Von S.-T.,University Tunku Abdul Rahman |
Seng H.-L.,University of Technology Malaysia |
Lee H.-B.,Cancer Research Initiatives Foundation |
Ng S.-W.,University of Malaya |
And 3 more authors.
Journal of Biological Inorganic Chemistry | Year: 2012
Abstract By inhibiting only two or three of 12 restriction enzymes, the series of [M(phen)(edda)] complexes [M(II) is Cu, Co, Zn; phen is 1,10-phenanthroline; edda is N,N0-ethylenediaminediacetate] exhibit DNA binding specificity. The Cu(II) and Zn(II) complexes could differentiate the palindromic sequences 50-CATATG-30 and 50-GTATAC-30, whereas the Co(II) analogue could not. This and other differences in their biological properties may arise from distinct differences in their octahedral structures. The complexes could inhibit topoisomerase I, stabilize or destabilize G-quadruplex, and lower the mitochondrial membrane potential of MCF7 breast cells. The pronounced stabilization of G-quadruplex by the Zn(II) complex may account for the additional ability of only the Zn(II) complex to induce cell cycle arrest in S phase. On the basis of the known action of anticancer compounds against the above-mentioned individual targets, we suggest the mode of action of the present complexes could involve multiple targets. Cytotoxicity studies with MCF10A and cisplatin-resistant MCF7 suggest that these complexes exhibit selectivity towards breast cancer cells over normal ones. © SBIC 2011.
Chang S.,U.S. National Cancer Institute |
Wang R.-H.,U.S. National Institute of Diabetes and Digestive and Kidney Diseases |
Akagi K.,Ohio State University |
Kim K.-A.,U.S. National Cancer Institute |
And 16 more authors.
Nature Medicine | Year: 2011
BRCA1, a well-known tumor suppressor with multiple interacting partners, is predicted to have diverse biological functions. However, so far its only well-established role is in the repair of damaged DNA and cell cycle regulation. In this regard, the etiopathological study of low-penetrant variants of BRCA1 provides an opportunity to uncover its other physiologically important functions. Using this rationale, we studied the R1699Q variant of BRCA1, a potentially moderate-risk variant, and found that it does not impair DNA damage repair but abrogates the repression of microRNA-155 (miR-155), a bona fide oncomir. Mechanistically, we found that BRCA1 epigenetically represses miR-155 expression via its association with HDAC2, which deacetylates histones H2A and H3 on the miR-155 promoter. We show that overexpression of miR-155 accelerates but the knockdown of miR-155 attenuates the growth of tumor cell lines in vivo. Our findings demonstrate a new mode of tumor suppression by BRCA1 and suggest that miR-155 is a potential therapeutic target for BRCA1-deficient tumors. © 2011 Nature America, Inc. All rights reserved.
Tan P.J.,Cancer Research Initiatives Foundation |
Appleton D.R.,University of Malaya |
Appleton D.R.,University Putra Malaysia |
Mustafa M.R.,University of Malaya |
Lee H.B.,Cancer Research Initiatives Foundation
Phytochemical Analysis | Year: 2012
Introduction Photodynamic therapy is a treatment modality that involves site-directed generation of cytotoxic reactive oxygen species by light-activated photosensitisers. Objective In order to rapidly identify new photosensitisers from natural extracts, we developed a liquid chromatography-photodiode array-mass spectrometry (LC-PDA-MS) method to rapidly identify plant extracts that contain photosensitisers, particularly those possessing a cyclic tetrapyrrole structure. Method Six previously isolated compounds (1-6) were identified in bioactive fractions derived from 15 plant extracts on the basis of their chromatographic retention times, UV-visible profiles, accurate mass and fragmentation patterns. Results Samples containing uncommon photosensitisers were rapidly identified using this method, and subsequent scale-up isolation efforts led to two new compounds (7 and 8) which were confirmed to be active photosensitisers in a photo-cytotoxicity assay. Conclusion This method serves as a useful tool in prioritising samples that may contain new photosensitisers out of a larger group of photo-cytotoxic natural products extracts. © 2011 John Wiley & Sons, Ltd.
Ng C.-H.,International Medical University |
Wang W.-S.,University Tunku Abdul Rahman |
Chong K.-V.,University Tunku Abdul Rahman |
Win Y.-F.,University Tunku Abdul Rahman |
And 5 more authors.
Dalton Transactions | Year: 2013
Chiral enantiomers [Cu(phen)(l-threo)(H2O)]NO31 and [Cu(phen)(d-threo)(H2O)]NO32 (threo = threoninate) underwent aldol-type condensation with formaldehyde, with retention of chirality, to yield their respective enantiomeric ternary copper(ii) complexes, viz.l- and d-[Cu(phen)(5MeOCA)(H2O)]NO3·xH 2O (3 and 4; phen = 1,10-phenanthroline; 5MeOCA = 5-methyloxazolidine-4-carboxylate; x = 0-3) respectively. These chiral complexes were characterized by FTIR, elemental analysis, circular dichroism, UV-Visible spectroscopy, fluorescence spectroscopy (FL), molar conductivity measurement, ESI-MS and X-ray crystallography. Analysis of restriction enzyme inhibition by these four complexes revealed modulation of DNA binding selectivity by the type of ligand, ligand modification and chirality. Their interaction with bovine serum albumin was investigated by FL and electronic spectroscopy. With the aid of the crystal structure of BSA, spectroscopic evidence suggested their binding at the cavity containing Trp134 with numerous Tyr residues in subdomain IA. The products were more antiproliferative than cisplatin against cancer cell lines HK-1, MCF-7, HCT116, HSC-2 and C666-1 except HL-60, and were selective towards nasopharyngeal cancer HK-1 cells over normal NP69 cells of the same organ type. © 2013 The Royal Society of Chemistry.
Lim K.P.,University of Bristol |
Lim K.P.,Cancer Research Initiatives Foundation |
Cirillo N.,University of Bristol |
Hassona Y.,University of Bristol |
And 6 more authors.
Journal of Pathology | Year: 2011
Oral cancer is a highly aggressive malignancy with poor prognosis. This study examined the behaviour of fibroblast strains from normal oral mucosa, dysplastic epithelial tissue, and genetically stable (minimal copy number alterations-CNA; minimal loss of heterozygosity-LOH; wild-type p53; wild-type p16INK4A) and unstable (extensive CNA and LOH; inactivation of p53 and p16INK4A) oral squamous cell carcinoma (OSCC). Fibroblasts from genetically unstable OSCC relative to the other fibroblast subtypes grew more slowly and stimulated the invasion of a non-tumourigenic keratinocyte cell line into fibroblast-rich collagen gels. To understand these findings, genome-wide transcriptional profiles were generated using the GeneChip® cDNA whole transcript microarray platform. Principal component analysis showed that the fibroblasts could be distinguished according to the stage of tumour development. Tumour progression was associated with down-regulation of cell cycle- and cytokinesis-related genes and up-regulation of genes encoding transmembrane proteins including cell adhesion molecules. Gene expression was validated in independent fibroblast strains using qRT-PCR. Gene connectivity and interactome-transcriptome associations were determined using a systems biology approach to interrogate the gene expression data. Clusters of gene signatures were identified that characterized genetically unstable and stable OSCCs relative to each other and to fibroblasts from normal oral mucosa. The expression of highly connected genes associated with unstable OSCCs, including those that encode α-SMA and the integrin α6, correlated with poor patient prognosis in an independent dataset of head and neck cancer. The results of this study demonstrate that fibroblasts from unstable OSCCs represent a phenotypically distinguishable subset that plays a major role in oral cancer biology. © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.