, matrix metalloproteinase (MMP)-9, mucin (MUC)-1, nonepithelial (N)-cadherin, Twist, vascular endothelial growth factor (VEGF) and vimentin, using immunohistochemistry, following oral treatment with F3 for 30 days.

Results: Significant growth arrest was observed with F3 IC values of 84.27 µg/ml (24 h) and 74.41 µg/ml (48 h) for MDA-MB-231, and 87.35 µg/ml (24 h) and 78.75 µg/ml (48 h) for 4T1 cells. F3 significantly inhibited migration of both BCC lines at 50 μg/ml for 24 h (p = 0.018 and p = 0.015, respectively). Similarly, significant inhibition of invasion was demonstrated in 4T1 (75 µg/ml, p = 0.016) and MDA-MB-231 (50 µg/ml, p = 0.040) cells compared to the untreated cultures. F3 treatment resulted in reduced tumor growth compared to untreated mice (p < 0.01) or mice treated with tamoxifen (p < 0.05). Statistical parameters (absolute count, proportion, intensity and overall scores) indicating upregulation of E-cadherin expression were statistically significant in F3-treated compared to the untreated tumor-bearing mice. Similarly, F3 significantly reduced the expression of MMP-9, MUC1, N-cadherin, Twist, VEGF and vimentin in comparison with the TM (p < 0.01) group CONCLUSIONS: Our findings suggest that F3 exerts anti-metastatic effects independent of its cytotoxic effects, and these are supported by the increased expression of E-cadherin concurrent with downregulation of MMP-9, MUC1, N-cadherin, Twist, VEGF and vimentin expression in breast cancer.
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http://dx.doi.org/10.1016/j.jep.2018.12.041DOI Listing
April 2019

Crosstalk between PPARγ Ligands and Inflammatory-Related Pathways in Natural T-Regulatory Cells from Type 1 Diabetes Mouse Model.

Biomolecules 2018 11 5;8(4). Epub 2018 Nov 5.

School of Health Sciences, Universiti Sains Malaysia, Kelantan, Kubang Kerian 16150, Malaysia.

Immunomodulation, as a means of immunotherapy, has been studied in major research and clinical laboratories for many years. T-Regulatory (Treg) cell therapy is one of the modulators used in immunotherapy approaches. Similarly, nuclear receptor peroxisome proliferator activated receptor gamma (PPARγ) has extensively been shown to play a role as an immuno-modulator during inflammation. Given their mutual roles in downregulating the immune response, current study examined the influence of PPARγ ligands i.e., thiazolidinedione (TZD) class of drugs on Forkhead Box P3 (Foxp3) expression and possible crosstalk between PPARγ and nTreg cells of Non-Obese Diabetes (NOD) and Non-Obese Diabetes Resistant (NOR) mice. Results showed that TZD drug, ciglitazone and natural ligand of PPARγ 15d-prostaglandin downregulated Foxp3 expression in activated nTreg cells from both NOD and NOR mice. Interestingly, addition of the PPARγ inhibitor, GW9662 further downregulated Foxp3 expression in these cells from both mice. We also found that PPARγ ligands negatively regulate Foxp3 expression in activated nTreg cells via PPARγ-independent mechanism(s). These results demonstrate that both natural and synthetic PPARγ ligands capable of suppressing Foxp3 expression in activated nTreg cells of NOD and NOR mice. This may suggest that the effect of PPARγ ligands in modulating Foxp3 expression in activated nTreg cells is different from their reported effects on effector T cells. Given the capability to suppress Foxp3 gene, it is possible to be tested as immunomodulators in cancer-related studies. The co-lateral use of PPARγ ligands in nTreg cells in inducing tolerance towards pseudo-self antigens as in tumor microenvironment may uphold beneficial outcomes.
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http://dx.doi.org/10.3390/biom8040135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6315476PMC
November 2018

Immunomodulatory effects of a bioactive fraction of Strobilanthes crispus in NMU-induced rat mammary tumor model.

J Ethnopharmacol 2018 Mar 1;213:31-37. Epub 2017 Nov 1.

Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia. Electronic address:

Ethnopharmacological Relevance: Strobilanthes crispus Blume is traditionally consumed among local Malay and indigenous communities for the treatment of cancer and other ailments such as gastrointestinal disorders, inflammatory wounds of snake bite and immune system activation amongst others. We previously demonstrated that a bioactive fraction of S. crispus leaves (F3) was cytotoxic to breast cancer cells in vitro and inhibited tumor growth in N-methyl-N-nitrosourea (NMU)-induced breast cancer rat model. F3 also normalized the white blood cell count in the tumor-bearing animals, indicating its potential immuno-stimulatory effect.

Aim Of The Study: To evaluate the immune stimulatory effects of F3 from S. crispus in NMU-induced rat mammary tumor model.

Materials And Methods: Immunohistochemistry analysis of cellular immune parameters (CD4 or CD8 T cells, CIITA, MHC-II and CD68) was performed on NMU-induced rat mammary tumor nodules, followed by evaluation of the serum level of 34 cytokines using the cytokine antibody array.

Results: Significant increase in MHC-II, CD4 and CD8 T cell and CIITA expression by tumor cells was observed in F3-treated rats compared to the tumor control group. F3-treated rats also displayed a significant decrease in the serum level of CCL2 and CD68 infiltrating macrophages. Serum IFN-γ level in this group was increased by 1.7-fold suggesting enhanced infiltration of T cells, and upregulation of CIITA and MHC-II expression in the tumor cells might be triggered by F3-induced production of IFN-γ.

Conclusion: Our findings demonstrated for the first time that a subfraction from S. crispus, F3, is capable of activating the immune system in rats-bearing NMU-induced mammary tumor, which may contribute to the anticancer effects of F3, and additionally support the traditional use of S. crispus leaves to boost the immune system.
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http://dx.doi.org/10.1016/j.jep.2017.10.024DOI Listing
March 2018

The role of REST and HDAC2 in epigenetic dysregulation of Nav1.5 and nNav1.5 expression in breast cancer.

Cancer Cell Int 2017 1;17:74. Epub 2017 Aug 1.

Institute for Research in Molecular Medicine (INFORMM), Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan Malaysia.

Background: Increased expression of voltage-gated sodium channels (VGSCs) have been implicated with strong metastatic potential of human breast cancer in vitro and in vivo where the main culprits are cardiac isoform Nav1.5 and its 'neonatal' splice variant, nNav1.5. Several factors have been associated with Nav1.5 and nNav1.5 gain of expression in breast cancer mainly hormones, and growth factors.

Aim: This study aimed to investigate the role of epigenetics via transcription repressor, repressor element silencing transcription factor (REST) and histone deacetylases (HDACs) in enhancing Nav1.5 and nNav1.5 expression in human breast cancer by assessing the effect of HDAC inhibitor, trichostatin A (TSA).

Methods: The less aggressive human breast cancer cell line, MCF-7 cells which lack Nav1.5 and nNav1.5 expression was treated with TSA at a concentration range 10-10,000 ng/ml for 24 h whilst the aggressive MDA-MB-231 cells was used as control. The effect of TSA on Nav1.5, nNav1.5, REST, HDAC1, HDAC2, HDAC3, MMP2 and N-cadherin gene expression level was analysed by real-time PCR. Cell growth (MTT assay) and metastatic behaviors (lateral motility and migration assays) were also measured.

Results: mRNA expression level of Nav1.5 and nNav1.5 were initially very low in MCF-7 compared to MDA-MB-231 cells. Inversely, mRNA expression level of REST, HDAC1, HDAC2, and HDAC3 were all greater in MCF-7 compared to MDA-MB-231 cells. Treatment with TSA significantly increased the mRNA expression level of Nav1.5 and nNav1.5 in MCF-7 cells. On the contrary, TSA significantly reduced the mRNA expression level of REST and HDAC2 in this cell line. Remarkably, despite cell growth inhibition by TSA, motility and migration of MCF-7 cells were enhanced after TSA treatment, confirmed with the up-regulation of metastatic markers, MMP2 and N-cadherin.

Conclusions: This study identified epigenetics as another factor that regulate the expression level of Nav1.5 and nNav1.5 in breast cancer where REST and HDAC2 play important role as epigenetic regulators that when lacking enhances the expression of Nav1.5 and nNav1.5 thus promotes motility and migration of breast cancer. Elucidation of the regulatory mechanisms for gain of Nav1.5 and nNav1.5 expression may be helpful for seeking effective strategies for the management of metastatic diseases.
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http://dx.doi.org/10.1186/s12935-017-0442-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540501PMC
August 2017

Compatibility of Porous Chitosan Scaffold with the Attachment and Proliferation of human Adipose-Derived Stem Cells .

J Stem Cells Regen Med 2016 29;12(2):79-86. Epub 2016 Nov 29.

Reconstructive Sciences Unit, School of Medical Sciences, Universiti Sains Malaysia, 16150, Kubang Kerian, Kelantan, Malaysia.

Adipose-derived stem cells (ASCs) have potential applications in the repair and regeneration of various tissues and organs. The use of various scaffold materials as an excellent template for mimicking the extracellular matrix to induce the attachment and proliferation of different cell types has always been of interest in the field of tissue engineering because ideal biomaterials are in great demand. Chitosan, a marine polysaccharide, have wide clinical applications and it acts as a promising scaffold for cell migration and proliferation. ASCs, with their multi-differentiation potential, and chitosan, with its great biocompatibility with ASCs, were investigated in the present study. ASCs were isolated and were characterized by two different methods: immunocytochemistry and flow cytometry, using the mesenchymal stem cell markers CD90, CD105, CD73 and CD29. The ASCs were then induced to differentiate into adipogenic, osteogenic and chondrogenic lineages. These ASCs were incorporated into a porous chitosan scaffold (PCS), and their structural morphology was studied using a scanning electron microscope and hematoxylin and eosin staining. The proliferation rate of the ASCs on the PCS was assessed using a PrestoBlue viability assay. The results indicated that the PCS provides an excellent template for the adhesion and proliferation of ASCs. Thus, this study revealed that PCS is a promising biomaterial for inducing the proliferation of ASCs, which could lead to successful tissue reconstruction in the field of tissue engineering.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5227107PMC
November 2016

The Immunomodulatory Potential of Selected Bioactive Plant-Based Compounds in Breast Cancer: A Review.

Anticancer Agents Med Chem 2017 ;17(6):770-783

Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia.

Breast cancer has continued to cause high cancer death rates among women worldwide. The use of plants' natural products in breast cancer treatment has received more attention in recent years due to their potentially wider safety margin and the potential to complement conventional chemotherapeutic drugs. Plantbased products have demonstrated anticancer potential through different biological pathways including modulation of the immune system. Immunomodulatory properties of medicinal plants have been shown to mitigate breast cancer cell growth. Different immune cell types participate in this process especially cytotoxic T cells and natural killer cells, and cytokines including chemokines and tumor necrosis factor-α. Medicinal plants such as Glycyrrhiza glabra, Uncaria tomentosa, Camellia sinensis, Panax ginseng, Prunus armenaica (apricot), Allium sativum, Arctium lappa and Curcuma longa were reported to hold strong potential in breast cancer treatment in various parts of the world. Interestingly, research findings have shown that these plants possess bioactive immunomodulators as their main constituents producing the anticancer effects. These immunomodulatory compounds include ajoene, arctigenin, β-carotene, curcumin, epigallocatechin-3-gallate, ginsan, glabridin and quinic acid. In this review, we discussed the ability of these eight immunomodulators in regulating the immune system potentially applicable in breast cancer treatment via anti-inflammatory (curcumin, arctigenin, glabridin and ajoene) and lymphocytes activation (β-carotene, epigallocatechin-3-gallate, quinic acid and ginsan) properties, as well as future research direction in their use for breast cancer treatment.
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http://dx.doi.org/10.2174/1871520616666160817111242DOI Listing
August 2017

15d-PGJ2 Induces Apoptosis of MCF-7 and MDA-MB-231 Cells via Increased Intracellular Calcium and Activation of Caspases, Independent of ERα and ERβ.

Asian Pac J Cancer Prev 2016 ;17(7):3223-8

affiliation E-mail : email.

Reports indicate that 15deoxydelta12,14prostaglandinJ2 (15dPGJ2) has anticancer activities, but its mechanisms of action have yet to be fully elucidated. We therefore investigated the effects of 15dPGJ2 on the human breast cancer cell lines, MCF7 (estrogen receptor ERα+/ERβ+) and MDAMB231 (ERα/ERβ+). Cellular proliferation and cytotoxicity were determined using the 3(4,5dimethylthiazol2yl)2,5diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays while apoptosis was determined by fluorescence microscopy and flow cytometry using annexin Vpropidium iodide (PI) staining. ER expression was determined by Western blotting. Intracellular calcium was stained with Fluo4 AM while intracellular caspase activities were detected with CaspaseFLICA® and measured by flow cytometry. We showed that 15dPGJ2 caused a significant increase in apoptosis in MCF7 and MDAMB231 cells. ERα protein expression was reduced in treated MCF7 cells but preincubation with the ERα inhibitor' ICI 182 780' did not affect the percentage of apoptotic cells. The expression of ERβ was unchanged in both cell lines. In addition, 15dPGJ2 increased intracellular calcium (Ca²+) staining and caspase 8, 9 and3/7 activities. We therefore conclude that 15dPGJ2 induces caspasedependent apoptosis that is associated with an influx of intracellular Ca²+ with no involvement of ER signaling.
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February 2017

The flavonoid fisetin as an anticancer agent targeting the growth signaling pathways.

Eur J Pharmacol 2016 Oct 2;789:8-16. Epub 2016 Jul 2.

Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia. Electronic address:

Epidemiological studies show that consumption of diets rich in fruits and vegetables is associated with lower risks of cancer. This evidence has kindled interest into research on bioactive food components and has till date resulted in the identification of many compounds with cancer preventive and therapeutic potential. Among such compounds is fisetin (3,7,3,4-tetrahydroxyflavone), a flavonol that is commonly found in many fruits and vegetables such as apples, persimmons, grapes, kiwis, strawberries, onions and cucumbers. Fisetin has been shown to inhibit or retard the growth of various cancer cells in culture and implanted tumors in vivo. Fisetin targets many components of intracellular signaling pathways including regulators of cell survival and apoptosis, tumor angiogenic and metastatic switches by modulating a distinct set of upstream kinases, transcription factors and their regulators. Current evidence supports the idea that fisetin is a promising agent for cancer treatment. This review summarizes reported anticancer effects of fisetin, and re-emphasizes its potential therapeutic role in the treatment of cancer.
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http://dx.doi.org/10.1016/j.ejphar.2016.07.001DOI Listing
October 2016

Report on von Willebrand Disease in Malaysia.

Open Access Maced J Med Sci 2016 Mar 29;4(1):112-7. Epub 2016 Feb 29.

Hemophilia Clinic, National Blood Centre (Pusat Darah Negara), Jalan Tun Razak, 50400, Wilayah Persekutuan, Kuala Lumpur, Malaysia.

Background: Von Willebrand disease (vWD) is an inherited hemostatic disorder that affects the hemostasis pathway. The worldwide prevalence of vWD is estimated to be 1% of the general population but only 0.002% in Malaysia.

Aim: Our present paper has been written to disclose the statistical counts on the number of vWD cases reported from 2011 to 2013.

Material And Methods: This article is based on sociodemographic data, diagnoses and laboratory findings of vWD in Malaysia. A total of 92 patients were reported to have vWD in Malaysia from 2011 to 2013.

Results: Sociodemographic-analysis revealed that 60% were females, 63% were of the Malay ethnicity, 41.3% were in the 19-44 year old age group and 15.2% were from Sabah, with the East region having the highest registered number of vWD cases. In Malaysia, most patients are predominately affected by vWD type 1 (77.2%). Factor 8, von Willebrand factor: Antigen and vWF: Collagen-Binding was the strongest determinants in the laboratory profiles of vWD.

Conclusion: This report has been done with great interest to provide an immense contribution from Malaysia, by revealing the statistical counts on vWD from 2011-2013.
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http://dx.doi.org/10.3889/oamjms.2016.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4884229PMC
March 2016

Cell Cycle Modulation of MCF-7 and MDA-MB-231 by a Sub- Fraction of Strobilanthes crispus and its Combination with Tamoxifen.

Asian Pac J Cancer Prev 2015 ;16(18):8135-40

Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia Health Campus, Kubang Kerian, Kelantan, Malaysia E-mail :

Background: Cell cycle regulatory proteins are suitable targets for cancer therapeutic development since genetic alterations in many cancers also affect the functions of these molecules. Strobilanthes crispus (S. crispus) is traditionally known for its potential benefits in treating various ailments. We recently reported that an active sub-fraction of S. crispus leaves (SCS) caused caspase-dependent apoptosis of human breast cancer MCF-7 and MDA-MB-231 cells.

Materials And Methods: Considering the ability of SCS to also promote the activity of the antiestrogen, tamoxifen, we further examined the effect of SCS in modulating cell cycle progression and related proteins in MCF-7 and MDA-MB-231 cells alone and in combination with tamoxifen. Expression of cell cycle- related transcripts was analysed based on a previous microarray dataset.

Results: SCS significantly caused G1 arrest of both types of cells, similar to tamoxifen and this was associated with modulation of cyclin D1, p21 and p53. In combination with tamoxifen, the anticancer effects involved downregulation of ERα protein in MCF-7 cells but appeared independent of an ER-mediated mechanism in MDA-MB-231 cells. Microarray data analysis confirmed the clinical relevance of the proteins studied.

Conclusions: The current data suggest that SCS growth inhibitory effects are similar to that of the antiestrogen, tamoxifen, further supporting the previously demonstrated cytotoxic and apoptotic actions of both agents.
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http://dx.doi.org/10.7314/apjcp.2015.16.18.8135DOI Listing
October 2016

Chitosan scaffold enhances growth factor release in wound healing in von Willebrand disease.

Int J Clin Exp Med 2015 15;8(9):15611-20. Epub 2015 Sep 15.

Industrial Biotechnology Research Centre, SIRIM Berhad No. 1 Persiaran Dato' Menteri, Section 2, P. O. Box 7035, Shah Alam 40700, Selangor, Malaysia.

Chitosan-derived biomaterials have been reported to adhere when in contact with blood by encouraging platelets to adhere, activate and aggregate at the sites of vascular injury, thus enhanced wound healing capacity. This study investigated platelet morphology changes and the expression level of transforming growth factor-β1 (TGF-β1) and platelet-derived growth factor-AB (PDGF-AB) in the adherence of two different types of chitosans in von Willebrand disease (vWD): N,O-carboxymethylchitosan (NO-CMC) and oligo-chitosan (O-C). Fourteen vWD voluntary subjects were recruited, and they provided written informed consent. Scanning electron microscopy and enzyme-linked immunosorbent assay test procedures were employed to achieve the objective of the study. The results suggest that the O-C group showed dramatic changes in the platelet's behaviors. Platelets extended filopodia and generated lamellipodia, leading to the formation of grape-like shaped aggregation. The platelet aggregation occurred depending on the severity of vWD. O-C was bound to platelets on approximately 90% of the surface membrane in vWD type 1; there was 70% and 50% coverage in vWD type II and III, respectively. The O-C chitosan group showed an elevated expression level of TGF-β1 and PDGF-AB. This finding suggests that O-C stimulates these mediators from the activated platelets to the early stage of restoring the damaged cells and tissues. This study demonstrated that the greater expression level of O-C assists in mediating the cytokine complex networks of TGF-β1 and PDGF-AB and induces platelet activities towards wound healing in vWD. With a better understanding of chitosan's mechanisms of action, researchers are able to accurately develop novel therapies to prevent hemorrhage.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4658944PMC
December 2015

Effect of the Novel Biodegradable N, O-Carboxymethylchitosan and Oligo-Chitosan on the Platelet Thrombogenicity Cascade in von Willebrand Disease.

Thromb Res 2015 Sep 30;136(3):625-33. Epub 2015 Jul 30.

Industrial Biotechnology Research Centre, SIRIM Berhad, No. 1 Persiaran Dato' Menteri, Section 2, P.O. Box 7035, 40700 Shah Alam, Selangor, Malaysia. Electronic address:

Introduction: Von Willebrand disease (vWD) is the second least common hemostatic disorder in Malaysia, and it has a low prevalence. This study examined the underlying platelet thrombogenicity cascades in the presence of different formulations of chitosan-derivatives in vWD patients. This paper aimed to determine the significant influence of chitosan biomaterial in stimulating the platelet thrombogenicity cascades that involve the von Willebrand factor, Factor 8, Thromboxane A2, P2Y12 and Glycoprotein IIb/IIIa in vWD.

Materials And Methods: Variable chitosan formulations of N,O-Carboxymethylchitosan (NO-CMC) and Oligo-Chitosan (O-C) were tested. Fourteen vWD subjects voluntarily participated in this study after signing informed consent forms. The patient's demographic profiles, family history, type of vWD, clinical symptoms and laboratory profiles were recorded and analyzed. Enzyme-linked immunosorbent assay, flow cytometry and Western blot tests were used to determine the level of the chitosan-adhered-platelet-mechanisms.

Results: The study revealed that most patients were predominantly affected by vWD type I. The O-C group of chitosan's scaffold pores is sufficient to allow for nutrients and cells. The O-C-stimulated-mediators are capable of initiating the platelet actions and were detected to expedite the blood coagulation processes. The oligo-group of chitosans was capable of amplifying and triggering more platelet activator's pathways via the studied mediators. The present findings suggest that the ability of each type of chitosan to coagulate blood varies depending on its chemical composition.

Conclusion: The oligo group of chitosans is potentially capable of triggering platelet thrombogenicity cascades by activating platelets in vWD patients to form a platelet plug for hemostasis process.
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http://dx.doi.org/10.1016/j.thromres.2015.07.027DOI Listing
September 2015

Anti-Tumor Action, Clinical Biochemistry Profile and Phytochemical Constituents of a Pharmacologically Active Fraction of S. crispus in NMU-Induced Rat Mammary Tumour Model.

PLoS One 2015 22;10(5):e0126426. Epub 2015 May 22.

Centre for Drug Research, Universiti Sains Malaysia, Pulau Pinang, Malaysia.

Cancer patients seek alternative remedies such as traditional medicinal plants for safe and effective treatment and help overcome the side effects of conventional therapy. Current knowledge indicates that extracts of Strobilanthes crispus of the Acanthaceae family exhibit potent anticancer properties in vitro and are non-toxic in vivo. S. crispus was also reported to be protective against chemical hepatocarcinogenesis. We previously showed that a bioactive fraction of S. crispus leaves also synergized with tamoxifen to cause apoptosis of human breast cancer cell lines without damaging non-malignant epithelial cells. The present study aimed to evaluate the antitumor effect of S. crispus dichloromethane fraction (F3) using N-methyl-N-Nitrosourea (NMU)-induced rat mammary tumor model. Tumor regression was observed in 75% of the rats following 8-week oral administration of F3 with no secondary tumour formation and no signs of anemia or infection. However, no improvement in the liver and renal function profiles was observed. Major constituents of F3 were identified as lutein, 131-hydroxy-132-oxo-pheophytin a, campesterol, stigmasterol, β-sitosterol, pheophytin a and 132-hydroxy-pheophytin a. These compounds however, may not significantly contribute to the antitumor effect of F3.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0126426PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4441459PMC
April 2016

Proliferation of keratinocytes induced by adipose-derived stem cells on a chitosan scaffold and its role in wound healing, a review.

Arch Plast Surg 2014 Sep 15;41(5):452-7. Epub 2014 Sep 15.

Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia.

In the field of tissue engineering and reconstruction, the development of efficient biomaterial is in high demand to achieve uncomplicated wound healing. Chronic wounds and excessive scarring are the major complications of tissue repair and, as this inadequate healing continues to increase, novel therapies and treatments for dysfunctional skin repair and reconstruction are important. This paper reviews the various aspects of the complications related to wound healing and focuses on chitosan because of its unique function in accelerating wound healing. The proliferation of keratinocytes is essential for wound closure, and adipose-derived stem cells play a significant role in wound healing. Thus, chitosan in combination with keratinocytes and adipose-derived stem cells may act as a vehicle for delivering cells, which would increase the proliferation of keratinocytes and help complete recovery from injuries.
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http://dx.doi.org/10.5999/aps.2014.41.5.452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4179346PMC
September 2014

Glycoprotein IIb/IIIa and P2Y12 induction by oligochitosan accelerates platelet aggregation.

Biomed Res Int 2014 28;2014:653149. Epub 2014 Aug 28.

Industrial Biotechnology Research Centre, SIRIM Berhad, No. 1 Persiaran Dato' Menteri, Section 2, P.O. Box 7035, 40700 Shah Alam, Selangor, Malaysia.

Platelet membrane receptor glycoprotein IIb/IIIa (gpiibiiia) is a receptor detected on platelets. Adenosine diphosphate (ADP) activates gpiibiiia and P2Y12, causing platelet aggregation and thrombus stabilization during blood loss. Chitosan biomaterials were found to promote surface induced hemostasis and were capable of activating blood coagulation cascades by enhancing platelet aggregation. Our current findings show that the activation of the gpiibiiia complex and the major ADP receptor P2Y12 is required for platelet aggregation to reach hemostasis following the adherence of various concentrations of chitosan biomaterials [7% N,O-carboxymethylchitosan (NO-CMC) with 0.45 mL collagen, 8% NO-CMC, oligochitosan (O-C), and oligochitosan 53 (O-C 53)]. We studied gpiibiiia and P2Y12 through flow cytometric analysis and western blotting techniques. The highest expression of gpiibiiia was observed with Lyostypt (74.3 ± 7.82%), followed by O-C (65.5 ± 7.17%). Lyostypt and O-C resulted in gpiibiiia expression increases of 29.2% and 13.9%, respectively, compared with blood alone. Western blot analysis revealed that only O-C 53 upregulated the expression of P2Y12 (1.12 ± 0.03-fold) compared with blood alone. Our findings suggest that the regulation of gpiibiiia and P2Y12 levels could be clinically useful to activate platelets to reach hemostasis. Further, we show that the novel oligochitosan is able to induce the increased expression of gpiibiiia and P2Y12, thus accelerating platelet aggregation in vitro.
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http://dx.doi.org/10.1155/2014/653149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4163351PMC
June 2015

Correlation of tumour response with starting tumour size and dose of tamoxifen in an N-methyl-N-nitrosourea (NMU)-induced rat mammary cancer model.

Asian Pac J Cancer Prev 2014 ;15(16):6721-6

Departments of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia, Kubang Kerian, Malaysia E-mail :

Background: The aim of this preliminary study was to address variations of responses observed with different starting tumor sizes of 10 and 15 mm, and the effects of different doses of tamoxifen (TAM) on experimental rat mammary tumors.

Materials And Methods: Thirty-five inbred female Sprague Dawley rats aged 43 days were administered with three weekly doses of N-methyl-N-nitrosourea (NMU) intraperitoneally (ip) at 50 mg/kg body weight. Animals were randomized (beginning from 10 mm tumor size) into four TAM-treated (50, 100, 200 and 500 μg/day) groups of six animals each, and another group (n=6) treated with TAM 100 μg/day at starting tumour size of 15 mm. The animals were treated by oral gavage daily for 8 weeks before sacrifice.

Results: Serum urea and creatinine, and overall physical tumor burden were significantly modulated in animals treated with variable doses of TAM compared to the untreated controls (n=5). Final body weight and tumor number were significantly different in the 10 mm-treated animals compared to those treated at 15 mm. There were no significant differences in histopathological features among all the groups.

Conclusions: Our findings suggest the importance of standardizing tumour size and drug doses before initiation of treatment, particularly in the direct comparison of basic end-tumour physical parameters.
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http://dx.doi.org/10.7314/apjcp.2014.15.16.6721DOI Listing
June 2015

Synergistic anticancer effects of a bioactive subfraction of Strobilanthes crispus and tamoxifen on MCF-7 and MDA-MB-231 human breast cancer cell lines.

BMC Complement Altern Med 2014 Jul 18;14:252. Epub 2014 Jul 18.

Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia.

Background: Development of tumour resistance to chemotherapeutic drugs and concerns over their toxic effects has led to the increased use of medicinal herbs or natural products by cancer patients. Strobilanthes crispus is a traditional remedy for many ailments including cancer. Its purported anticancer effects have led to the commercialization of the plant leaves as medicinal herbal tea, although the scientific basis for its use has not been established. We previously reported that a bioactive subfraction of Strobilanthes crispus leaves (SCS) exhibit potent cytotoxic activity against human breast cancer cell lines. The current study investigates the effect of this subfraction on cell death activities induced by the antiestrogen drug, tamoxifen, in estrogen receptor-responsive and nonresponsive breast cancer cells.

Methods: Cytotoxic activity of SCS and tamoxifen in MCF-7 and MDA-MB-231 human breast cancer cells was determined using lactate dehydrogenase release assay and synergism was evaluated using the CalcuSyn software. Apoptosis was quantified by flow cytometry following Annexin V and propidium iodide staining. Cells were also stained with JC-1 dye to determine changes in the mitochondrial membrane potential. Fluorescence imaging using FAM-FLICA assay detects caspase-8 and caspase-9 activities. DNA damage in the non-malignant breast epithelial cell line, MCF-10A, was evaluated using Comet assay.

Results: The combined SCS and tamoxifen treatment displayed strong synergistic inhibition of MCF-7 and MDA-MB-231 cell growth at low doses of the antiestrogen. SCS further promoted the tamoxifen-induced apoptosis that was associated with modulation of mitochondrial membrane potential and activation of caspase-8 and caspase-9, suggesting the involvement of intrinsic and extrinsic signaling pathways. Interestingly, the non-malignant MCF-10A cells displayed no cytotoxicity or DNA damage when treated with either SCS or SCS-tamoxifen combination.

Conclusions: The combined use of SCS and lower tamoxifen dose could potentially reduce the side effects/toxicity of the drug. However, further studies are needed to determine the effectiveness and safety of the combination treatment in vivo.
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http://dx.doi.org/10.1186/1472-6882-14-252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4223515PMC
July 2014

Cytotoxic benzophenone and triterpene from Garcinia hombroniana.

Bioorg Chem 2014 Jun 23;54:60-7. Epub 2014 Apr 23.

Department of Chemistry, Kohat University of Science and Technology, Kohat, 26000 Kohat, Khyber Pakhtunkhwa, Pakistan.

Garcinia hombroniana (seashore mangosteen) in Malaysia is used to treat itching and as a protective medicine after child birth. This study was aimed to investigate the bioactive chemical constituents of the bark of G. hombroniana. Ethyl acetate and dichloromethane extracts of G. hombroniana yielded two new (1, 9) and thirteen known compounds which were characterized by the spectral techniques of NMR, UV, IR and EI/ESI-MS, and identified as; 2,3',4,5'-tetrahydroxy-6-methoxybenzophenone(1), 2,3',4,4'-tetrahydroxy-6-methoxybenzophenone (2), 2,3',4,6-tetrahydroxybenzophenone (3), 1,3,6,7-tetrahydroxyxanthone (4), 3,3',4',5,7-pentahydroxyflavone (5),3,3',5,5',7-pentahydroxyflavanone (6), 3,3',4',5,5',7-hexahydroxyflavone (7), 4',5,7-trihydroxyflavanone-7-rutinoside (8), 18(13→17)-abeo-3β-acetoxy-9α,13β-lanost-24E-en-26-oic acid (9), garcihombronane B (10), garcihombronane D (11), friedelan-3-one (12), lupeol (13), stigmasterol (14) and stigmasterol glucoside (15). In the in vitro cytotoxicity against MCF-7, DBTRG, U2OS and PC-3 cell lines, compounds 1 and 9 displayed good cytotoxic effects against DBTRG cancer cell lines. Compounds 1-8 were also found to possess significant antioxidant activities. Owing to these properties, this study can be further extended to explore more significant bioactive components of this plant.
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http://dx.doi.org/10.1016/j.bioorg.2014.04.003DOI Listing
June 2014

Comparison of cytotoxicity and genotoxicity of 4-hydroxytamoxifen in combination with Tualang honey in MCF-7 and MCF-10A cells.

BMC Complement Altern Med 2014 Mar 19;14:106. Epub 2014 Mar 19.

Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia, Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia.

Background: The Malaysian Tualang honey (TH) is not only cytotoxic to human breast cancer cell lines but it has recently been reported to promote the anticancer activity induced by tamoxifen in MCF-7 and MDA-MB-231 cells suggesting its potential as an adjuvant for the chemotherapeutic agent. However, tamoxifen produces adverse effects that could be due to its ability to induce cellular DNA damage. Therefore, the study is undertaken to determine the possible modulation of the activity of 4-hydroxytamoxifen (OHT), an active metabolite of tamoxifen, by TH in non-cancerous epithelial cell line, MCF-10A, in comparison with MCF-7 cells.

Methods: MCF-7 and MCF-10A cells were treated with TH, OHT or the combination of both and cytotoxicity and antiproliferative activity were determined using LDH and MTT assays, respectively. The effect on cellular DNA integrity was analysed by comet assay and the expression of DNA repair enzymes was determined by Western blotting.

Results: OHT exposure was cytotoxic to both cell lines whereas TH was cytotoxic to MCF-7 cells only. TH also significantly decreased the cytotoxic effect of OHT in MCF-10A but not in MCF-7 cells. TH induced proliferation of MCF10A cells but OHT caused growth inhibition that was abrogated by the concomitant treatment with TH. While TH enhanced the OHT-induced DNA damage in the cancer cells, it dampened the genotoxic effect of OHT in the non-cancerous cells. This was supported by the increased expression of DNA repair proteins, Ku70 and Ku80, in MCF-10A cells by TH.

Conclusion: The findings indicate that TH could afford protection of non-cancerous cells from the toxic effects of tamoxifen by increasing the efficiency of DNA repair mechanism in these cells.
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http://dx.doi.org/10.1186/1472-6882-14-106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3994783PMC
March 2014

Influence of 17β-estradiol on 15-deoxy-δ12,14 prostaglandin J2 -induced apoptosis in MCF-7 and MDA-MB-231 cells.

Asian Pac J Cancer Prev 2013 ;14(11):6761-7

Department of Chemical Pathology, Universiti Sains Malaysia, Health Campus, Kelantan, Malaysia E-mail :

The nuclear receptor, peroxisome proliferator-activated receptor gamma (PPARγ), is expressed in various cancer cells including breast, prostate, colorectal and cervical examples. An endogenous ligand of PPARγ, 15-deoxy-Δ12,14 prostaglandin J2 (PGJ2), is emerging as a potent anticancer agent but the exact mechanism has not been fully elucidated, especially in breast cancer. The present study compared the anticancer effects of PGJ2 on estrogen receptor alpha (ERα)-positive (MCF-7) and ERα-negative (MDA-MB-231) human breast cancer cells. Based on the reported signalling cross-talk between PPARγ and ERα, the effect of the ERα ligand, 17β-estradiol (E2) on the anticancer activities of PGJ2 in both types of cells was also explored. Here we report that PGJ2 inhibited proliferation of both MCF-7 and MDA-MB-231 cells by inducing apoptotic cell death with active involvement of mitochondria. The presence of E2 potentiated PGJ2-induced apoptosis in MCF-7, but not in MDA-MB-231 cells. The PPARγ antagonist, GW9662, failed to block PGJ2-induced activities but potentiated its effects in MCF-7 cells, instead. Interestingly, GW9662 also proved capable of inducing apoptotic cell death. It can be concluded that E2 enhances PPARγ-independent anticancer effects of PGJ2 in the presence of its receptor.
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http://dx.doi.org/10.7314/apjcp.2013.14.11.6761DOI Listing
August 2014

Tualang honey promotes apoptotic cell death induced by tamoxifen in breast cancer cell lines.

Evid Based Complement Alternat Med 2013 13;2013:989841. Epub 2013 Feb 13.

Department of Chemical Pathology, School of Medical Sciences, Universiti Sains Malaysia, Malaysia Health Campus, 16150 Kubang Kerian, Kelantan, Malaysia.

Tualang honey (TH) is rich in flavonoids and phenolic acids and has significant anticancer activity against breast cancer cells comparable to the effect of tamoxifen (TAM), in vitro. The current study evaluated the effects of TH when used in combination with TAM on MCF-7 and MDA-MB-231 cells. We observed that TH promoted the anticancer activity of TAM in both the estrogen receptor-(ER-)responsive and ER-nonresponsive human breast cancer cell lines. Flow cytometric analyses indicated accelerated apoptosis especially in MDA-MB-231 cells and with the involvement of caspase-3/7, -8 and -9 activation as shown by fluorescence microscopy. Depolarization of the mitochondrial membrane was also increased in both cell lines when TH was used in combination with TAM compared to TAM treatment alone. TH may therefore be a potential adjuvant to be used with TAM for reducing the dose of TAM, hence, reducing TAM-induced adverse effects.
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http://dx.doi.org/10.1155/2013/989841DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3586458PMC
April 2013

Keloid pathogenesis via Drosophila similar to mothers against decapentaplegic (SMAD) signaling in a primary epithelial-mesenchymal in vitro model treated with biomedical-grade chitosan porous skin regenerating template.

J Biosci Bioeng 2013 Apr 22;115(4):453-8. Epub 2012 Nov 22.

Department of Orthopaedic Surgery, University of Malaya, Kuala Lumpur, Malaysia.

The effects of locally produced chitosan (CPSRT-NC-bicarbonate) in the intervention of keloid pathogenesis were investigated in vitro. A human keratinocyte-fibroblast co-culture model was established to investigate the protein levels of human collagen type-I, III and V in a western blotting analysis, the secreted transforming growth factor-β1 (TGF-β1) in an enzyme-linked immunosorbent assay (ELISA) and the mRNA levels of TGF-β1's intracellular signaling molecules (SMAD2, 3, 4 and 7) in a real-time PCR analysis. Keratinocyte-fibroblast co-cultures were maintained in DKSFM:DMEM:F12 (2:2:1) medium. Collagen type-I was found to be the dominant form in primary normal human dermal fibroblast (pNHDF) co-cultures, whereas collagen type-III was more abundant in primary keloid-derived human dermal fibroblast (pKHDF) co-cultures. Collagen type-V was present as a minor component in the skin. TGF-β1, SMAD2 and SMAD4 were expressed more in the pKHDF than the pNHDF co-cultures. Co-cultures with normal keratinocytes suppressed collagen type-III, SMAD2, SMAD4 and TGF-β1 expressions and CPSRT-NC-bicarbonate enhanced this effect. In conclusion, the CPSRT-NC-bicarbonate in association with normal-derived keratinocytes demonstrated an ability to reduce TGF-β1, SMAD2 and SMAD4 expressions in keloid-derived fibroblast cultures, which may be useful in keloid intervention.
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http://dx.doi.org/10.1016/j.jbiosc.2012.10.010DOI Listing
April 2013

The modulation of PPARγ1 and PPARγ2 mRNA expression by ciglitazone in CD3/CD28-activated naïve and memory CD4+ T cells.

Clin Dev Immunol 2012 2;2012:849195. Epub 2012 Apr 2.

School of Health Sciences, Universiti Sains Malaysia, Kelantan, 16150 Kubang Kerian, Malaysia.

Given their roles in immune regulation, the expression of the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) 1 and 2 isoforms was investigated in human naïve (CD45RA+) and memory (CD45RO+) CD4+ T cells. Stimulation of both types of cells via the CD3/CD28 pathway resulted in high expression of both PPARγ receptors as measured by real-time PCR. Treatment with the PPARγ agonist, ciglitazone, increased PPARγ1 expression but decreased PPARγ2 expression in stimulated naïve and memory cells. Furthermore, when present, the magnitude of both PPARγ receptors expression was lower in naïve cells, perhaps suggesting a lower regulatory control of these cells. Similar profiles of selected proinflammatory cytokines were expressed by the two cell types following stimulation. The induction of PPARγ1 and suppression of PPARγ2 expressions in naïve and memory CD4+ T cells in the presence of ciglitazone suggest that the PPARγ subtypes may have different roles in the regulation of T-cell function.
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http://dx.doi.org/10.1155/2012/849195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3323850PMC
March 2013