Displaying publications 1 - 20 of 62 in total

  1. Kam TS, Sim KM, Koyano T, Toyoshima M, Hayashi M, Komiyama K
    Bioorg. Med. Chem. Lett., 1998 Jul 7;8(13):1693-6.
    PMID: 9873417
    Four new bisindoles of the vobasine-iboga type, conodiparines A-D were obtained from Tabernaemontana corymbosa which showed appreciable activity in reversing resistance in vincristine-resistant KB cells.
    Matched MeSH terms: Drug Resistance, Neoplasm*
  2. Teoh SL, Das S
    Curr. Pharm. Des., 2017;23(12):1845-1859.
    PMID: 28231756 DOI: 10.2174/1381612822666161027120043
    The incidence and mortality due to breast cancer is increasing worldwide. There is a constant quest to know the underlying molecular biology of breast cancer in order to arrive at diagnosis and plan better treatment options. MicroRNAs (miRNAs) are small non-coding and single stranded RNAs which influence the gene expression and physiological condition in any tumor. The miRNAs may act on different pathways in various cancers. Recently, there are research reports on various miRNAs being linked to breast cancers. The important miRNAs associated with breast cancers include miR-21, miR-155, miR-27a, miR-205, miR-145 and miR-320a. In the present review we discuss the role of miRNAs in breast cancer, its importance as diagnostic markers, prognosis and metastasis markers. We also highlight the role of miRNAs with regard to resistance to few anticancerous drugs such as Tamoxifen and Trastuzumab. The role of miRNA in resistance to treatment is one of the core issues discussed in the present review. Much information on the miRNA roles is available particularly in the neoadjuvant chemotherapy setting, because this protocol allows the rapid association of miRNA expression with the treatment response. This review opens the door for designing better therapeutic options in drug resistance cases in breast cancer.
    Matched MeSH terms: Drug Resistance, Neoplasm/genetics*
  3. Khamisipour G, Jadidi-Niaragh F, Jahromi AS, Zandi K, Hojjat-Farsangi M
    Tumour Biol., 2016 Aug;37(8):10021-39.
    PMID: 27155851 DOI: 10.1007/s13277-016-5059-1
    Resistance to chemotherapy agents is a major challenge infront of cancer patient treatment and researchers. It is known that several factors, such as multidrug resistance proteins and ATP-binding cassette families, are cell membrane transporters that can efflux several substrates such as chemotherapy agents from the cell cytoplasm. To reduce the adverse effects of chemotherapy agents, various targeted-based cancer therapy (TBCT) agents have been developed. TBCT has revolutionized cancer treatment, and several agents have shown more specific effects on tumor cells than chemotherapies. Small molecule inhibitors and monoclonal antibodies are specific agents that mostly target tumor cells but have low side effects on normal cells. Although these agents have been very useful for cancer treatment, however, the presence of natural and acquired resistance has blunted the advantages of targeted therapies. Therefore, development of new options might be necessary. A better understanding of tumor cell resistance mechanisms to current treatment agents may provide an appropriate platform for developing and improving new treatment modalities. Therefore, in this review, different mechanisms of tumor cell resistance to chemotherapy drugs and current targeted therapies have been described.
    Matched MeSH terms: Drug Resistance, Neoplasm/drug effects; Drug Resistance, Neoplasm/genetics; Drug Resistance, Neoplasm/physiology*
  4. Lim SZ, Chua EW
    Front Pharmacol, 2018;9:1107.
    PMID: 30349479 DOI: 10.3389/fphar.2018.01107
    Azathioprine and 6-mercaptopurine, often referred to as thiopurine compounds, are commonly used in the management of inflammatory bowel disease. However, patients receiving these drugs are prone to developing adverse drug reactions or therapeutic resistance. Achieving predefined levels of two major thiopurine metabolites, 6-thioguanine nucleotides and 6-methylmercaptopurine, is a long-standing clinical practice in ensuring therapeutic efficacy; however, their correlation with treatment response is sometimes unclear. Various genetic markers have also been used to aid the identification of patients who are thiopurine-sensitive or refractory. The recent discovery of novel Asian-specific DNA variants, namely those in the NUDT15 gene, and their link to thiopurine toxicity, have led clinicians and scientists to revisit the utility of Caucasian biomarkers for Asian individuals with inflammatory bowel disease. In this review, we explore the limitations associated with the current methods used for therapeutic monitoring of thiopurine metabolites and how the recent discovery of ethnicity-specific genetic markers can complement thiopurine metabolites measurement in formulating a strategy for more accurate prediction of thiopurine response. We also discuss the challenges in thiopurine therapy, alongside the current strategies used in patients with reduced thiopurine response. The review is concluded with suggestions for future work aiming at using a more comprehensive approach to optimize the efficacy of thiopurine compounds in inflammatory bowel disease.
    Matched MeSH terms: Drug Resistance, Neoplasm
  5. Chieng CK, Say YH
    Tumour Biol., 2015 Sep;36(10):8107-20.
    PMID: 25983001 DOI: 10.1007/s13277-015-3530-z
    As the cellular prion protein (PrP(C)) has been implicated in carcinogenesis, we aimed to investigate the effects of cancer cell-specific PrP(C) overexpression from the invasion, metastasis, and apoptosis aspects, by performing cell motility assays, cell proliferation assays under anchorage-dependent and anchorage-independent conditions, and apoptosis evasion when subjected to multiple anti-cancer drugs. Overexpression of PrP(C) in LS 174T was achieved by stable transfection. PrP(C) overexpression was shown to increase cell proliferation in anchorage-dependent and anchorage-independent manners, as shown by more viable cells in 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, more colonies formed in soft agar assay and increased resistance to anoikis in poly-2-hydroxyethyl methacrylate-coated surface. PrP(C) overexpression also increased cell motility and invasiveness of LS 174T. Cell adhesion to extracellular matrix using collagen- and fibronectin-coated surfaces revealed increased cell attachment in LS 174T cells overexpressing PrP(C). Analysis of apoptotic and necrotic cells by propidium iodide/annexin V-fluorescein isothiocyanate microscopy and 7-amino-actinomycin D/annexin V-phycoerythrin flow cytometry revealed that PrP(C) overexpression attenuated doxorubicin-induced apoptosis. Human apoptosis antibody array with 35 apoptosis-related proteins revealed that three inhibitor of apoptosis proteins (IAPs)-survivin, X-linked inhibitor of apoptosis protein (XIAP), and cellular inhibitor of apoptosis protein-1 (cIAP-1)-were upregulated in LS 174T cells overexpressing PrP(C) in doxorubicin-induced apoptosis. In conclusion, the overexpression of PrP(C) could enhance the invasiveness and survival of LS 174T colorectal cancer cells, indicating that PrP(C) plays a role in colorectal cancer biology.
    Matched MeSH terms: Drug Resistance, Neoplasm*
  6. Fatemian T, Chowdhury EH
    Curr Cancer Drug Targets, 2014;14(7):599-609.
    PMID: 25308718
    Malfunctions in membrane transporters or disruptions in signaling cascades induce resistance to chemotherapy in cancer cells resulting in treatment failure. To adjust the genetic alterations leading to these cellular protective measures, dissection and verification of the contributing routes would be required. In justification of knockdown of the key genes, RNA interference provides a reliable probing tool, enabling exploration of phenotypic manifestation of targeted genes. Investigation of the non-transporter targets, predominantly oncogenes and tumor suppressor genes, by means of small interfering RNA with the aim to re-sensitize cancer cells to therapeutics will be discussed in this review.
    Matched MeSH terms: Drug Resistance, Neoplasm*
  7. Abubakar IB, Loh HS
    J. Pharm. Pharmacol., 2016 Apr;68(4):423-32.
    PMID: 26887962 DOI: 10.1111/jphp.12523
    OBJECTIVES: Tabernaemontana is a genus from the plant family, Apocynaceae with vast medicinal application and widespread distribution in the tropics and subtropics of Africa, Americas and Asia. The objective of this study is to critically evaluate the ethnobotany, medicinal uses, pharmacology and phytochemistry of the species, Tabernaemontana corymbosa (Roxb. ex Wall.) and provide information on the potential future application of alkaloids isolated from different parts of the plant.

    KEY FINDINGS: T. corymbosa (Roxb. ex Wall.) parts are used as poultice, boiled juice, decoctions and infusions for treatment against ulceration, fracture, post-natal recovery, syphilis, fever, tumours and orchitis in Malaysia, China, Thailand and Bangladesh. Studies recorded alkaloids as the predominant phytochemicals in addition to phenols, saponins and sterols with vast bioactivities such as antimicrobial, analgesic, anthelmintic, vasorelaxation, antiviral and cytotoxicity.

    SUMMARY: An evaluation of scientific data and traditional medicine revealed the medicinal uses of different parts of T. corymbosa (Roxb. ex Wall.) across Asia. Future studies exploring the structure-bioactivity relationship of alkaloids such as jerantinine and vincamajicine among others could potentially improve the future application towards reversing anticancer drug resistance.

    Matched MeSH terms: Drug Resistance, Neoplasm/drug effects
  8. Fatemian T, Othman I, Chowdhury EH
    Drug Discov. Today, 2014 Jan;19(1):71-8.
    PMID: 23974068 DOI: 10.1016/j.drudis.2013.08.007
    Resistance of cancer cells to anticancer drugs is the main reason for the failure of traditional cancer treatments. Various cellular components and different loops within the signaling pathways contribute to drug resistance which could be modulated with the aim to restore drug efficacy. Unveiling the molecular mechanisms for cancer drug resistance has now paved the way for the development of novel approaches to regulate the response rates to anticancer drugs at the genetic level. The recent progress on identification and validation of the vital genes directly or indirectly involved in development of cancer drug resistance with the aid of the specific knock down ability of RNA interference technology is discussed in this review.
    Matched MeSH terms: Drug Resistance, Neoplasm*
  9. Wong RS, Cheong SK
    Malays J Pathol, 2012 Dec;34(2):77-88.
    PMID: 23424769 MyJurnal
    Although there have been many new developments in the treatment of leukaemia with the use of new anti-leukaemic agents and stem cell transplantation, drug resistance and treatment failure remain a great challenge for the attending physician. Several studies have suggested that leukaemic stem cells (LSCs) play a pivotal role in chemoresistance and metastasis and the mechanisms by which these cells do so have also been elucidated. There is increasing evidence to show that there exists a large pool of therapeutic targets in LSCs and that the eradication of these cells is feasible with some promising results. This article gives an overview of different types of cancer stem cells (CSCs) derived from various types of leukaemia, the mechanisms by which LSCs contribute to drug resistance and metastasis and some recent advances in targeted therapy against LSCs.
    Matched MeSH terms: Drug Resistance, Neoplasm/immunology*
  10. Lim SH, Sim KM, Abdullah Z, Hiraku O, Hayashi M, Komiyama K, et al.
    J. Nat. Prod., 2007 Aug;70(8):1380-3.
    PMID: 17608533
    Four new indole alkaloids were obtained from two Kopsia species, 6-oxoleuconoxine (1) from the leaf extract of K. griffithii and kopsinitarine E (2), kopsijasminine (3), and kopsonoline (4) from the stem-bark extract of K. teoi. The structures of these alkaloids were determined using NMR and MS analysis. Kopsijasminine (3) showed moderate activity in reversing multidrug resistance in vincristine-resistant KB cells.
    Matched MeSH terms: Drug Resistance, Neoplasm/drug effects
  11. Weiland F, Arentz G, Klingler-Hoffmann M, McCarthy P, Lokman NA, Kaur G, et al.
    J. Proteome Res., 2016 11 04;15(11):4073-4081.
    PMID: 27569743
    Although acetylation is regarded as a common protein modification, a detailed proteome-wide profile of this post-translational modification may reveal important biological insight regarding differential acetylation of individual proteins. Here we optimized a novel peptide IEF fractionation method for use prior to LC-MS/MS analysis to obtain a more in depth coverage of N-terminally acetylated proteins from complex samples. Application of the method to the analysis of the serous ovarian cancer cell line OVCAR-5 identified 344 N-terminally acetylated proteins, 12 of which are previously unreported. The protein peptidyl-prolyl cis-trans isomerase A (PPIA) was detected in both the N-terminally acetylated and unmodified forms and was further analyzed by data-independent acquisition in carboplatin-responsive parental OVCAR-5 cells and carboplatin-resistant OVCAR-5 cells. This revealed a higher ratio of unacetylated to acetylated N-terminal PPIA in the parental compared with the carboplatin-resistant OVCAR-5 cells and a 4.1-fold increase in PPIA abundance overall in the parental cells relative to carboplatin-resistant OVCAR-5 cells (P = 0.015). In summary, the novel IEF peptide fractionation method presented here is robust, reproducible, and can be applied to the profiling of N-terminally acetylated proteins. All mass spectrometry data is available as a ProteomeXchange repository (PXD003547).
    Matched MeSH terms: Drug Resistance, Neoplasm*
  12. Tan SJ, Low YY, Choo YM, Abdullah Z, Etoh T, Hayashi M, et al.
    J. Nat. Prod., 2010 Nov 29;73(11):1891-7.
    PMID: 21043460 DOI: 10.1021/np100552b
    A total of 25 alkaloids were isolated from the leaf and stem-bark extracts of Alstonia spatulata, of which five are new alkaloids of the strychnan type (alstolucines A-E, 1-5) and the other, a new alkaloid of the secoangustilobine A type (alstolobine A, 6). The structures of these alkaloids were established using NMR and MS analysis and, in the case of alstolucine B (2), also confirmed by X-ray diffraction analysis. A reinvestigation of the stereochemical assignment of scholaricine (13) by NMR and X-ray analyses indicated that the configuration at C-20 required revision. Alkaloids 1, 2, 6, 7, 9, 10, and 13 reversed multidrug resistance in vincristine-resistant KB cells.
    Matched MeSH terms: Drug Resistance, Neoplasm/drug effects
  13. Ankathil R, Azlan H, Dzarr AA, Baba AA
    Pharmacogenomics, 2018 04;19(5):475-393.
    PMID: 29569526 DOI: 10.2217/pgs-2017-0193
    Despite the excellent efficacy and improved clinical responses obtained with imatinib mesylate (IM), development of resistance in a significant proportion of chronic myeloid leukemia (CML) patients on IM therapy have emerged as a challenging problem in clinical practice. Resistance to imatinib can be due to heterogeneous array of factors involving BCR/ABL-dependent and BCR/ABL-independent pathways. Although BCR/ABL mutation is the major contributory factor for IM resistance, reduced bio-availability of IM in leukemic cells is also an important pharmacokinetic factor that contributes to development of resistance to IM in CML patients. The contribution of polymorphisms of the pharmacogenes in relation to IM disposition and treatment outcomes have been studied by various research groups in numerous population cohorts. However, the conclusions arising from these studies have been highly inconsistent. This review encompasses an updated insight into the impact of pharmacogenetic variability on treatment response of IM in CML patients.
    Matched MeSH terms: Drug Resistance, Neoplasm/genetics
  14. Abu N, Hon KW, Jeyaraman S, Jamal R
    Future Oncol, 2018 Dec;14(29):3085-3095.
    PMID: 30468082 DOI: 10.2217/fon-2018-0303
    Since its discovery, cisplatin has become the key drug in chemotherapy for cancers. Nevertheless, chemoresistance in cancers has become an impediment in using cisplatin for cancer treatment. The resistance toward cisplatin is multifaceted as it involves multiple cellular pathways. Ever since the knowledge of long noncoding RNAs as modulators of various molecular pathways came to light, the interest in the biological function of lncRNAs as biomarkers has increased dramatically. Numerous studies have reported the link between the dysregulation of lncRNAs and drug resistance in cancers. More importantly, several lncRNAs were found to be vital in regulating cisplatin resistance. Therefore, this review summarizes the recent efforts in linking between cisplatin resistance and different types of lncRNAs.
    Matched MeSH terms: Drug Resistance, Neoplasm/genetics*
  15. Satar NA, Fakiruddin KS, Lim MN, Mok PL, Zakaria N, Fakharuzi NA, et al.
    Oncol. Rep., 2018 Aug;40(2):669-681.
    PMID: 29845263 DOI: 10.3892/or.2018.6461
    Through the specific identification and direct targeting of cancer stem cells (CSCs), it is believed that a better treatment efficacy of cancer may be achieved. Hence, the present study aimed to identify a CSC subpopulation from adenocarcinoma cells (A549) as a model of non‑small cell lung cancer (NSCLC). Ιnitially, we sorted two subpopulations known as the triple‑positive (EpCAM+/CD166+/CD44+) and triple‑negative (EpCAM-/CD166-/CD44-) subpopulation using fluorescence-activated cell sorting (FACS). Sorted cells were subsequently evaluated for proliferation and chemotherapy-resistance using a viability assay and were further characterized for their clonal heterogeneity, self-renewal characteristics, cellular migration, alkaline dehydrogenase (ALDH) activity and the expression of stemness-related genes. According to our findings the triple‑positive subpopulation revealed significantly higher (P<0.01) proliferation activity, exhibited better clonogenicity, was mostly comprised of holoclones and had markedly bigger (P<0.001) spheroid formation indicating a better self-renewal capacity. A relatively higher resistance to both 5‑fluouracil and cisplatin with 80% expression of ALDH was observed in the triple‑positive subpopulation, compared to only 67% detected in the triple‑negative subpopulation indicated that high ALDH activity contributed to greater chemotherapy-resistance characteristics. Higher percentage of migrated cells was observed in the triple‑positive subpopulation with 56% cellular migration being detected, compared to only 19% in the triple‑negative subpopulation on day 2. This was similarly observed on day 3 in the triple‑positive subpopulation with 36% higher cellular migration compared to the triple‑negative subpopulation. Consistently, elevated levels of the stem cell genes such as REX1 and SSEA4 were also found in the triple‑positive subpopulation indicating that the subpopulation displayed a strong characteristic of pluripotency. In conclusion, our study revealed that the triple‑positive subpopulation demonstrated similar characteristics to CSCs compared to the triple‑negative subpopulation. It also confirmed the feasibility of using the triple‑positive (EpCAM+/CD166+/CD44+) marker as a novel candidate marker that may lead to the development of novel therapies targeting CSCs of NSCLC.
    Matched MeSH terms: Drug Resistance, Neoplasm/drug effects; Drug Resistance, Neoplasm/genetics*
  16. Stebbing J, Shah K, Lit LC, Gagliano T, Ditsiou A, Wang T, et al.
    Oncogene, 2018 06;37(23):3113-3130.
    PMID: 29540829 DOI: 10.1038/s41388-018-0197-0
    Lemur tyrosine kinase 3 (LMTK3) is an oncogenic kinase that is involved in different types of cancer (breast, lung, gastric, colorectal) and biological processes including proliferation, invasion, migration, chromatin remodeling as well as innate and acquired endocrine resistance. However, the role of LMTK3 in response to cytotoxic chemotherapy has not been investigated thus far. Using both 2D and 3D tissue culture models, we found that overexpression of LMTK3 decreased the sensitivity of breast cancer cell lines to cytotoxic (doxorubicin) treatment. In a mouse model we showed that ectopic overexpression of LMTK3 decreases the efficacy of doxorubicin in reducing tumor growth. Interestingly, breast cancer cells overexpressing LMTK3 delayed the generation of double strand breaks (DSBs) after exposure to doxorubicin, as measured by the formation of γH2AX foci. This effect was at least partly mediated by decreased activity of ataxia-telangiectasia mutated kinase (ATM) as indicated by its reduced phosphorylation levels. In addition, our RNA-seq analyses showed that doxorubicin differentially regulated the expression of over 700 genes depending on LMTK3 protein expression levels. Furthermore, these genes were found to promote DNA repair, cell viability and tumorigenesis processes / pathways in LMTK3-overexpressing MCF7 cells. In human cancers, immunohistochemistry staining of LMTK3 in pre- and post-chemotherapy breast tumor pairs from four separate clinical cohorts revealed a significant increase of LMTK3 following both doxorubicin and docetaxel based chemotherapy. In aggregate, our findings show for the first time a contribution of LMTK3 in cytotoxic drug resistance in breast cancer.
    Matched MeSH terms: Drug Resistance, Neoplasm/drug effects; Drug Resistance, Neoplasm/physiology*
  17. Tan BS, Tiong KH, Choo HL, Chung FF, Hii LW, Tan SH, et al.
    Cell Death Dis, 2015;6:e1826.
    PMID: 26181206 DOI: 10.1038/cddis.2015.191
    p53 is the most frequently mutated tumor-suppressor gene in human cancers. Unlike other tumor-suppressor genes, p53 mutations mainly occur as missense mutations within the DNA-binding domain, leading to the expression of full-length mutant p53 protein. Mutant p53 proteins not only lose their tumor-suppressor function, but may also gain new oncogenic functions and promote tumorigenesis. Here, we showed that silencing of endogenous p53-R273H contact mutant, but not p53-R175H conformational mutant, reduced AKT phosphorylation, induced BCL2-modifying factor (BMF) expression, sensitized BIM dissociation from BCL-XL and induced mitochondria-dependent apoptosis in cancer cells. Importantly, cancer cells harboring endogenous p53-R273H mutant were also found to be inherently resistant to anoikis and lack BMF induction following culture in suspension. Underlying these activities is the ability of p53-R273H mutant to suppress BMF expression that is dependent on constitutively active PI3K/AKT signaling. Collectively, these findings suggest that p53-R273H can specifically drive AKT signaling and suppress BMF expression, resulting in enhanced cell survivability and anoikis resistance. These findings open the possibility that blocking of PI3K/AKT will have therapeutic benefit in mutant p53-R273H expressing cancers.
    Matched MeSH terms: Drug Resistance, Neoplasm/genetics
  18. Gan CY, Yoganathan K, Sim KS, Low YY, Lim SH, Kam TS
    Phytochemistry, 2014 Dec;108:234-42.
    PMID: 25442910 DOI: 10.1016/j.phytochem.2014.09.014
    Eleven indole alkaloids, comprising four corynanthean, two eburnane, one aspidofractinine, one secoleuconoxine, one andranginine, and two pauciflorine type alkaloids were isolated from the stem-bark and leaf extracts of Kopsia pauciflora. Their structures were determined using NMR and MS analyses. The catharinensine type alkaloid kopsirensine B and the secoleuconoxine alkaloid arboloscine A showed moderate to weak activity in reversing MDR in vincristine-resistant KB cells. The alkaloid content was markedly different compared to that of a sample from Malaysian Borneo.
    Matched MeSH terms: Drug Resistance, Neoplasm/drug effects
  19. Yap WS, Gan CY, Sim KS, Lim SH, Low YY, Kam TS
    J. Nat. Prod., 2016 Jan 22;79(1):230-9.
    PMID: 26717050 DOI: 10.1021/acs.jnatprod.5b00992
    Eleven new indole alkaloids (1-11) comprising seven aspidofractinine and four eburnane alkaloids, were isolated from the stem-bark extract of Kopsia pauciflora occurring in Malaysian Borneo. The aspidofractinine alkaloids include a ring-contracted, an additional ring-fused, a paucidactine regioisomer, two paucidactine, and one kopsine alkaloid. The structures of several of these alkaloids were also confirmed by X-ray diffraction analyses. The bisindole alkaloids isolated, norpleiomutine and kopsoffinol, showed in vitro growth inhibitory activity against human PC-3, HCT-116, MCF-7, and A549 cells and moderate effects in reversing multidrug-resistance in vincristine-resistant human KB cells.
    Matched MeSH terms: Drug Resistance, Neoplasm/drug effects
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