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  1. Fulltext Viral persistence in colorectal cancer cells infected by Newcastle disease virus
    Chia SL, Yusoff K, Shafee N
    Virol J, 2014 May 16;11:91.
    PMID: 24886301 DOI: 10.1186/1743-422X-11-91
    BACKGROUND: Newcastle disease virus (NDV), a single-stranded RNA virus of the family Paramyxoviridae, is a candidate virotherapy agent in cancer treatment. Promising responses were observed in clinical studies. Despite its high potential, the possibility of the virus to develop a persistent form of infection in cancer cells has not been investigated. Occurrence of persistent infection by NDV in cancer cells may cause the cells to be less susceptible to the virus killing. This would give rise to a population of cancer cells that remains viable and resistant to treatment.

    RESULTS: During infection experiment in a series of colorectal cancer cell lines, we adventitiously observed a development of persistent infection by NDV in SW480 cells, but not in other cell lines tested. This cell population, designated as SW480P, showed resistancy towards NDV killing in a re-infection experiment. The SW480P cells retained NDV genome and produced virus progeny with reduced plaque forming ability.

    CONCLUSION: These observations showed that NDV could develop persistent infection in cancer cells and this factor needs to be taken into consideration when using NDV in clinical settings.

  2. Synthesis and in-vitro anti-cancer evaluations of multi-methoxylated asymmetrical diarylpentanoids as intrinsic apoptosis inducer against colorectal cancer
    Leong SW, Chia SL, Abas F, Yusoff K
    Bioorg Med Chem Lett, 2020 04 15;30(8):127065.
    PMID: 32127259 DOI: 10.1016/j.bmcl.2020.127065
    In the present study, a series of nine stable 3,4,5-methoxylphenyl-containing asymmetrical diarylpentanoids, derivatives of curcuminoids, have been synthesized, characterized and evaluated for their in-vitro anti-cancer potential against a panel of BRAF- and KRAS-mutated colorectal cancer cell lines including T84, LoVo and SW620, HT29, RKO and NCI-H508, respectively. Structure-activity relationship study on cytotoxicity of tested compounds suggested that the presence of meta-hydroxyl and adjacent dimethoxyl groups are crucial for enhanced cytotoxicity of diarylpentanoids. Among the evaluated analogs, 8 has been identified as the lead compound due to its highest chemotherapeutic index of 9.9 and nano molar scale cytotoxicity against SW620 and RKO. Colonies formation and cell cycle analyses on 8-treated RKO cells showed that 8 exhibits strong anti-proliferative activity by inducing G2/M-phase cell arrest. Subsequent flow cytometry based annexin-V and DCFHDA studies suggested that 8 could induce apoptosis through intracellular ROS-dependent pathway. Further Western blot studies confirmed that 8 has induced intrinsic apoptosis in RKO cells through the up-regulations of Bad and Bax pro-apoptotic proteins and down-regulations of Bcl-2 and Bcl-xL pro-survival proteins. In all, the present results suggest that 8 could be a potent lead which deserves further modification and investigation in the development of small molecule-based anti-colorectal cancer agents.
  3. Inhibition of Autophagy Does Not Affect Innate Cytokine Production in Human Lung Epithelial Cells During Respiratory Syncytial Virus Infection
    Azman AF, Chia SL, Sekawi Z, Yusoff K, Ismail S
    Viral Immunol, 2021 04 09;34(6):421-426.
    PMID: 33835870 DOI: 10.1089/vim.2020.0217
    Human respiratory syncytial virus (RSV) is one of the major causes of childhood acute lower respiratory tract infection worldwide. Autophagy is an intracellular pathway involved in nutrient recycling. Recently, autophagy has been reported to play a role in regulating host cytokine response to several viruses, including vesicular stomatitis virus and human immunodeficiency virus. Previous in vivo studies using mouse model has shown that inhibition of autophagy reduces RSV-induced cytokine production. However, the role of autophagy in modulating RSV-induced cytokine response in human cells has not been reported. We investigated the role of autophagy in regulating the production of the cytokines C-X-C motif ligand 8 (CXCL8) and C-C motif ligand 5 (CCL5), in RSV-infected human bronchial epithelium BEAS-2B cells. Fluorescent microscopic analysis showed that RSV infection induced autophagosome formation in BEAS-2B cells. This autophagy inducing ability of RSV was further confirmed by flow cytometry. The effects of pharmacological inhibition of autophagy by SAR405 or chloroquine on cell death and cytokine release were quantified using lactate dehydrogenase assay and enzyme-linked immunosorbent assay (ELISA), respectively. We found that SAR405 or chloroquine did not cause cell death. Importantly, ELISA analysis showed that pharmacological inhibition of autophagy by SAR405 or chloroquine did not affect the productions of both CXCL5 and CXCL8. In contrast to the previous studies using mouse model, our data suggest that pharmacological inhibition of autophagy may not be a suitable strategy in controlling RSV-induced airway inflammation.
  4. Fulltext Newcastle disease virus strain AF2240 as an oncolytic virus: A review
    Kalyanasundram J, Hamid A, Yusoff K, Chia SL
    Acta Trop, 2018 Jul;183:126-133.
    PMID: 29626432 DOI: 10.1016/j.actatropica.2018.04.007
    The discovery of tumour selective virus-mediated apoptosis marked the birth of an alternative cancer treatment in the form of oncolytic viruses. Even though, its oncolytic efficiency was demonstrated more than 50 years ago, safety concerns which resulted from mild to lethal side effects hampered the progress of oncolytic virus research. Since the classical oncolytic virus studies rely heavily on its natural oncolytic ability, virus manipulation was limited, thereby, restricted efforts to improve its safety. In order to circumvent such restriction, experiments involving non-human viruses such as the avian Newcastle disease virus (NDV) was conducted using cultured cells, animal models and human subjects. The corresponding reports on its significant tumour cytotoxicity along with impressive safety profile initiated immense research interest in the field of oncolytic NDV. The varying degree of oncolytic efficiency and virulency among NDV strains encouraged researchers from all around the world to experiment with their respective local NDV isolates in order to develop an oncolytic virus with desirable characteristics. Such desirable features include high tumour-killing ability, selectivity and low systemic cytotoxicity. The Malaysian field outbreak isolate, NDV strain AF2240, also currently, receives significant research attention. Apart from its high cytotoxicity against tumour cells, this strain also provided fundamental insight into NDV-mediated apoptosis mechanism which involves Bax protein recruitment as well as death receptor engagement. Studies on its ability to selectively induce apoptosis in tumour cells also resulted in a proposed p38 MAPK/NF-κB/IκBα pathway. The immunogenicity of AF2240 was also investigated through PBMC stimulation and macrophage infection. In addition, the enhanced oncolytic ability of this strain under hypoxic condition signifies its dynamic tumour tropism. This review is aimed to introduce and discuss the aforementioned details of the oncolytic AF2240 strain along with its current challenges which outlines the future research direction of this virus.
  5. Asymmetrical meta-methoxylated diarylpentanoids: Rational design, synthesis and anti-cancer evaluation in-vitro
    Leong SW, Chia SL, Abas F, Yusoff K
    Eur J Med Chem, 2018 Sep 05;157:716-728.
    PMID: 30138803 DOI: 10.1016/j.ejmech.2018.08.039
    In the present study, a series of forty-five asymmetrical meta-methoxylated diarylpentanoids have been synthesized, characterized and evaluated for their in-vitro anti-cancer potential. Among the forty-five analogs, three compounds (20, 33 and 42) have been identified as lead compounds due to their excellent inhibition against five human cancer cell lines including SW620, A549, EJ28, HT1080 and MCF-7. Structure-activity relationship study on cytotoxicity of tested compounds suggested that the presence of meta-oxygenated phenyl ring played a critical role in enhancing their cytotoxic effects. Compounds 33 and 42 in particular, exhibited strongest cytotoxicity against tested cell lines with the IC50 values ranging from 1.1 to 4.3 μM. Subsequent colony formation assay on SW620 cell line showed that both compounds 33 and 42 possessed strong anti-proliferative activity. In addition, flow cytometry based experiments revealed that these compounds could trigger intracellular ROS production thus inducing G2/M-phase cell arrest and apoptosis. All these results suggested that poly meta-oxygenated diarylpentnoid is a promising scaffold which deserved further modification and investigation in the development of natural product-based anti-cancer drug.
  6. Fulltext In-Vitro and In-Silico Evaluations of Heterocyclic-Containing Diarylpentanoids as Bcl-2 Inhibitors Against LoVo Colorectal Cancer Cells
    Leong SW, Chia SL, Abas F, Yusoff K
    Molecules, 2020 Aug 26;25(17).
    PMID: 32858795 DOI: 10.3390/molecules25173877
    In the present study, we investigated the in-vitro anti-cancer potential of six diarylpentanoids against a panel of BRAF- and KRAS-mutated colorectal cancer cell lines including T84, SW620, LoVo, HT29, NCI-H508, RKO, and LS411N cells. Structure-activity relationship study suggested that the insertions of tetrahydro-4H-thiopyran-4-one and brominated phenyl moieties are essential for better cytotoxicity. Among the evaluated analogs, 2e has been identified as the lead compound due to its low IC50 values of approximately 1 µM across all cancer cell lines and high chemotherapeutic index of 7.1. Anti-proliferative studies on LoVo cells showed that 2e could inhibit cell proliferation and colony formations by inducing G2/M cell cycle arrest. Subsequent cell apoptosis assay confirmed that 2e is a Bcl-2 inhibitor that could induce intrinsic cell apoptosis by creating a cellular redox imbalance through its direct inhibition on the Bcl-2 protein. Further molecular docking studies revealed that the bromophenyl moieties of 2e could interact with the Bcl-2 surface pocket through hydrophobic interaction, while the tetrahydro-4H-thiopyran-4-one fragment could form additional Pi-sulfur and Pi-alkyl interactions in the same binding site. In all, the present results suggest that 2e could be a potent lead that deserves further modification and investigation in the development of a new Bcl-2 inhibitor.
  7. Autophagy inhibition suppresses Newcastle disease virus-induced cell death by inhibiting viral replication in human breast cancer cells
    Rozilah MI, Yusoff K, Chia SL, Ismail S
    Virology, 2024 Feb;590:109957.
    PMID: 38100982 DOI: 10.1016/j.virol.2023.109957
    Newcastle disease virus (NDV) is an oncolytic virus which selectively replicates in cancer cells without harming normal cells. Autophagy is a cellular mechanism that breaks down unused cytoplasmic constituents into nutrients. In previous studies, autophagy enhanced NDV-induced oncolysis in lung cancer and glioma cells. However, the effect of autophagy inhibition on NDV-induced oncolysis in breast cancer cells remains unknown. This study aimed to examine the effect of autophagy inhibition on NDV-induced oncolysis in human breast cancer cells, MCF7. To inhibit autophagy, we knocked down the expression of the autophagy protein beclin-1 (BECN1) by short interfering RNA (siRNA). The cells were infected with the recombinant NDV strain AF2240 expressing green fluorescent protein. We found that NDV induced autophagy and knockdown of BECN1 significantly reduced the NDV-induced autophagy in MCF7 cells. Importantly, BECN1 knockdown significantly suppressed cell death by inhibiting viral replication, as observed at 24 h post infection. Overall, our data suggest that autophagy inhibition may not be a suitable strategy to enhance NDV oncolytic efficacy against breast cancer.
  8. Structural analysis of peptides that interact with Newcastle disease virus
    Chia SL, Tan WS, Shaari K, Abdul Rahman N, Yusoff K, Satyanarayanajois SD
    Peptides, 2006 Jun;27(6):1217-25.
    PMID: 16377031
    A peptide with the sequence CTLTTKLYC has previously been identified to inhibit the propagation of Newcastle disease virus (NDV) in embryonated chicken eggs and tissue culture. NDV has been classified into two main groups: the velogenic group, and mesogenic with lentogenic strains as the other group based on its dissociation constants. In this study the peptide, CTLTTKLYC, displayed on the pIII protein of a filamentous M13 phage was synthesized and mutated in order to identify the amino acid residues involved in the interactions with NDV. Mutations of C1 and K6 to A1 and A6 did not affect the binding significantly, but substitution of Y8 with A8 dramatically reduced the interaction. This suggests that Y8 plays an important role in the peptide-virus interaction. The three-dimensional structure of the peptide was determined using circular dichroism (CD), nuclear magnetic resonance (NMR), and molecular modeling. The peptide exhibited two possible conformers. One that consists of consecutive beta-turns around T2-L3-T4-T5 and K6-L7-Y8-C9. The other conformer exhibited a beta-hairpin bend type of structure with a bend around L3-T4-T5-K6.
  9. Fulltext Group B adenovirus enadenotucirev infects polarised colorectal cancer cells efficiently from the basolateral surface expected to be encountered during intravenous delivery to treat disseminated cancer
    Chia SL, Lei J, Ferguson DJP, Dyer A, Fisher KD, Seymour LW
    Virology, 2017 05;505:162-171.
    PMID: 28260622 DOI: 10.1016/j.virol.2017.02.011
    Enadenotucirev (EnAd) is a group B oncolytic adenovirus developed for systemic delivery and currently undergoing clinical evaluation for advanced cancer therapy. For differentiated carcinomas, systemic delivery would likely expose virus particles to the basolateral surface of cancer cells rather than the apical surface encountered during natural infection. Here, we compare the ability of EnAd and adenovirus type-5 (Ad5) to infect polarised colorectal carcinoma cells from the apical or basolateral surfaces. Whereas Ad5 infection was more efficient via the apical than basolateral surface, EnAd readily infected cells from either surface. Progeny particles from EnAd were released preferentially via the apical surface for all cell lines and routes of infection. These data further support the utility of group B adenoviruses for systemic delivery and suggest that progeny virus are more likely to be released into the tumour rather than back through the basolateral surface into the blood stream.
  10. Fulltext Patient-reported Outcome Measures of Revision Total Hip Arthroplasty for Prosthetic Joint Infection is not Inferior to Aseptic Revision Total Hip Arthroplasty
    Lim J, Pang HN, Tay K, Chia SL, Yeo SJ, Lo NN
    Malays Orthop J, 2020 Nov;14(3):73-81.
    PMID: 33403065 DOI: 10.5704/MOJ.2011.012
    Introduction: This study aims to investigate whether patients undergoing two-stage revision total hip arthroplasty (THA) for prosthetic joint infection (PJI) and one-stage revision THA for aseptic reasons have similar clinical outcomes and patient satisfaction during their post-operative follow-up. We hypothesise that the two-stage revision THA for PJI is associated with poorer outcomes as compared to aseptic revision THA.

    Materials and Methods: We reviewed prospectively collected data in our tertiary hospital arthroplasty registry and identified patients who underwent revision THA between 2001 and 2014, with a minimum of two years follow-up. The study group (two-stage revision THA for PJI) consists of 23 patients and the control group (one-stage revision THA for aseptic reasons) consists of 231 patients. Patient demographics, Western Ontario and McMaster Universities Arthritis Index (WOMAC), Oxford Hip Score (OHS), Short Form-36 (SF-36) scores and patient reported satisfaction were evaluated. Student's t-test was used to compare continuous variables between the two groups. Statistical significance was defined as p <0.05.

    Results: The pre-operative demographics and clinical scores were relatively similar between the two groups of patients. At two years, patients who underwent revision THA for PJI reported a better WOMAC Pain Score and OHS as compared to aseptic revision THA. A similar proportion of patients were satisfied with their results of surgery in both groups (p=0.093).

    Conclusions: Although patients who underwent revision THA for PJI had poorer pre-operative functional scores (WOMAC function and SF-36 PF), at two years follow-up, these two groups of patients have comparable post-operative outcomes. Interestingly, patients who had revision THA for PJI reported a better clinical outcome in terms of OHS and WOMAC Pain score as compared to the aseptic group. We conclude that the revision THA for PJI is not inferior to aseptic revision THA in terms of patient satisfaction and clinical outcomes.

  11. Virotherapy: Current Trends and Future Prospects for Treatment of Colon and Rectal Malignancies
    Lee CL, Veeramani S, Molouki A, Lim SHE, Thomas W, Chia SL, et al.
    Cancer Invest, 2019;37(8):393-414.
    PMID: 31502477 DOI: 10.1080/07357907.2019.1660887
    Colorectal cancer (CRC) is one of the most common malignancies. In recent decades, early diagnosis and conventional therapies have resulted in a significant reduction in mortality. However, late stage metastatic disease still has very limited effective treatment options. There is a growing interest in using viruses to help target therapies to tumour sites. In recent years the evolution of immunotherapy has emphasised the importance of directing the immune system to eliminate tumour cells; we aim to give a state-of-the-art over-view of the diverse viruses that have been investigated as potential oncolytic agents for the treatment of CRC.
  12. Fulltext Synthesis and Optimization of Mesoporous Silica Nanoparticles for Ruthenium Polypyridyl Drug Delivery
    Harun SN, Ahmad H, Lim HN, Chia SL, Gill MR
    Pharmaceutics, 2021 Jan 24;13(2).
    PMID: 33498795 DOI: 10.3390/pharmaceutics13020150
    The ruthenium polypyridyl complex [Ru(dppz)2PIP]2+ (dppz: dipyridophenazine, PIP: (2-(phenyl)-imidazo[4,5-f ][1,10]phenanthroline), or Ru-PIP, is a potential anticancer drug that acts by inhibiting DNA replication. Due to the poor dissolution of Ru-PIP in aqueous media, a drug delivery agent would be a useful approach to overcome its limited bioavailability. Mesoporous silica nanoparticles (MSNs) were synthesized via a co-condensation method by using a phenanthrolinium salt with a 16 carbon length chain (Phen-C16) as the template. Optimization of the synthesis conditions by Box-Behnken design (BBD) generated MSNs with high surface area response at 833.9 m2g-1. Ru-PIP was effectively entrapped in MSNs at 18.84%. Drug release profile analysis showed that Ru-PIP is gradually released, with a cumulative release percentage of approximately 50% at 72 h. The release kinetic profile implied that Ru-PIP was released from MSN by diffusion. The in vitro cytotoxicity of Ru-PIP, both free and MSN-encapsulated, was studied in Hela, A549, and T24 cancer cell lines. While treatment of Ru-PIP alone is moderately cytotoxic, encapsulated Ru-PIP exerted significant cytotoxicity upon all the cell lines, with half maximal inhibitory concentration (IC50) values determined by MTT (([3-(4,5-dimethylthiazol-2-yl)-2,5-dephenyltetrazolium bromide]) assay at 48 h exposure substantially decreasing from >30 µM to <10 µM as a result of MSN encapsulation. The mechanistic potential of cytotoxicity on cell cycle distribution showed an increase in G1/S phase populations in all three cell lines. The findings indicate that MSN is an ideal drug delivery agent, as it is able to sustainably release Ru-PIP by diffusion in a prolonged treatment period.
  13. Fulltext Surface display of glycosylated Tyrosinase related protein-2 (TRP-2) tumour antigen on Lactococcus lactis
    Kalyanasundram J, Chia SL, Song AA, Raha AR, Young HA, Yusoff K
    BMC Biotechnol, 2015;15:113.
    PMID: 26715153 DOI: 10.1186/s12896-015-0231-z
    The exploitation of the surface display system of food and commensal lactic acid bacteria (LAB) for bacterial, viral, or protozoan antigen delivery has received strong interest recently. The Generally Regarded as Safe (GRAS) status of the Lactococcus lactis coupled with a non-recombinant strategy of in-trans surface display, provide a safe platform for therapeutic drug and vaccine development. However, production of therapeutic proteins fused with cell-wall anchoring motifs is predominantly limited to prokaryotic expression systems. This presents a major disadvantage in the surface display system particularly when glycosylation has been recently identified to significantly enhance epitope presentation. In this study, the glycosylated murine Tyrosinase related protein-2 (TRP-2) with the ability to anchor onto the L. lactis cell wall was produced in suspension adapted Chinese Hamster Ovary (CHO-S) cells by expressing TRP-2 fused with cell wall anchoring LysM motif (cA) at the C-terminus.
  14. Fulltext Comparative demographics, ROM, and function after TKA in Chinese, Malays, and Indians
    Siow WM, Chin PL, Chia SL, Lo NN, Yeo SJ
    Clin Orthop Relat Res, 2013 May;471(5):1451-7.
    PMID: 23299954 DOI: 10.1007/s11999-012-2776-7
    There is marked racial disparity in TKA use rates, demographics, and outcomes between white and Afro-Caribbean Americans. Comparative studies of ethnicity in patients undergoing TKAs have been mostly in American populations with an underrepresentation of Asian groups. It is unclear whether these disparities exist in Chinese, Malays, and Indians.
  15. Fulltext An improved method for the rescue of recombinant Newcastle disease virus
    Cheow PS, Tan TK, Song AA, Yusoff K, Chia SL
    Biotechniques, 2020 02;68(2):96-100.
    PMID: 31937115 DOI: 10.2144/btn-2019-0110
    Reverse genetics has been used to generate recombinant Newcastle disease virus with enhanced immunogenic properties for vaccine development. The system, which involves co-transfecting the viral antigenomic plasmid with three helper plasmids into a T7 RNA polymerase-expressing cell to produce viral progenies, poses a great challenge. We have modified the standard transfection method to improve the transfection efficiency of the plasmids, resulting in a higher titer of virus progeny production. Two transfection reagents (i.e., lipofectamine and polyethylenimine) were used to compare the transfection efficiency of the four plasmids. The virus progenies produced were quantitated with flow cytometry analysis of the infectious virus unit. The modified transfection method increased the titer of virus progenies compared with that of the standard transfection method.
  16. Fulltext Synergy of ruthenium metallo-intercalator, [Ru(dppz)2(PIP)]2+, with PARP inhibitor Olaparib in non-small cell lung cancer cells
    Yusoh NA, Chia SL, Saad N, Ahmad H, Gill MR
    Sci Rep, 2023 Jan 26;13(1):1456.
    PMID: 36702871 DOI: 10.1038/s41598-023-28454-x
    Poly(ADP-ribose) polymerase (PARP) are critical DNA repair enzymes that are activated as part of the DNA damage response (DDR). Although inhibitors of PARP (PARPi) have emerged as small molecule drugs and have shown promising therapeutic effects, PARPi used as single agents are clinically limited to patients with mutations in germline breast cancer susceptibility gene (BRCA). Thus, novel PARPi combination strategies may expand their usage and combat drug resistance. In recent years, ruthenium polypyridyl complexes (RPCs) have emerged as promising anti-cancer candidates due to their attractive DNA binding properties and distinct mechanisms of action. Previously, we reported the rational combination of the RPC DNA replication inhibitor [Ru(dppz)2(PIP)]2+ (dppz = dipyrido[3,2-a:2',3'-c]phenazine, PIP = 2-(phenyl)-imidazo[4,5-f][1,10]phenanthroline), "Ru-PIP", with the PARPi Olaparib in breast cancer cells. Here, we expand upon this work and examine the combination of Ru-PIP with Olaparib for synergy in lung cancer cells, including in 3D lung cancer spheroids, to further elucidate mechanisms of synergy and additionally assess toxicity in a zebrafish embryo model. Compared to single agents alone, Ru-PIP and Olaparib synergy was observed in both A549 and H1975 lung cancer cell lines with mild impact on normal lung fibroblast MRC5 cells. Employing the A549 cell line, synergy was confirmed by loss in clonogenic potential and reduced migration properties. Mechanistic studies indicated that synergy is accompanied by increased double-strand break (DSB) DNA damage and reactive oxygen species (ROS) levels which subsequently lead to cell death via apoptosis. Moreover, the identified combination was successfully able to inhibit the growth of A549 lung cancer spheroids and acute zebrafish embryos toxicity studies revealed that this combination showed reduced toxicity compared to single-agent Ru-PIP.
  17. Discovery of a novel dual functional phenylpyrazole-styryl hybrid that induces apoptotic and autophagic cell death in bladder cancer cells
    Leong SW, Wang J, Okuda KS, Su Q, Zhang Y, Abas F, et al.
    Eur J Med Chem, 2023 Apr 20;254:115335.
    PMID: 37098306 DOI: 10.1016/j.ejmech.2023.115335
    Unpleasant side effects and resistance development remained the Achilles heel of chemotherapy. Since low tumor-selectivity and monotonous effect of chemotherapy are closely related to such bottleneck, targeting tumor-selective multi-functional anticancer agents may be an ideal strategy in the search of new safer drugs. Herein, we report the discovery of compound 21, a nitro-substituted 1,5-diphenyl-3-styryl-1H-pyrazole that possesses dual functional characteristics. The 2D- and 3D-culture-based studies revealed that 21 not only could induce ROS-independent apoptotic and EGFR/AKT/mTOR-mediated autophagic cell deaths in EJ28 cells simultaneously but also has the ability in inducing cell death at both proliferating and quiescent zones of EJ28 spheroids. The molecular modelling analysis showed that 21 possesses EGFR targeting capability as it forms stable interactions in the EGFR active site. Together with its good safety profile in the zebrafish-based model, the present study showed that 21 is promising and may lead to the discovery of tumor-selective multi-functional anti-cancer agents.
  18. In silico selection of aptamers against SARS-CoV-2
    Akmal Shukri AM, Wang SM, Feng C, Chia SL, Mohd Nawi SFA, Citartan M
    Analyst, 2024 Sep 02.
    PMID: 39221970 DOI: 10.1039/d4an00812j
    Aptamers are molecular recognition elements that have been extensively deployed in a wide array of applications ranging from diagnostics to therapeutics. Due to their unique properties as compared to antibodies, aptamers were also largely isolated during the COVID-19 pandemic for multiple purposes. Typically generated by conventional SELEX, the inherent drawbacks of the process including the time-consuming, cumbersome and resource-intensive nature catalysed the move to adopt in silico approaches to isolate aptamers. Impressive performances of these in silico-derived aptamers in their respective assays have been documented thus far, bearing testimony to the huge potential of the in silico approaches, akin to the traditional SELEX in isolating aptamers. In this study, we provide an overview of the in silico selection of aptamers against SARS-CoV-2 by providing insights into the basic steps involved, which comprise the selection of the initial single-stranded nucleic acids, determination of the secondary and tertiary structures and in silico approaches that include both rigid docking and molecular dynamics simulations. The different approaches involving aptamers against SARS-CoV-2 were illuminated and the need to verify these aptamers by experimental validation was also emphasized. Cognizant of the need to continuously improve aptamers, the strategies embraced thus far for post-in silico selection modifications were enumerated. Shedding light on the steps involved in the in silico selection can set the stage for further improvisation to augment the functionalities of the aptamers in the future.
  19. Fulltext Persistent Newcastle disease virus infection in bladder cancer cells is associated with putative pro-survival and anti-viral transcriptomic changes
    Chan LC, Kalyanasundram J, Leong SW, Masarudin MJ, Veerakumarasivam A, Yusoff K, et al.
    BMC Cancer, 2021 May 27;21(1):625.
    PMID: 34044804 DOI: 10.1186/s12885-021-08345-y
    BACKGROUND: Newcastle disease virus (NDV) is an oncolytic virus with excellent selectivity against cancer cells, both in vitro and in vivo. Unfortunately, prolonged in vitro NDV infection results in the development of persistent infection in the cancer cells which are then able to resist NDV-mediated oncolysis. However, the mechanism of persistency of infection remains poorly understood.

    METHODS: In this study, we established persistently NDV-infected EJ28 bladder cancer cells, designated as EJ28P. Global transcriptomic analysis was subsequently carried out by microarray analysis. Differentially expressed genes (DEGs) between EJ28 and EJ28P cells identified by the edgeR program were further analysed by Gene Set Enrichment Analysis (GSEA) and Ingenuity Pathway Analysis (IPA) analyses. In addition, the microarray data were validated by RT-qPCR.

    RESULTS: Persistently NDV-infected EJ28 bladder cancer cells were successfully established and confirmed by flow cytometry. Microarray analysis identified a total of 368 genes as differentially expressed in EJ28P cells when compared to the non-infected EJ28 cells. GSEA revealed that the Wnt/β-catenin and KRAS signalling pathways were upregulated while the TGF-β signalling pathway was downregulated. Findings from this study suggest that the upregulation of genes that are associated with cell growth, pro-survival, and anti-apoptosis may explain the survivability of EJ28P cells and the development of persistent infection of NDV.

    CONCLUSIONS: This study provides insights into the transcriptomic changes that occur and the specific signalling pathways that are potentially involved in the development and maintenance of NDV persistency of infection in bladder cancer cells. These findings warrant further investigation and is crucial towards the development of effective NDV oncolytic therapy against cancer.

  20. Metallointercalator [Ru(dppz)2(PIP)]2+ Renders BRCA Wild-Type Triple-Negative Breast Cancer Cells Hypersensitive to PARP Inhibition
    Yusoh NA, Leong SW, Chia SL, Harun SN, Rahman MBA, Vallis KA, et al.
    ACS Chem. Biol., 2020 02 21;15(2):378-387.
    PMID: 31898884 DOI: 10.1021/acschembio.9b00843
    There is a need to improve and extend the use of clinically approved poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi), including for BRCA wild-type triple-negative breast cancer (TNBC). The demonstration that ruthenium(II) polypyridyl complex (RPC) metallointercalators can rapidly stall DNA replication fork progression provides the rationale for their combination alongside DNA damage response (DDR) inhibitors to achieve synergism in cancer cells. The aim of the present study was to evaluate use of the multi-intercalator [Ru(dppz)2(PIP)]2+ (dppz = dipyrido[3,2-a:2',3'-c]phenazine, PIP = (2-(phenyl)imidazo[4,5-f][1,10]phenanthroline, Ru-PIP) alongside the PARPi olaparib and NU1025. Cell proliferation and clonogenic survival assays indicated a synergistic relationship between Ru-PIP and olaparib in MDA-MB-231 TNBC and MCF7 human breast cancer cells. Strikingly, low dose Ru-PIP renders both cell lines hypersensitive to olaparib, with a >300-fold increase in olaparib potency in TNBC, the largest nongenetic PARPi enhancement effect described to date. A negligible impact on the viability of normal human fibroblasts was observed for any combination tested. Increased levels of DNA double-strand break (DSB) damage and olaparib abrogation of Ru-PIP-activated pChk1 signaling are consistent with PARPi-facilitated collapse of Ru-PIP-associated stalled replication forks. This results in enhanced G2/M cell-cycle arrest, apoptosis, and decreased cell motility for the combination treatment compared to single-agent conditions. This work establishes that an RPC metallointercalator can be combined with PARPi for potent synergy in BRCA-proficient breast cancer cells, including TNBC.
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