Publications by authors named "Mat Jusoh Siti Asmaa"

6 Publications

  • Page 1 of 1

Transcriptomic Profiles of MV4-11 and Kasumi 1 Acute Myeloid Leukemia Cell Lines Modulated by Epigenetic Modifiers Trichostatin A and 5-Azacytidine.

Int J Hematol Oncol Stem Cell Res 2020 Jan;14(1):72-92

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

Acute myeloid leukemia (AML) is the most common form of acute leukemias in adults which is clinically and molecularly heterogeneous. Several risk and genetic factors have been widely investigated to characterize AML. However, the concomitant epigenetic factors in controlling the gene expression lead to AML transformation was not fully understood. This study was aimed to identify epigenetically regulated genes in AML cell lines induced by epigenetic modulating agents, Trichostatin A (TSA) and 5-Azacytidine (5-Aza). MV4-11 and Kasumi 1 were treated with TSA and/or 5-Aza at IC concentration. Gene expression profiling by microarray was utilized using SurePrint G3 Human Gene Expression v3. Gene ontology and KEGG pathway annotations were analyzed by DAVID bioinformatics software using EASE enrichment score. mRNA expression of the differentially expressed genes were verified by quantitative real time PCR. Gene expression analysis revealed a significant changes in the expression of 24,822, 15,720, 15,654 genes in MV4-11 and 12,598, 8828, 18,026 genes in Kasumi 1, in response to TSA, 5-Aza and combination treatments, respectively, compared to non-treated (<0.05). 7 genes (, , , , , and ) and 4 genes (, , and ) shown to be predominantly expressed in MV4-11 and Kasumi 1, respectively (EASE<0.1). The analysis also revealed phagosome pathway commonly activated in both cell lines. Our data showed a distinct optimal biological characteristic and pathway in different types of leukemic cell lines. These finding may help in the identification of cell-specific epigenetic biomarker in the pathogenesis of AML.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167603PMC
January 2020

Re-Expression of Bone Marrow Proteoglycan-2 by 5-Azacytidine is associated with STAT3 Inactivation and Sensitivity Response to Imatinib in Resistant CML Cells

Asian Pac J Cancer Prev 2018 Jun 25;19(6):1585-1590. Epub 2018 Jun 25.

Diagnostic and Biomedicine, Faculty of Health Science, Universiti Sultan Zainal Abidin, Gong Badak Compus, Kuala Nerus, Terengganu, Malaysia. Email:

Background: Epigenetic silencing of tumor suppressor genes (TSG) is involved in development and progression of cancers. Re-expression of TSG is inversely proportionate with STAT3 signaling pathways. Demethylation of DNA by 5-Azacytidine (5-Aza) results in re-expression of silenced TSG. Forced expression of PRG2 by 5-Aza induced apoptosis in cancer cells. Imatinib is a tyrosine kinase inhibitor that potently inhibits BCR/ ABL tyrosine kinase resulting in hematological remission in CML patients. However, majority of CML patients treated with imatinib would develop resistance under prolonged therapy. Methods: CML cells resistant to imatinib were treated with 5-Aza and cytotoxicity of imatinib and apoptosis were determined by MTS and annexin-V, respectively. Gene expression analysis was detected by real time-PCR, STATs activity examined using Western blot and methylation status of PRG2 was determined by pyrosequencing analysis. Result: Expression of PRG2 was significantly higher in K562-R+5-Aza cells compared to K562 and K562-R (p=0.001). Methylation of PRG2 gene was significantly decreased in K562-R+5-Aza cells compared to other cells (p=0.021). STAT3 was inactivated in K562-R+5-Aza cells which showed higher sensitivity to imatinib. Conclusion: PRG2 gene is a TSG and its overexpression might induce sensitivity to imatinib. However, further studies are required to evaluate the negative regulations of PRG2 on STAT3 signaling.
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http://dx.doi.org/10.22034/APJCP.2018.19.6.1585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6103584PMC
June 2018

Anti-Proliferative Effects of Dendrophthoe pentandra Methanol Extract on BCR/ABL-Positive and Imatinib-Resistant Leukemia Cell Lines

Asian Pac J Cancer Prev 2016 11 1;17(11):4857-4861. Epub 2016 Nov 1.

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

Background: Imatinib mesylate, a tyrosine kinase inhibitor specifically targeting the BCR/ABL fusion protein, induces hematological remission in patients with chronic myeloid leukemia (CML). However, the majority of CML patients treated with imatinib develop resistance with prolonged therapy. Dendrophthoe pentandra (L.) Miq. is a Malaysian mistletoe species that has been used as a traditional treatment for several ailments such as smallpox, ulcers, and cancers. Methods: We developed a resistant cell line (designated as K562R) by long-term co-culture of a BCR/ ABL positive CML cell line, K562, with imatinib mesylate. We then investigated the anti-proliferative effects of D. pentandra methanol extract on parental K562 and resistant K562R cells. Trypan blue exclusion assays were performed to determine the IC50 concentration; apoptosis and cell cycle analysis were conducted by flow cytometry. Results: D. pentandra extract had greater anti-proliferative effects towards K562R (IC50= 192 μg/mL) compared to K562 (500 μg/ mL) cells. Upon treatment with D. pentandra extract at the IC50. concentration: K562 but not K562R demonstrated increase in apoptosis and cell cycle arrest in the G2/M phase. Conclusion: D. pentandra methanol extract exerts potent anti-proliferative effect on BCR/ABL positive K562 cells.
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http://dx.doi.org/10.22034/APJCP.2016.17.11.4857DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454686PMC
November 2016

Enhancing SHP-1 expression with 5-azacytidine may inhibit STAT3 activation and confer sensitivity in lestaurtinib (CEP-701)-resistant FLT3-ITD positive acute myeloid leukemia.

BMC Cancer 2015 Nov 7;15:869. Epub 2015 Nov 7.

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

Background: Tumor-suppressor genes are inactivated by methylation in several cancers including acute myeloid leukemia (AML). Src homology-2 (SH2)-containing protein-tyrosine phosphatase 1 (SHP-1) is a negative regulator of the JAK/STAT pathway. Transcriptional silencing of SHP-1 plays a critical role in the development and progression of cancers through STAT3 activation. 5-Azacytidine (5-Aza) is a DNA methyltransferase inhibitor that causes DNA demethylation resulting in re-expression of silenced SHP-1. Lestaurtinib (CEP-701) is a multi-targeted tyrosine kinase inhibitor that potently inhibits FLT3 tyrosine kinase and induces hematological remission in AML patients harboring the internal tandem duplication of the FLT3 gene (FLT3-ITD). However, the majority of patients in clinical trials developed resistance to CEP-701. Therefore, the aim of this study, was to assess the effect of re-expression of SHP-1 on sensitivity to CEP-701 in resistant AML cells.

Methods: Resistant cells harboring the FLT3-ITD were developed by overexposure of MV4-11 to CEP-701, and the effects of 5-Aza treatment were investigated. Apoptosis and cytotoxicity of CEP-701 were determined using Annexin V and MTS assays, respectively. Gene expression was performed by quantitative real-time PCR. STATs activity was examined by western blotting and the methylation profile of SHP-1 was studied using MS-PCR and pyrosequencing analysis. Repeated-measures ANOVA and Kruskal-Wallis tests were used for statistical analysis.

Results: The cytotoxic dose of CEP-701 on resistant cells was significantly higher in comparison with parental and MV4-11R-cep + 5-Aza cells (p = 0.004). The resistant cells showed a significant higher viability and lower apoptosis compared with other cells (p < 0.001). Expression of SHP-1 was 7-fold higher in MV4-11R-cep + 5-Aza cells compared to parental and resistant cells (p = 0.011). STAT3 was activated in resistant cells. Methylation of SHP-1 was significantly decreased in MV4-11R-cep + 5-Aza cells (p = 0.002).

Conclusions: The restoration of SHP-1 expression induces sensitivity towards CEP-701 and could serve as a target in the treatment of AML. Our findings support the hypothesis that, the tumor-suppressor effect of SHP-1 is lost due to epigenetic silencing and its re-expression might play an important role in re-inducing sensitivity to TKIs. Thus, SHP-1 is a plausible candidate for a role in the development of CEP-701 resistance in FLT3-ITD+ AML patients.
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http://dx.doi.org/10.1186/s12885-015-1695-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4637135PMC
November 2015

Growth inhibitory effects of crude pomegranate peel extract on chronic myeloid leukemia, K562 cells.

Int J Appl Basic Med Res 2015 May-Aug;5(2):100-5

Advanced Medical and Dental Institute, Universiti Sains Malaysia, Kepala Batas, Penang, Malaysia.

Background: Pomegranate (Punica granatum) is currently a member of Lythraceae family which has potentially cytotoxic activities. Numerous studies have been done on cytotoxic components of pomegranate's juices, barks and leaves. The peels, which considered as a waste, contain higher antioxidant components compared with other parts of the plant.

Aim: To investigate the potential anti-cancer activity of pomegranate peel on growth and cell death mechanisms of chronic myeloid leukemic (CML) cells, K562.

Materials And Methods: Punica granatum peels extract (PGPE) was extracted by successive ethanol extraction, 80% (v/v), freeze dried, diluted to 20 mg/mL working concentration and was subjected to phytochemical screening. K562 cell was treated with crude PGPE for 72 h. Following IC50 concentration, the apoptosis, cell cycle and protein analysis were evaluated. Cell growth inhibition assay was performed by conventional trypan blue exclusion assay. Apoptosis and cell cycle were analyzed by flow-cytometry using BD apoptosis and cell cycle kits and protein analysis by western blotting. All the results are expressed as mean ± standard error of mean of three independent experiments. Statistical analysis was performed by nonparametric Mann-Whitney U-test.

Results: Results demonstrated that PGPE promotes growth inhibition of K562 cells mainly via G2/M phase arrest while still conserving apoptosis induction, but at a lower rate. Apoptosis activities were proposed by the up-regulation of caspases and cytochrome c with an elevated level of p21 and p53.

Conclusion: PGPE caused an inhibition in cell proliferation of CML cell mainly by cell cycle arrest.
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http://dx.doi.org/10.4103/2229-516X.157154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4456882PMC
June 2015

Apoptosis induction in MV4-11 and K562 human leukemic cells by Pereskia sacharosa (Cactaceae) leaf crude extract.

Asian Pac J Cancer Prev 2014 ;15(1):475-81

Department of Haematology, School of Medical Sciences, Universiti Sains Malaysia, Kelantan, Malaysia E-mail :

Background: Pereskia sacharosa is a genus of cacti widely used in folk medicine for cancer-related treatment. Anti-proliferative effects have been studied in recent years against colon, breast, cervical and lung cancer cell lines, with promising results. We here extended study of anti-proliferative effects to a blood malignancy, leukemia.

Materials And Methods: Two leukemic cell lines, MV4-11 (acute myeloid leukemia) and K562 (chronic myeloid leukemia), were studied. IC50 concentrations were determined and apoptosis and cell cycle regulation were studied by flow cytometric analysis. The expression of apoptosis and cell-cycle related regulatory proteins was assessed by Western blotting.

Results: P sacharosa inhibited growth of MV4-11 and K562 cells in a dose-dependent manner. The mode of cell death was via induction of intrinsic apoptotic pathways and cell cycle arrest. There was profound up-regulation of cytochrome c, caspases, p21 and p53 expression and repression of Akt and Bcl-2 expression in treated cells.

Conclusions: These results suggest that P sacharosa induces leukemic cell death via apoptosis induction and changes in cell cycle checkpoint, thus deserves further study for anti-leukemic potential.
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http://dx.doi.org/10.7314/apjcp.2014.15.1.475DOI Listing
November 2014