Displaying publications 21 - 40 of 52 in total

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  1. SRJ09, a promising anticancer drug lead: Elucidation of mechanisms of antiproliferative and apoptogenic effects and assessment of in vivo antitumor efficacy
    Wong CC, Lim SH, Sagineedu SR, Lajis NH, Stanslas J
    Pharmacol Res, 2016 05;107:66-78.
    PMID: 26940565 DOI: 10.1016/j.phrs.2016.02.024
    SRJ09 (3,19-(2-bromobenzylidene)andrographolide), a semisynthetic andrographolide (AGP) derivative, was shown to induce G1 cell cycle arrest and eventually apoptosis in breast and colon cancer cell lines. The present investigation was carried out to elucidate the mechanisms cell cycle arrest and apoptosis and evaluate the in vivo antitumor activity of SRJ09. The in vitro growth inhibitory properties of compounds were assessed in colon (HCT-116) and breast (MCF-7) cancer cell lines. Immunoblotting was utilized to quantitate the protein levels in cells. The gene expressions were determined using reverse transcriptase PCR (RT-PCR). Pharmacokinetic investigation was carried out by determining SRJ09 levels in plasma of Balb/C mice using HPLC. In vivo antitumor activity was evaluated in athymic mice carrying HCT-116 colon tumor xenografts. SRJ09 displayed improved in vitro activity when compared with AGP by producing rapid cell killing effect in vitro. Its activity was not compromised in MES-SA/Dx5 multidrug resistant (MDR) cells expressing p-glycoprotein. Cells treated with SRJ09 (0.1-10μM) displayed increased p21 protein level, which corresponded with gene expression. Whereas CDK4 protein level and gene expression was suppressed. The treatment did not affect cyclin D1. Changes of these proteins paralleled G1 cell cycle arrest in both cell lines as determined by flow cytometry. Induction of apoptosis by SRJ09 in HCT-116 cells which occurred independent of p53 and bcl-2 was inhibited in the presence of caspase 8 inhibitor, implicating the extrinsic apoptotic pathway. A single dose (100mg/kg, i.p) of SRJ09 produced a plasma concentration range of 12-30.4μM. At 400mg/kg (q4dX3), it significantly retarded growth of tumor xenografts. The antitumor activity of SRJ09 is suggested mediated via the induction of p21 expression and suppression of CDK-4 expression without affecting cyclin D1 to trigger G1 arrest leading to apoptosis.
    Matched MeSH terms: Xenograft Model Antitumor Assays
  2. Fulltext Knockdown of Tousled‑like kinase 1 inhibits survival of glioblastoma multiforme cells
    Ibrahim K, Abdul Murad NA, Harun R, Jamal R
    Int J Mol Med, 2020 Aug;46(2):685-699.
    PMID: 32468002 DOI: 10.3892/ijmm.2020.4619
    Glioblastoma multiforme (GBM) is an aggressive type of brain tumour that commonly exhibits resistance to treatment. The tumour is highly heterogenous and complex kinomic alterations have been reported leading to dysregulation of signalling pathways. The present study aimed to investigate the novel kinome pathways and to identify potential therapeutic targets in GBM. Meta‑analysis using Oncomine identified 113 upregulated kinases in GBM. RNAi screening was performed on identified kinases using ON‑TARGETplus siRNA library on LN18 and U87MG. Tousled‑like kinase 1 (TLK1), which is a serine/threonine kinase was identified as a potential hit. In vitro functional validation was performed as the role of TLK1 in GBM is unknown. TLK1 knockdown in GBM cells significantly decreased cell viability, clonogenicity, proliferation and induced apoptosis. TLK1 knockdown also chemosensitised the GBM cells to the sublethal dose of temozolomide. The downstream pathways of TLK1 were examined using microarray analysis, which identified the involvement of DNA replication, cell cycle and focal adhesion signalling pathways. In vivo validation of the subcutaneous xenografts of stably transfected sh‑TLK1 U87MG cells demonstrated significantly decreased tumour growth in female BALB/c nude mice. Together, these results suggested that TLK1 may serve a role in GBM survival and may serve as a potential target for glioma.
    Matched MeSH terms: Xenograft Model Antitumor Assays
  3. Fulltext Antitumor and Anti-Metastatic Effects of Citral-Loaded Nanostructured Lipid Carrier in 4T1-Induced Breast Cancer Mouse Model
    Nordin N, Yeap SK, Rahman HS, Zamberi NR, Mohamad NE, Abu N, et al.
    Molecules, 2020 Jun 09;25(11).
    PMID: 32526880 DOI: 10.3390/molecules25112670
    Cancer nano-therapy has been progressing rapidly with the introduction of many novel drug delivery systems. The previous study has reported on the in vitro cytotoxicity of citral-loaded nanostructured lipid carrier (NLC-Citral) on MDA-MB-231 cells and some preliminary in vivo antitumor effects on 4T1 breast cancer cells challenged mice. However, the in vivo apoptosis induction and anti-metastatic effects of NLC-Citral have yet to be reported. In this study, the in vitro cytotoxic, anti-migration, and anti-invasion effects of NLC-Citral were tested on 4T1 breast cancer cells. In addition, the in vivo antitumor effects of oral delivery of NLC-Citral was also evaluated on BALB/c mice induced with 4T1 cells. In vitro cytotoxicity results showed that NLC-Citral and citral gave similar IC50 values on 4T1 cells. However, wound healing, migration, and invasion assays reflected better in vitro anti-metastasis potential for NLC-Citral than citral alone. Results from the in vivo study indicated that both NLC-Citral and citral have anti-tumor and anti-metastasis effects, whereby the NLC-Citral showed better efficacy than citral in all experiments. Also, the delay of tumor progression was through the suppression of the c-myc gene expression and induction of apoptosis in the tumor. In addition, the inhibition of metastasis of 4T1 cells to lung and bone marrow by the NLC-Citral and citral treatments was correlated with the downregulation of metastasis-related genes expression including MMP-9, ICAM, iNOS, and NF-kB and the angiogenesis-related proteins including G-CSF alpha, Eotaxin, bFGF, VEGF, IL-1alpha, and M-CSF in the tumor. Moreover, NLC-Citral showed greater downregulation of MMP-9, iNOS, ICAM, Eotaxin, bFGF, VEGF, and M-CSF than citral treatment in the 4T1-challenged mice, which may contribute to the better anti-metastatic effect of the encapsulated citral. This study suggests that NLC is a potential and effective delivery system for citral to target triple-negative breast cancer.
    Matched MeSH terms: Xenograft Model Antitumor Assays
  4. Silencing of ZFP36L2 increases sensitivity to temozolomide through G2/M cell cycle arrest and BAX mediated apoptosis in GBM cells
    Che Mat MF, Mohamad Hanif EA, Abdul Murad NA, Ibrahim K, Harun R, Jamal R
    Mol Biol Rep, 2021 Feb;48(2):1493-1503.
    PMID: 33590411 DOI: 10.1007/s11033-021-06144-z
    Despite the advancements in primary brain tumour diagnoses and treatments, the mortality rate remains high, particularly in glioblastoma (GBM). Chemoresistance, predominantly in recurrent cases, results in decreased mean survival of patients with GBM. We aimed to determine the chemosensitisation and oncogenic characteristics of zinc finger protein 36-like 2 (ZFP36L2) in LN18 GBM cells via RNA interference (RNAi) delivery. We conducted a meta-analysis of microarray datasets and RNAi screening using pooled small interference RNA (siRNA) to identify the druggable genes responsive to GBM chemosensitivity. Temozolomide-resistant LN18 cells were used to evaluate the effects of gene silencing on chemosensitisation to the sub-lethal dose (1/10 of the median inhibitory concentration [IC50]) of temozolomide. ZFP36L2 protein expression was detected by western blotting. Cell viability, proliferation, cell cycle and apoptosis assays were carried out using commercial kits. A human apoptosis array kit was used to determine the apoptosis pathway underlying chemosensitisation by siRNA against ZFP36L2 (siZFP36L2). Statistical analyses were performed using one-way analysis of variance; p > 0.05 was considered significant. The meta-analysis and RNAi screening identified ZFP36L2 as a potential marker of GBM. ZFP36L2 knockdown significantly induced apoptosis (p 
    Matched MeSH terms: Xenograft Model Antitumor Assays
  5. Fulltext A novel benzimidazole derivative, MBIC inhibits tumor growth and promotes apoptosis via activation of ROS-dependent JNK signaling pathway in hepatocellular carcinoma
    Dai X, Wang L, Deivasigamni A, Looi CY, Karthikeyan C, Trivedi P, et al.
    Oncotarget, 2017 Feb 21;8(8):12831-12842.
    PMID: 28086233 DOI: 10.18632/oncotarget.14606
    A prior screening programme carried out using MTT assay by our group identified a series of novel benzimidazole derivatives, among which Methyl 2-(5-fluoro-2-hydroxyphenyl)-1H- benzo[d]imidazole-5-carboxylate (MBIC) showed highest anticancer efficacy compared to that of chemotherapeutic agent, cisplatin. In the present study, we found that MBIC inhibited cell viability in different hepatocellular carcinoma (HCC) cell lines without exerting significant cytotoxic effects on normal liver cells. Annexin V-FITC/PI flow cytometry analysis and Western blotting results indicated that MBIC can induce apoptosis in HCC cells, which was found to be mediated through mitochondria associated proteins ultimately leading to the activation of caspase-3. The exposure to MBIC also resulted in remarkable impairment of HCC cell migration and invasion. In addition, treatment with MBIC led to a rapid generation of reactive oxygen species (ROS) and substantial activation of c-Jun-N-terminal kinase (JNK). The depletion of ROS by N-Acetyl cysteine (NAC) partially blocked MBIC-induced apoptosis and JNK activation in HCC cells. Finally, MBIC significantly inhibited tumor growth at a dose of 25 mg/kg in an orthotopic HCC mouse model. Taken together, these results demonstrate that MBIC may inhibit cell proliferation via ROS-mediated activation of the JNK signaling cascade in HCC cells.
    Matched MeSH terms: Xenograft Model Antitumor Assays
  6. Eurycoma longifolia, A Potential Phytomedicine for the Treatment of Cancer: Evidence of p53-mediated Apoptosis in Cancerous Cells
    Thu HE, Hussain Z, Mohamed IN, Shuid AN
    Curr Drug Targets, 2018;19(10):1109-1126.
    PMID: 28721818 DOI: 10.2174/1389450118666170718151913
    BACKGROUND: Eurycoma longifolia is a well-documented herbal medicine that has gained widespread recognition due to its versatile pharmacological activities including anticancer, antimalarial, antimicrobial, antioxidant, aphrodisiac, anti-inflammatory, anxiolytic, anti-diabetic, antirheumatism and anti-ulcer. Plethora of in vitro and in vivo studies evidenced their excellent antiproliferative and anticancer efficacy against various types of human cancers.

    OBJECTIVE: This review was aimed to critically analyze the therapeutic viability and anticancer efficacy of Eurycoma longifolia in the treatment of cancer and also to propose its molecular and translational mechanism of cytotoxicity against cancerous cells.

    RESULTS: Among a range of medicinally active compounds isolated from various parts (roots, stem, bark and leaves) of Eurycoma longifolia, 16 compounds have shown promising anti-proliferative and anticancer efficacies. Eurycomanone, one of the most active medicinal compounds of Eurycoma longifolia, displayed a strong dose-dependent anticancer efficacy against lung carcinoma (A-549 cells) and breast cancer (MCF-7 cells); however, showed moderate efficacy against gastric (MGC-803 cells) and intestinal carcinomas (HT-29 cells). The prime mode of cytotoxicity of Eurycoma longifolia and its medicinal compounds is the induction of apoptosis (programmed cell death) via the up-regulation of the expression of p53 (tumor suppressor protein) and pro-apoptotic protein (Bax) and downregulation of the expression of anti-apoptotic protein (Bcl-2). A remarkable alleviation in the mRNA expression of various cancer-associated biomarkers including heterogeneous nuclear ribonucleoprotein (hnRNP), prohibitin (PHB), annexin-1 (ANX1) and endoplasmic reticulum protein-28 (ERp28) has also been evidenced.

    CONCLUSION: Eurycoma longifolia and its medicinal constituents exhibit promising anticancer efficacy and thus can be considered as potential complementary therapy for the treatment of various types of human cancers.

    Matched MeSH terms: Xenograft Model Antitumor Assays
  7. Treatment of novel IL17A inhibitor in glioblastoma implementing 3rd generation co-culture cell line and patient-derived tumor model
    Khan MSS, Asif M, Basheer MKA, Kang CW, Al-Suede FS, Ein OC, et al.
    Eur J Pharmacol, 2017 May 15;803:24-38.
    PMID: 28322833 DOI: 10.1016/j.ejphar.2017.03.031
    Despite many treatment options, cancer remains a growing problem and has become the second leading cause of death globally. Here, we present fluorescence molecular tomography (FMT) data regarding the reversion of third generation co-cultured U87+DBTRG and patient-derived GBM tumor model after treatment with novel IL17A inhibitor named FLVM and FLVZ (organic derivatives of caffeic acid). FMT was used to determine tumor angiogenesis volume (assessment of number of blood vessel; the expression of angiogenic factors CD34 and other angiogenic cancer bio-markers) in U87+DBTRG and patient-derived gliomas. Immunohistochemistry was used to determine microvessel density [CD34], and cell proliferation [Ki67]. Western blot was used to assess the interleukin 17A [IL17A], vascular endothelial growth factor [VEGF] and hypoxia-inducible factor-1α [HIF-1α]. Antibody array was used to assess the cancer bio-markers in co-cultured U87+DBTRG gliomas. Animal survival was found to be significantly increased (P<0.0001) after FLVM treatment compared with control-IL17A. After FMT detection, FLVM, administered orally, was found to decrease tumor growth (P<0.0001). FLVM and FLVZ administration resulted in significant decreases in tumor hypoxia [HIF-1α (P<0.05)], angiogenesis [CD34 (P<0.05)], VEGF, IL17A and cell proliferation [Ki67 (P<0.05)] and caused a significant increase of Bax, caspase and FasL (P<0.05), compared with untreated animals. Additionally, Leptin, LPL (P<0.01), FFA (P<0.05) and adipogenesis were downregulated and no additive toxicity was found in mice except calorie-restriction like effect. Use of FLVM can be considered as a novel inhibitor of IL17A for the treatment of human gliomas.
    Matched MeSH terms: Xenograft Model Antitumor Assays
  8. Fulltext Anti-EGFR anchored paclitaxel loaded PLGA nanoparticles for the treatment of triple negative breast cancer. In-vitro and in-vivo anticancer activities
    Venugopal V, Krishnan S, Palanimuthu VR, Sankarankutty S, Kalaimani JK, Karupiah S, et al.
    PLoS One, 2018;13(11):e0206109.
    PMID: 30408068 DOI: 10.1371/journal.pone.0206109
    The aim of the present study is to analyze the viability of anti-EGFR anchored immunonanoparticle (INP) bearing Paclitaxel (PTX) to specifically bind the EGFR protein on the TNBC cells. The NP was prepared by nanoprecipitation and characterized the particle size, charge, entrapment of drug and release of it. The anti-EGFR anchored and the integrity was confirmed by SDS-PAGE. Cytotoxicity and NPs cellular uptake was analyzed with MDA-MB-468 type cancer cells and the EGFR expression was confirmed by PCR, qualitatively and quantitatively. The in-vivo antitumor activity of INP was determined by using athymic mice model and targeting efficiency was measured by calculating the PTX accumulation in the tumor plasma. The prepared INP with the size of 336.3 nm and the charge of -3.48 mV showed sustained drug release upto 48 h. The INP showed significant reduction of cancer cell viability of 10.6% for 48 h with 93 fold higher PTX accumulation in the tumor plasma compared with NPs. Based on these reports, we recommend that anti-EGFR anchored PTX loaded NP may have the ability to target the TNBC cells and improve the therapeutic action and subsidize the side effects of PTX for the treatment of TNBC.
    Matched MeSH terms: Xenograft Model Antitumor Assays
  9. Fulltext MicroRNA-362 negatively and positively regulates SMAD4 expression in TGF-β/SMAD signaling to suppress cell migration and invasion
    Cheng HP, Huang CJ, Tsai ML, Ong HT, Cheong SK, Choo KB, et al.
    Int J Med Sci, 2021;18(8):1798-1809.
    PMID: 33746597 DOI: 10.7150/ijms.50871
    Cell migration and invasion are modulated by epithelial-to-mesenchymal transition (EMT) and the reverse MET process. Despite the detection of microRNA-362 (miR-362, both the miR-362-5p and -3p species) in cancers, none of the identified miR-362 targets is a mesenchymal or epithelial factor to link miR-362 with EMT/MET and metastasis. Focusing on the TGF-β/SMAD signaling pathway in this work, luciferase assays and western blot data showed that miR-362 targeted and negatively regulated expression of SMAD4 and E-cadherin, but not SNAI1, which is regulated by SMAD4. However, miR-362 knockdown also down-regulated SMAD4 and SNAI1, but up-regulated E-cadherin expression. Wound-healing and transwell assays further showed that miR-362 knockdown suppressed cell migration and invasion, effects which were reversed by over-expressing SMAD4 or SNAI1, or by knocking down E-cadherin in the miR-362 knockdown cells. In orthotopic mice, miR-362 knockdown inhibited metastasis, and displayed the same SMAD4 and E-cadherin expression profiles in the tumors as in the in vitro studies. A scheme is proposed to integrate miR-362 negative regulation via SMAD4, and to explain miR-362 positive regulation of SMAD4 via miR-362 targeting of known SMAD4 suppressors, BRK and DACH1, which would have resulted in SMAD4 depletion and annulment of subsequent involvement in TGF-β signaling actions. Hence, miR-362 both negatively and positively regulates SMAD4 expression in TGF-β/SMAD signaling pathway to suppress cell motility and invasiveness and metastasis, and may explain the reported clinical association of anti-miR-362 with suppressed metastasis in various cancers. MiR-362 knockdown in miR-362-positive cancer cells may be used as a therapeutic strategy to suppress metastasis.
    Matched MeSH terms: Xenograft Model Antitumor Assays
  10. Fulltext Hyperthermia by near infrared radiation induced immune cells activation and infiltration in breast tumor
    Wan Mohd Zawawi WFA, Hibma MH, Salim MI, Jemon K
    Sci Rep, 2021 05 13;11(1):10278.
    PMID: 33986437 DOI: 10.1038/s41598-021-89740-0
    Breast cancer is the most common cancer that causes death in women. Conventional therapies, including surgery and chemotherapy, have different therapeutic effects and are commonly associated with risks and side effects. Near infrared radiation is a technique with few side effects that is used for local hyperthermia, typically as an adjuvant to other cancer therapies. The understanding of the use of near NIR as a monotherapy, and its effects on the immune cells activation and infiltration, are limited. In this study, we investigate the effects of HT treatment using NIR on tumor regression and on the immune cells and molecules in breast tumors. Results from this study demonstrated that local HT by NIR at 43 °C reduced tumor progression and significantly increased the median survival of tumor-bearing mice. Immunohistochemical analysis revealed a significant reduction in cells proliferation in treated tumor, which was accompanied by an abundance of heat shock protein 70 (Hsp70). Increased numbers of activated dendritic cells were observed in the draining lymph nodes of the mice, along with infiltration of T cells, NK cells and B cells into the tumor. In contrast, tumor-infiltrated regulatory T cells were largely diminished from the tumor. In addition, higher IFN-γ and IL-2 secretion was observed in tumor of treated mice. Overall, results from this present study extends the understanding of using local HT by NIR to stimulate a favourable immune response against breast cancer.
    Matched MeSH terms: Xenograft Model Antitumor Assays
  11. Metastasized lung cancer suppression by Morinda citrifolia (Noni) leaf compared to Erlotinib via anti-inflammatory, endogenous antioxidant responses and apoptotic gene activation
    Lim SL, Mustapha NM, Goh YM, Bakar NA, Mohamed S
    Mol Cell Biochem, 2016 May;416(1-2):85-97.
    PMID: 27106908 DOI: 10.1007/s11010-016-2698-x
    Metastasized lung and liver cancers cause over 2 million deaths annually, and are amongst the top killer cancers worldwide. Morinda citrifolia (Noni) leaves are traditionally consumed as vegetables in the tropics. The macro and micro effects of M. citrifolia (Noni) leaves on metastasized lung cancer development in vitro and in vivo were compared with the FDA-approved anti-cancer drug Erlotinib. The extract inhibited the proliferation and induced apoptosis in A549 cells (IC50 = 23.47 μg/mL) and mouse Lewis (LL2) lung carcinoma cells (IC50 = 5.50 μg/mL) in vitro, arrested cancer cell cycle at G0/G1 phases and significantly increased caspase-3/-8 without changing caspase-9 levels. The extract showed no toxicity on normal MRC5 lung cells. Non-small-cell lung cancer (NSCLC) A549-induced BALB/c mice were fed with 150 and 300 mg/kg M. citrifolia leaf extract and compared with Erlotinib (50 mg/kg body weight) for 21 days. It significantly increased the pro-apoptotic TRP53 genes, downregulated the pro-tumourigenesis genes (BIRC5, JAK2/STAT3/STAT5A) in the mice tumours, significantly increased the anti-inflammatory IL4, IL10 and NR3C1 expression in the metastasized lung and hepatic cancer tissues and enhanced the NFE2L2-dependent antioxidant responses against oxidative injuries. The extract elevated serum neutrophils and reduced the red blood cells, haemoglobin, corpuscular volume and cell haemoglobin concentration in the lung cancer-induced mammal. It suppressed inflammation and oedema, and upregulated the endogenous antioxidant responses and apoptotic genes to suppress the cancer. The 300 mg/kg extract was more effective than the 50 mg/kg Erlotinib for most of the parameters measured.
    Matched MeSH terms: Xenograft Model Antitumor Assays
  12. Fulltext Affimer Tagged Cubosomes: Targeting of Carcinoembryonic Antigen Expressing Colorectal Cancer Cells Using In Vitro and In Vivo Models
    Pramanik A, Xu Z, Shamsuddin SH, Khaled YS, Ingram N, Maisey T, et al.
    ACS Appl Mater Interfaces, 2022 Mar 09;14(9):11078-11091.
    PMID: 35196008 DOI: 10.1021/acsami.1c21655
    Nanomedicines, while having been approved for cancer therapy, present many challenges such as low stability, rapid clearance, and nonspecificity leading to off-target toxicity. Cubosomes are porous lyotropic liquid crystalline nanoparticles that have shown great premise as drug delivery vehicles; however, their behavior in vivo is largely underexplored, hindering clinical translation. Here, we have engineered cubosomes based on the space group Im3m that are loaded with copper acetylacetonate as a model drug, and their surfaces are functionalized for the first time with Affimer proteins via copper-free click chemistry to actively target overexpressed carcinoembryonic antigens on LS174T colorectal cancer cells. Unlike nontargeted cubosomes, Affimer tagged cubosomes showed preferential accumulation in cancer cells compared to normal cells not only in vitro (2D monolayer cell culture and 3D spheroid models) but also in vivo in colorectal cancer mouse xenografts, while exhibiting low nonspecific absorption and toxicity in other vital organs. Cancerous spheroids had maximum cell death compared to noncancerous cells upon targeted delivery. Xenografts subjected to targeted drug-loaded cubosomes showed a 5-7-fold higher drug accumulation in the tumor tissue compared to the liver, kidneys, and other vital organs, a significant decrease in tumor growth, and an increased survival rate compared to the nontargeted group. This work encompasses the first thorough preclinical investigation of Affimer targeted cubosomes as a cancer therapeutic.
    Matched MeSH terms: Xenograft Model Antitumor Assays
  13. Wnt5A regulates ABCB1 expression in multidrug-resistant cancer cells through activation of the non-canonical PKA/β-catenin pathway
    Hung TH, Hsu SC, Cheng CY, Choo KB, Tseng CP, Chen TC, et al.
    Oncotarget, 2014 Dec 15;5(23):12273-90.
    PMID: 25401518
    Multidrug resistance in cancer cells arises from altered drug permeability of the cell. We previously reported activation of the Wnt pathway in ABCB1-overexpressed human uterus sarcoma drug-resistant MES-SA/Dx5 cells through active β-catenin and associated transactivation activities, and upregulation of Wnt-targeting genes. In this study, Wnt5A was found to be significantly upregulated in MES-SA/Dx5 and MCF7/ADR2 cells, suggesting an important role for the Wnt5A signaling pathway in cancer drug resistance. Higher cAMP response elements and Tcf/Lef transcription activities were shown in the drug-resistant cancer cells. However, expression of Wnt target genes and CRE activities was downregulated in Wnt5A shRNA stably-transfected MES-SA/Dx5 cells. Cell viability of the drug-resistant cancer cells was also reduced by doxorubicin treatment and Wnt5A shRNA transfection, or by Wnt5A depletion. The in vitro data were supported by immunohistochemical analysis of 24 paired breast cancer biopsies obtained pre- and post-chemotherapeutic treatment. Wnt5A, VEGF and/or ABCB1 were significantly overexpressed after treatment, consistent with clinical chemoresistance. Taken together, the Wnt5A signaling pathway was shown to contribute to regulating the drug-resistance protein ABCB1 and β-catenin-related genes in antagonizing the toxic effects of doxorubicin in the MDR cell lines and in clinical breast cancer samples.
    Matched MeSH terms: Xenograft Model Antitumor Assays
  14. Heterotrimeric G-protein alpha-12 (Gα12) subunit promotes oral cancer metastasis
    Gan CP, Patel V, Mikelis CM, Zain RB, Molinolo AA, Abraham MT, et al.
    Oncotarget, 2014 Oct 30;5(20):9626-40.
    PMID: 25275299
    Oral squamous cell carcinoma (OSCC) has a propensity to spread to the cervical lymph nodes (LN). The presence of cervical LN metastases severely impacts patient survival, whereby the two-year survival for oral cancer patients with involved LN is ~30% compared to over 80% in patients with non-involved LN. Elucidation of key molecular mechanisms underlying OSCC metastasis may afford an opportunity to target specific genes, to prevent the spread of OSCC and to improve patient survival. In this study, we demonstrated that expression of the heterotrimeric G-protein alpha-12 (Gα12) is highly up-regulated in primary tumors and LN of OSCC patients, as assessed by quantitative polymerase chain reaction (qPCR) and immunohistochemistry (IHC). We also found that exogenous expression of the constitutively activated-form of Gα12 promoted cell migration and invasion in OSCC cell lines. Correspondingly, inhibition of Gα12 expression by shRNA consistently inhibited OSCC cell migration and invasion in vitro. Further, the inhibition of G12 signaling by regulator of G-protein signaling (RGS) inhibited Gα12-mediated RhoA activation, which in turn resulted in reduced LN metastases in a tongue-orthotopic xenograft mouse model of oral cancer. This study provides a rationale for future development and evaluation of drug candidates targeting Gα12-related pathways for metastasis prevention.
    Matched MeSH terms: Xenograft Model Antitumor Assays
  15. Fulltext Multimeric disintegrin protein polymer fusions that target tumor vasculature
    Janib SM, Gustafson JA, Minea RO, Swenson SD, Liu S, Pastuszka MK, et al.
    Biomacromolecules, 2014 Jul 14;15(7):2347-58.
    PMID: 24871936 DOI: 10.1021/bm401622y
    Recombinant protein therapeutics have increased in number and frequency since the introduction of human insulin, 25 years ago. Presently, proteins and peptides are commonly used in the clinic. However, the incorporation of peptides into clinically approved nanomedicines has been limited. Reasons for this include the challenges of decorating pharmaceutical-grade nanoparticles with proteins by a process that is robust, scalable, and cost-effective. As an alternative to covalent bioconjugation between a protein and nanoparticle, we report that biologically active proteins may themselves mediate the formation of small multimers through steric stabilization by large protein polymers. Unlike multistep purification and bioconjugation, this approach is completed during biosynthesis. As proof-of-principle, the disintegrin protein called vicrostatin (VCN) was fused to an elastin-like polypeptide (A192). A significant fraction of fusion proteins self-assembled into multimers with a hydrodynamic radius of 15.9 nm. The A192-VCN fusion proteins compete specifically for cell-surface integrins on human umbilical vein endothelial cells (HUVECs) and two breast cancer cell lines, MDA-MB-231 and MDA-MB-435. Confocal microscopy revealed that, unlike linear RGD-containing protein polymers, the disintegrin fusion protein undergoes rapid cellular internalization. To explore their potential clinical applications, fusion proteins were characterized using small animal positron emission tomography (microPET). Passive tumor accumulation was observed for control protein polymers; however, the tumor accumulation of A192-VCN was saturable, which is consistent with integrin-mediated binding. The fusion of a protein polymer and disintegrin results in a higher intratumoral contrast compared to free VCN or A192 alone. Given the diversity of disintegrin proteins with specificity for various cell-surface integrins, disintegrin fusions are a new source of biomaterials with potential diagnostic and therapeutic applications.
    Matched MeSH terms: Xenograft Model Antitumor Assays
  16. Fulltext 1'-Acetoxychavicol acetate inhibits growth of human oral carcinoma xenograft in mice and potentiates cisplatin effect via proinflammatory microenvironment alterations
    In LL, Arshad NM, Ibrahim H, Azmi MN, Awang K, Nagoor NH
    BMC Complement Altern Med, 2012;12:179.
    PMID: 23043547 DOI: 10.1186/1472-6882-12-179
    Oral cancers although preventable, possess a low five-year survival rate which has remained unchanged over the past three decades. In an attempt to find a more safe, affordable and effective treatment option, we describe here the use of 1'S-1'-acetoxychavicol acetate (ACA), a component of Malaysian ginger traditionally used for various medicinal purposes.
    Matched MeSH terms: Xenograft Model Antitumor Assays
  17. Cat's whiskers tea (Orthosiphon stamineus) extract inhibits growth of colon tumor in nude mice and angiogenesis in endothelial cells via suppressing VEGFR phosphorylation
    Ahamed MB, Aisha AF, Nassar ZD, Siddiqui JM, Ismail Z, Omari SM, et al.
    Nutr Cancer, 2012;64(1):89-99.
    PMID: 22136553 DOI: 10.1080/01635581.2012.630160
    Cat's whiskers (Orthosiphon stamineus) is commonly used as Java tea to treat kidney stones including a variety of angiogenesis-dependent diseases such as tumorous edema, rheumatism, diabetic blindness, and obesity. In the present study, antitumor potential of standardized 50% ethanol extract of O. stamineus leaves (EOS) was evaluated against colorectal tumor in athymic mice and antiangiogenic efficacy of EOS was investigated in human umbilical vein endothelial cells (HUVEC). EOS at 100 mg/kg caused 47.62 ± 6.4% suppression in tumor growth, while at 200 mg/kg it caused 83.39 ± 4.1% tumor regression. Tumor histology revealed significant reduction in extent of vascularization. Enzyme-linked immunosorbent assay showed EOS (200 mg/kg) significantly reduced the vascular endothelial growth factor (VEGF) level in vitro (211 ± 0.26 pg/ml cell lysate) as well as in vivo (90.9 ± 2 pg/g tissue homogenate) when compared to the control (378 ± 5 and 135.5 ± 4 pg, respectively). However, EOS was found to be noncytotoxic to colon cancer and endothelial cells. In vitro, EOS significantly inhibited the migration and tube formation of human umbilical vein endothelial cells (HUVECs). EOS suppressed VEGF-induced phosphorylation of VEGF receptor-2 in HUVECs. High performance liquid chromatography (HPLC) analysis of EOS showed high rosmarinic acid contents, whereas phytochemical analysis revealed high protein and phenolic contents. These results demonstrated that the antitumor activity of EOS may be due to its VEGF-targeted antiangiogenicity.
    Matched MeSH terms: Xenograft Model Antitumor Assays
  18. Fulltext Clinacanthus nutans (Burm. f.) Lindau Ethanol Extract Inhibits Hepatoma in Mice through Upregulation of the Immune Response
    Huang D, Guo W, Gao J, Chen J, Olatunji JO
    Molecules, 2015;20(9):17405-28.
    PMID: 26393569 DOI: 10.3390/molecules200917405
    Clinacanthans nutans (Burm. f.) Lindau is a popular medicinal vegetable in Southern Asia, and its extracts have displayed significant anti-proliferative effects on cancer cells in vitro. However, the underlying mechanism for this effect has yet to be established. This study investigated the antitumor and immunomodulatory activity of C. nutans (Burm. f.) Lindau 30% ethanol extract (CN30) in vivo. CN30 was prepared and its main components were identified using high-performance liquid chromatography (HPLC) and mass spectrometry (LC/MS/MS). CN30 had a significant inhibitory effect on tumor volume and weight. Hematoxylin and eosin (H & E) staining and TUNEL assay revealed that hepatoma cells underwent significant apoptosis with CN30 treatment, while expression levels of proliferation markers PCNA and p-AKT were significantly decreased when treated with low or high doses of CN30 treatment. Western blot analysis of PAPR, caspase-3, BAX, and Bcl2 also showed that CN30 induced apoptosis in hepatoma cells. Furthermore, intracellular staining analysis showed that CN30 treatment increased the number of IFN-γ⁺ T cells and decreased the number of IL-4⁺ T cells. Serum IFN-γ and interleukin-2 levels also significantly improved. Our findings indicated that CN30 demonstrated antitumor properties by up-regulating the immune response, and warrants further evaluation as a potential therapeutic agent for the treatment and prevention of cancers.
    Matched MeSH terms: Xenograft Model Antitumor Assays
  19. Fulltext Genetically-defined novel oral squamous cell carcinoma cell lines for the development of molecular therapies
    Fadlullah MZ, Chiang IK, Dionne KR, Yee PS, Gan CP, Sam KK, et al.
    Oncotarget, 2016 May 10;7(19):27802-18.
    PMID: 27050151 DOI: 10.18632/oncotarget.8533
    Emerging biological and translational insights from large sequencing efforts underscore the need for genetically-relevant cell lines to study the relationships between genomic alterations of tumors, and therapeutic dependencies. Here, we report a detailed characterization of a novel panel of clinically annotated oral squamous cell carcinoma (OSCC) cell lines, derived from patients with diverse ethnicity and risk habits. Molecular analysis by RNAseq and copy number alterations (CNA) identified that the cell lines harbour CNA that have been previously reported in OSCC, for example focal amplications in 3q, 7p, 8q, 11q, 20q and deletions in 3p, 5q, 8p, 18q. Similarly, our analysis identified the same cohort of frequently mutated genes previously reported in OSCC including TP53, CDKN2A, EPHA2, FAT1, NOTCH1, CASP8 and PIK3CA. Notably, we identified mutations (MLL4, USP9X, ARID2) in cell lines derived from betel quid users that may be associated with this specific risk factor. Gene expression profiles of the ORL lines also aligned with those reported for OSCC. By focusing on those gene expression signatures that are predictive of chemotherapeutic response, we observed that the ORL lines broadly clustered into three groups (cell cycle, xenobiotic metabolism, others). The ORL lines noted to be enriched in cell cycle genes responded preferentially to the CDK1 inhibitor RO3306, by MTT cell viability assay. Overall, our in-depth characterization of clinically annotated ORL lines provides new insight into the molecular alterations synonymous with OSCC, which can facilitate in the identification of biomarkers that can be used to guide diagnosis, prognosis, and treatment of OSCC.
    Matched MeSH terms: Xenograft Model Antitumor Assays
  20. Synergistic Growth Inhibition by Afatinib and Trametinib in Preclinical Oral Squamous Cell Carcinoma Models
    Yee PS, Zainal NS, Gan CP, Lee BKB, Mun KS, Abraham MT, et al.
    Target Oncol, 2019 04;14(2):223-235.
    PMID: 30806895 DOI: 10.1007/s11523-019-00626-8
    BACKGROUND: Given that aberrant activation of epidermal growth factor receptor family receptors (ErbB) is a common event in oral squamous cell carcinoma, and that high expression of these receptor proteins is often associated with poor prognosis, this rationalizes the approach of targeting ErbB signaling pathways to improve the survival of patients with oral squamous cell carcinoma. However, monotherapy with the ErbB blocker afatinib has shown limited survival benefits.

    OBJECTIVES: This study was performed to identify mechanisms of afatinib resistance and to explore potential afatinib-based combination treatments with other targeted inhibitors in oral squamous cell carcinoma.

    METHODS: We determined the anti-proliferative effects of afatinib on a panel of oral squamous cell carcinoma cell lines using a crystal violet-growth inhibition assay, click-iT 5-ethynyl-2'-deoxyuridine staining, and cell-cycle analysis. Biochemical assays were performed to study the underlying mechanism of drug treatment as a single agent or in combination with the MEK inhibitor trametinib. We further evaluated and compared the anti-tumor effects of single agent and combined treatment by using oral squamous cell carcinoma xenograft models.

    RESULTS: In this study, we showed that afatinib inhibited oral squamous cell carcinoma cell proliferation via cell-cycle arrest at the G0/G1 phase, and inhibited tumor growth in xenograft mouse models. Interestingly, we demonstrated reactivation of the mitogen-activated protein kinase (ERK1/2) pathway in vitro, which possibly reduced the effects of ErbB inhibition. Concomitant treatment of oral squamous cell carcinoma cells with afatinib and trametinib synergized the anti-tumor effects in oral squamous cell carcinoma-bearing mouse models.

    CONCLUSIONS: Our findings provide insight into the molecular mechanism of resistance to afatinib and support further clinical evaluation into the combination of afatinib and MEK inhibition in the treatment of oral squamous cell carcinoma.

    Matched MeSH terms: Xenograft Model Antitumor Assays
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