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  1. Fulltext Effects of open-top chamber on soil chemical properties and microbial growth
    Kqueen, Cheah Yoke, Maryam Abdulla Seif, Mohamed Ikhtifar Rafi, Lim, Wei Meng, Ling, Clemente Michael Wong Vui, Tan, Geok Yuan Annie
    Life Sciences, Medicine and Biomedicine, 2018;2(3):10-15.
    MyJurnal
    Global warming is the main concern in today’s century as it comes with numerous side effects to the natural environment. Open Top Chambers (OTC) consist of metal constructions with transparent vertical side-walls and a frustum on top. An opening in the middle of the frustum allows an air exchange to reduce temperature and humidity effects in the chamber. The size of the open top chamber which is located in Universiti Putra Malaysia is slanted 60o, 50cm tall, 2.08m basal diameter hexagon chamber. The Open Top Chamber experiments were carried out to determine how much global warming has affected and is still affecting the temperature, pH, the moisture and the growth of the microbes in the tropical soil. The aim of this study is to elucidate the effects of temperature increase on the soil microbes’ population and on the pH of the soil. The study was conducted to observe the effect of heat on the population of soil microbes and the pH of the soil which was collected on the same day for 6 consecutive months. The microbes from the samples were grown on agar plates. The population of microbes on the plates were used as values were for Colony Forming Unit (CFU) value calculations. The effects of OTCs on mean temperature showed a large range of CFU values throughout the 6 months but did not differ significantly between studies. Increases in mean monthly and diurnal temperature were strongly related, indicating that the presence of warming effect by the OTCs. Such predictive power allows a better mechanistic understanding of observed biotic response to experimental warming. This study will be useful for the understanding of the global warming effect on microbes. The Open Top Chamber experiment has proven to be one of the effective model for global warming research and data collected especially on the growth of soil microbial obtained would be of great use for further experiments.
  2. Fulltext Formulation and delivery of itraconazole to the brain using a nanolipid carrier system
    Lim WM, Rajinikanth PS, Mallikarjun C, Kang YB
    Int J Nanomedicine, 2014;9:2117-26.
    PMID: 24833900 DOI: 10.2147/IJN.S57565
    The objectives of this study were to develop and characterize itraconazole (ITZ)-loaded nanostructured lipid carriers (NLCs) and to study their potential for drug delivery into the brain. Precirol(®) ATO 5 and Transcutol(®) HP were selected as the lipid phase, and Tween(®) 80 and Solutol(®) HS15 as surfactants. The ITZ-NLCs were prepared by a hot and high-pressure homogenization method. The entrapment efficiency for the best formulation batch was analyzed using high-performance liquid chromatography and was found to be 70.5%±0.6%. The average size, zeta potential, and polydispersity index for the ITZ-NLCs used for animal studies were found to be 313.7±15.3 nm, -18.7±0.30 mV, and 0.562±0.070, respectively. Transmission electron microscopy confirmed that ITZ-NLCs were spherical in shape, with a size of less than 200 nm. Differential scanning calorimetry and X-ray diffractometry analysis showed that ITZ was encapsulated in the lipid matrix and present in the amorphous form. The in vitro release study showed that ITZ-NLCs achieved a sustained release, with cumulative release of 80.6%±5.3% up to 24 hours. An in vivo study showed that ITZ-NLCs could increase the ITZ concentration in the brain by almost twofold. These results suggest that ITZ-NLCs can be exploited as nanocarriers to achieve sustained release and brain-targeted delivery.
  3. Fulltext Comparison of vegetable oils on the uptake of lutein and zeaxanthin by ARPE-19 cells
    Baek J, Mai CW, Lim WM, Wong LC
    Int J Ophthalmol, 2023;16(1):40-46.
    PMID: 36659939 DOI: 10.18240/ijo.2023.01.06
    AIM: To compare the effect of vegetable oils on the uptake of lutein and zeaxanthin by adult retinal pigment epithelial (ARPE)-19 cells in vitro.

    METHODS: ARPE-19 cells were cultured in Dulbecco's Modified Eagle Medium-F-12 supplemented with 10% foetal bovine serum and 1% penicillin-streptomycin in a humidified 5% CO2 incubator maintained at 37°C. Cells were treated with 247 µmol/L lutein, 49 µmol/L zeaxanthin and 1% (v/v) of either coconut oil, corn oil, peanut oil, olive oil, sunflower oil, soybean oil, castor oil, or linseed oil for 48h. Lutein and zeaxanthin concentration in the cells were quantified by high performance liquid chromatography.

    RESULTS: Among the oils tested, the highest lutein and zeaxanthin uptake was observed with coconut oil while the lowest was observed with linseed oil.

    CONCLUSION: ARPE-19 uptake of lutein and zeaxanthin are found to be dependent on the type of oils.

  4. Fulltext Development of In-Situ Spray for Local Delivery of Antibacterial Drug for Hidradenitis Suppurativa: Investigation of Alternative Formulation
    Wong YL, Pandey M, Choudhury H, Lim WM, Bhattamisra SK, Gorain B
    Polymers (Basel), 2021 Aug 18;13(16).
    PMID: 34451309 DOI: 10.3390/polym13162770
    Hidradenitis suppurativa (HS) has been considered an orphan disease with limited treatments available. The available topical treatment for this condition is clindamycin lotion; however, short retention and frequent application are the main setbacks. Thus, the present study aimed to attain an optimized antibacterial in situ spray formulation for the hidradenitis suppurativa skin condition, which gels once in contact with the skin surface at around 37 °C and possesses bioadhesion as well as sustained-release properties of the incorporated drug. Different concentrations of thermo-reversible gelling polymer, Pluronic F-127, were investigated along with the selected bioadhesive polymers, HPMC and SA. The optimized formulation F3 consisting of 18% Pluronic F-127 with 0.2% HPMC and 0.2% SA was characterized based on various physicochemical properties. The gelation temperature of F3 was found to be 29.0 ± 0.50 °C with a gelation time of 1.35 ± 0.40 min and a pH of 5.8. F3 had the viscosity of 178.50 ± 5.50 cP at 25 °C and 7800 ± 200 cP at 37 °C as the gel set. The optimized formulation was found to be bioadhesive and cytocompatible. Cumulative drug release was 65.05% within the time-frame of 8 h; the release pattern of the drug followed zero-order kinetics with the Higuchi release mechanism. The average zone of inhibition was found to be 43.44 ± 1.34 mm. The properties of F3 formulation reflect to improve residence time at the site of application and can enhance sustained drug release. Therefore, it could be concluded that optimized formulation has better retention and enhanced antimicrobial activity for superior efficacy against HS.
  5. Fulltext Molecular Hybrids Integrated with Benzimidazole and Pyrazole Structural Motifs: Design, Synthesis, Biological Evaluation, and Molecular Docking Studies
    Sivaramakarthikeyan R, Iniyaval S, Saravanan V, Lim WM, Mai CW, Ramalingan C
    ACS Omega, 2020 May 05;5(17):10089-10098.
    PMID: 32391496 DOI: 10.1021/acsomega.0c00630
    Synthesis of a series of benzimidazole-ornamented pyrazoles, 6a-6j has been obtained from arylhydrazine and aralkyl ketones via a multistep synthetic strategy. Among them, a hybrid-possessing para-nitrophenyl moiety connected to a pyrazole scaffold (6a) exerted the highest anti-inflammatory activity, which is superior to the standard, diclofenac sodium. While executing the 2,2-diphenyl-1-picrylhydrazyl radical-scavenging activity, a hybrid-possessing para-bromophenyl unit integrated at the pyrazole structural motif (6i) exhibited the highest activity among the hybrids examined. Besides, evaluation of anticancer potency of the synthesized hybrids revealed that the one containing a para-fluorophenyl unit tethered at the pyrazole nucleus (6h) showed the highest activity against both the pancreatic cancer cells (SW1990 and AsPCl) investigated. Considerable binding affinity between B-cell lymphoma and the hybrid, 6h has been reflected while performing molecular docking studies (-8.65 kcal/mol). The outcomes of the investigation expose that these hybrids could be used as effective intermediates to construct more potent biological agents.
  6. Fulltext Additivity vs Synergism: Investigation of the Additive Interaction of Cinnamon Bark Oil and Meropenem in Combinatory Therapy
    Yang SK, Yusoff K, Mai CW, Lim WM, Yap WS, Lim SE, et al.
    Molecules, 2017 Nov 04;22(11).
    PMID: 29113046 DOI: 10.3390/molecules22111733
    Combinatory therapies have been commonly applied in the clinical setting to tackle multi-drug resistant bacterial infections and these have frequently proven to be effective. Specifically, combinatory therapies resulting in synergistic interactions between antibiotics and adjuvant have been the main focus due to their effectiveness, sidelining the effects of additivity, which also lowers the minimal effective dosage of either antimicrobial agent. Thus, this study was undertaken to look at the effects of additivity between essential oils and antibiotic, via the use of cinnamon bark essential oil (CBO) and meropenem as a model for additivity. Comparisons between synergistic and additive interaction of CBO were performed in terms of the ability of CBO to disrupt bacterial membrane, via zeta potential measurement, outer membrane permeability assay and scanning electron microscopy. It has been found that the additivity interaction between CBO and meropenem showed similar membrane disruption ability when compared to those synergistic combinations which was previously reported. Hence, results based on our studies strongly suggest that additive interaction acts on a par with synergistic interaction. Therefore, further investigation in additive interaction between antibiotics and adjuvant should be performed for a more in depth understanding of the mechanism and the impacts of such interaction.
  7. Fulltext Roles of Inflammasomes in Epstein-Barr Virus-Associated Nasopharyngeal Cancer
    Looi CK, Hii LW, Chung FF, Mai CW, Lim WM, Leong CO
    Cancers (Basel), 2021 Apr 08;13(8).
    PMID: 33918087 DOI: 10.3390/cancers13081786
    Epstein-Barr virus (EBV) infection is recognised as one of the causative agents in most nasopharyngeal carcinoma (NPC) cases. Expression of EBV viral antigens can induce host's antiviral immune response by activating the inflammasomes to produce pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and IL-18. These cytokines are known to be detrimental to a wide range of virus-infected cells, in which they can activate an inflammatory cell death program, called pyroptosis. However, aberrant inflammasome activation and production of its downstream cytokines lead to chronic inflammation that may contribute to various diseases, including NPC. In this review, we summarise the roles of inflammasomes during viral infection, how EBV evades inflammasome-mediated immune response, and progress into tumourigenesis. The contrasting roles of inflammasomes in cancer, as well as the current therapeutic approaches used in targeting inflammasomes, are also discussed in this review. While the inflammasomes appear to have dual roles in carcinogenesis, there are still many questions that remain unanswered. In particular, the exact molecular mechanism responsible for the regulation of the inflammasomes during carcinogenesis of EBV-associated NPC has not been explored thoroughly. Furthermore, the current practical application of inflammasome inhibitors is limited to specific tumour types, hence, further studies are warranted to discover the potential of targeting the inflammasomes for the treatment of NPC.
  8. Fulltext Antibacterial Activity and Mode of Action of β-caryophyllene on Bacillus cereus
    Moo CL, Yang SK, Osman MA, Yuswan MH, Loh JY, Lim WM, et al.
    Pol J Microbiol, 2020;69:1-6.
    PMID: 32162852 DOI: 10.33073/pjm-2020-007
    Natural products such as essential oils (EOs) are secondary metabolites that can be obtained from either plant or animal sources or produced by microorganisms. Much attention has been given to exploring the use of secondary metabolites as natural antibacterial agents. This study investigates the antibacterial activity and mechanism of β-caryophyllene, a compound that can be found in various EOs, against Bacillus cereus. The minimum inhibitory concentration of β-caryophyllene against B. cereus was 2.5% (v/v), whereas killing kinetics of β-caryophyllene at minimum inhibitory concentration recorded complete bactericidal activity within 2 hours. Zeta-potential measurement in the cells treated with half the minimum inhibitory concentration of β-caryophyllene at 1.25% (v/v) showed an increase in the membrane permeability surface charge to -3.98 mV, compared to untreated cells (-5.46 mV). Intracellular contents leakage of UV-absorbing materials was detected in the cells treated with β-caryophyllene. Additionally, β-caryophyllene does not interfere with the efflux activity of B. cereus via the ethidium bromide influx/efflux activity. The results revealed that β-caryophyllene was able to alter membrane permeability and integrity of B. cereus, leading to membrane damage and intracellular content leakage, which eventually caused cell death.

    Natural products such as essential oils (EOs) are secondary metabolites that can be obtained from either plant or animal sources or produced by microorganisms. Much attention has been given to exploring the use of secondary metabolites as natural antibacterial agents. This study investigates the antibacterial activity and mechanism of β-caryophyllene, a compound that can be found in various EOs, against Bacillus cereus. The minimum inhibitory concentration of β-caryophyllene against B. cereus was 2.5% (v/v), whereas killing kinetics of β-caryophyllene at minimum inhibitory concentration recorded complete bactericidal activity within 2 hours. Zeta-potential measurement in the cells treated with half the minimum inhibitory concentration of β-caryophyllene at 1.25% (v/v) showed an increase in the membrane permeability surface charge to –3.98 mV, compared to untreated cells (–5.46 mV). Intracellular contents leakage of UV-absorbing materials was detected in the cells treated with β-caryophyllene. Additionally, β-caryophyllene does not interfere with the efflux activity of B. cereus via the ethidium bromide influx/efflux activity. The results revealed that β-caryophyllene was able to alter membrane permeability and integrity of B. cereus, leading to membrane damage and intracellular content leakage, which eventually caused cell death.

  9. Fulltext Functional Roles of JNK and p38 MAPK Signaling in Nasopharyngeal Carcinoma
    Pua LJW, Mai CW, Chung FF, Khoo AS, Leong CO, Lim WM, et al.
    Int J Mol Sci, 2022 Jan 20;23(3).
    PMID: 35163030 DOI: 10.3390/ijms23031108
    c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) family members integrate signals that affect proliferation, differentiation, survival, and migration in a cell context- and cell type-specific way. JNK and p38 MAPK activities are found upregulated in nasopharyngeal carcinoma (NPC). Studies have shown that activation of JNK and p38 MAPK signaling can promote NPC oncogenesis by mechanisms within the cancer cells and interactions with the tumor microenvironment. They regulate multiple transcription activities and contribute to tumor-promoting processes, ranging from cell proliferation to apoptosis, inflammation, metastasis, and angiogenesis. Current literature suggests that JNK and p38 MAPK activation may exert pro-tumorigenic functions in NPC, though the underlying mechanisms are not well documented and have yet to be fully explored. Here, we aim to provide a narrative review of JNK and p38 MAPK pathways in human cancers with a primary focus on NPC. We also discuss the potential therapeutic agents that could be used to target JNK and p38 MAPK signaling in NPC, along with perspectives for future works. We aim to inspire future studies further delineating JNK and p38 MAPK signaling in NPC oncogenesis which might offer important insights for better strategies in diagnosis, prognosis, and treatment decision-making in NPC patients.
  10. Fulltext Impact of Microplastics and Nanoplastics on Human Health
    Yee MS, Hii LW, Looi CK, Lim WM, Wong SF, Kok YY, et al.
    Nanomaterials (Basel), 2021 Feb 16;11(2).
    PMID: 33669327 DOI: 10.3390/nano11020496
    Plastics have enormous impacts to every aspect of daily life including technology, medicine and treatments, and domestic appliances. Most of the used plastics are thrown away by consumers after a single use, which has become a huge environmental problem as they will end up in landfill, oceans and other waterways. These plastics are discarded in vast numbers each day, and the breaking down of the plastics from micro- to nano-sizes has led to worries about how toxic these plastics are to the environment and humans. While, there are several earlier studies reported the effects of micro- and nano-plastics have on the environment, there is scant research into their impact on the human body at subcellular or molecular levels. In particular, the potential of how nano-plastics move through the gut, lungs and skin epithelia in causing systemic exposure has not been examined thoroughly. This review explores thoroughly on how nanoplastics are created, how they behave/breakdown within the environment, levels of toxicity and pollution of these nanoplastics, and the possible health impacts on humans, as well as suggestions for additional research. This paper aims to inspire future studies into core elements of micro- and nano-plastics, the biological reactions caused by their specific and unusual qualities.
  11. Fulltext Inhibition of Janus Kinase 1 synergizes docetaxel sensitivity in prostate cancer cells
    Nalairndran G, Chung I, Abdul Razack AH, Chung FF, Hii LW, Lim WM, et al.
    J Cell Mol Med, 2021 Sep;25(17):8187-8200.
    PMID: 34322995 DOI: 10.1111/jcmm.16684
    Prostate cancer (PCa) is the second most common malignancy and is the fifth leading cause of cancer mortality among men globally. Docetaxel-based therapy remains the first-line treatment for metastatic castration-resistant prostate cancer. However, dose-limiting toxicity including neutropenia, myelosuppression and neurotoxicity is the major reason for docetaxel dose reductions and fewer cycles administered, despite a recent study showing a clear survival benefit with increased total number of docetaxel cycles in PCa patients. Although previous studies have attempted to improve the efficacy and reduce docetaxel toxicity through drug combination, no drug has yet demonstrated improved overall survival in clinical trial, highlighting the challenges of improving the activity of docetaxel monotherapy in PCa. Herein, we identified 15 lethality hits for which inhibition could enhance docetaxel sensitivity in PCa cells via a high-throughput kinome-wide loss-of-function screen. Further drug-gene interactions analyses identified Janus kinase 1 (JAK1) as a viable druggable target with existing experimental inhibitors and FDA-approved drugs. We demonstrated that depletion of endogenous JAK1 enhanced docetaxel-induced apoptosis in PCa cells. Furthermore, inhibition of JAK1/2 by baricitinib and ruxolitinib synergizes docetaxel sensitivity in both androgen receptor (AR)-negative DU145 and PC3 cells, but not in the AR-positive LNCaP cells. In contrast, no synergistic effects were observed in cells treated with JAK2-specific inhibitor, fedratinib, suggesting that the synergistic effects are mainly mediated through JAK1 inhibition. In conclusion, the combination therapy with JAK1 inhibitors and docetaxel could be a useful therapeutic strategy in the treatment of prostate cancers.
  12. Nose to brain delivery of rotigotine loaded chitosan nanoparticles in human SH-SY5Y neuroblastoma cells and animal model of Parkinson's disease
    Bhattamisra SK, Shak AT, Xi LW, Safian NH, Choudhury H, Lim WM, et al.
    Int J Pharm, 2020 Apr 15;579:119148.
    PMID: 32084576 DOI: 10.1016/j.ijpharm.2020.119148
    Rotigotine, a non-ergoline dopamine agonist, has been shown to be highly effective for the treatment of Parkinson's disease (PD). However, despite its therapeutic potential, its' clinical applications were hindered due to low aqueous solubility, first-pass metabolism and low bioavailability. Therefore, we developed rotigotine-loaded chitosan nanoparticles (RNPs) for nose-to-brain delivery and evaluated its neuronal uptake, antioxidant and neuroprotective effects using cell-based studies. The pharmacological effects of nose-to-brain delivery of the RNPs were also evaluated in an animal model of PD. The average particle size, particle size distribution and entrapment efficiency of the RNPs were found to be satisfactory. Exposure of RNPs for 24 h did not show any cytotoxicity towards SH-SY5Y human neuroblastoma cells. Furthermore, the RNPs caused a decrease in alpha-synuclein (SNCA) and an increase in tyrosine hydroxylase (TH) expression in these cells, suggestion that the exposure alleviated some of the direct neurotoxic effects of 6-OHDA. Behavioral and biochemical testing of RNPs in haloperidol-induced PD rats showed a reversal of catalepsy, akinesia and restoration of swimming ability. A decrease in lactate dehydrogenase (LDH) and an increase in catalase activities were also observed in the brain tissues. The results from the animal model of PD show that intranasally-administered RNPs enhanced brain targeting efficiency and drug bioavailability. Thus, RNPs for nose-to-brain delivery has significant potential to be developed as a treatment approach for PD.
  13. Enantiomeric pairs of ternary copper(ii) complexes and their aldol-type condensation products: synthesis, characterization, and anticancer and epigenetic properties
    Lee KY, Ng YL, Wang WS, Ng PY, Chan CW, Lai JW, et al.
    Dalton Trans, 2019 Apr 09;48(15):4987-4999.
    PMID: 30916098 DOI: 10.1039/c9dt00506d
    Chiral enantiomers [Cu(phen)(l-ser)(H2O)]NO31 and [Cu(phen)(d-ser)(H2O)]NO32 (ser = serinato) 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)(OCA)(H2O)]NO3·xH2O (3 and 4; phen = 1,10-phenanthroline; OCA = oxazolidine-4-carboxylate; x = 1/2, 0-2) 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. The crystal structures of 1 and 3 showed both the cationic complexes to have a square pyramidal geometry. These complexes were about nine fold more potent than cisplatin against metastatic MDA-MB-231 breast cancer cells, inducing apoptotic cell death via ROS generation and a massive drop in mitochondrial membrane potential. The results of monitoring EZH1, EZH2 and H3K27me3 revealed that the mode of action of 1-4 also involved the downregulation of EZH2 and it seemed to be independent of the H3K27me3 status.
  14. Fulltext Phosphoinositide-dependent Kinase-1 (PDPK1) regulates serum/glucocorticoid-regulated Kinase 3 (SGK3) for prostate cancer cell survival
    Nalairndran G, Hassan Abdul Razack A, Mai CW, Fei-Lei Chung F, Chan KK, Hii LW, et al.
    J Cell Mol Med, 2020 Oct;24(20):12188-12198.
    PMID: 32926495 DOI: 10.1111/jcmm.15876
    Prostate cancer (PCa) is the most common malignancy and is the second leading cause of cancer among men globally. Using a kinome-wide lentiviral small-hairpin RNA (shRNA) library screen, we identified phosphoinositide-dependent kinase-1 (PDPK1) as a potential mediator of cell survival in PCa cells. We showed that knock-down of endogenous human PDPK1 induced significant tumour-specific cell death in PCa cells (DU145 and PC3) but not in the normal prostate epithelial cells (RWPE-1). Further analyses revealed that PDPK1 mediates cancer cell survival predominantly via activation of serum/glucocorticoid-regulated kinase 3 (SGK3). Knock-down of endogenous PDPK1 in DU145 and PC3 cells significantly reduced SGK3 phosphorylation while ectopic expression of a constitutively active SGK3 completely abrogated the apoptosis induced by PDPK1. In contrast, no such effect was observed in SGK1 and AKT phosphorylation following PDPK1 knock-down. Importantly, PDPK1 inhibitors (GSK2334470 and BX-795) significantly reduced tumour-specific cell growth and synergized docetaxel sensitivity in PCa cells. In summary, our results demonstrated that PDPK1 mediates PCa cells' survival through SGK3 signalling and suggest that inactivation of this PDPK1-SGK3 axis may potentially serve as a novel therapeutic intervention for future treatment of PCa.
  15. Monomeric, Dimeric, and Trimeric Tropane Alkaloids from Pellacalyx saccardianus
    Chan ZY, Krishnan P, Modaresi SM, Hii LW, Mai CW, Lim WM, et al.
    J Nat Prod, 2021 08 27;84(8):2272-2281.
    PMID: 34342431 DOI: 10.1021/acs.jnatprod.1c00374
    Seven new tropane alkaloids, including five monomeric (1-5), one dimeric (6), and one trimeric (7) 3α-nortropane ester, along with two known monomeric nortropane alkaloids (8 and 9), were isolated from the leaves and bark of Pellacalyx saccardianus. Their structures, including the absolute configuration of the enantiomeric pair of (±)-6, were elucidated by comprehensive spectroscopic analyses. Alkaloids 6 and 7 showed cytotoxicity toward human pancreatic cancer cell lines (AsPC-1, BxPC3, PANC-1, and SW1990). Alkaloids 1, 4, and 9 induced a smooth muscle relaxation effect comparable to that of atropine (Emax 106.1 ± 7.5%, 97.0 ± 5.2%, 100.9 ± 1.4%, 111.7 ± 1.7%, respectively) on isolated rat tracheal rings.
  16. Parallel genome-wide RNAi screens identify lymphocyte-specific protein tyrosine kinase (LCK) as a targetable vulnerability of cell proliferation and chemoresistance in nasopharyngeal carcinoma
    Liew K, Yu GQS, Wei Pua LJ, Wong LZ, Tham SY, Hii LW, et al.
    Cancer Lett, 2021 Apr 28;504:81-90.
    PMID: 33587980 DOI: 10.1016/j.canlet.2021.02.006
    Despite recent in advances in the management of nasopharyngeal carcinoma (NPC), development of targeted therapy remains challenging particularly in patients with recurrent or metastatic disease. To search for clinically relevant targets for the treatment of NPC, we carried out parallel genome-wide functional screens to identified essential genes that are required for NPC cells proliferation and cisplatin resistance. We identified lymphocyte-specific protein tyrosine kinase (LCK) as a key vulnerability of both proliferation and cisplatin resistance. Depletion of endogenous LCK or treatment of cells with LCK inhibitor induced tumor-specific cell death and synergized cisplatin sensitivity in EBV-positive C666-1 and EBV-negative SUNE1 cells. Further analyses demonstrated that LCK is regulating the proliferation and cisplatin resistance through activation of signal transducer and activator of transcription 5 (STAT5). Taken together, our study provides a molecular basis for targeting LCK and STAT5 signaling as potential druggable targets for the management of NPC.
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