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Fulltext Ultrastructure Microscopic Characterization of Apoptosis in Myelomoncytic Leukemia Cell Line Treated with Velogenic Viscerotropic Newcastle Disease Virus Strain AF 2240

Ali-Saeed R, Alabsi AM, Al-Garadi MA, Abdelwahab SI, Samrot AV, Subramaniyan V, et al.

Asian Pac J Cancer Prev, 2024 Sep 01;25(9):2991-2998.
PMID: 39342575 DOI: 10.31557/APJCP.2024.25.9.2991

OBJECTIVE: Leukemia is a group of hematologic malignancies in the bonemarrow that arise from the dysfunctional proliferation of developing leukocytes. It is classified as either acute or chronic based on the rapidity of proliferation and as myelocytic or lymphocytic based on the cell of origin. Newcastle Disease Virus (NDV) is an avian paramyxovirus, which has been demonstrated to possess significant oncolytic activity against mammalian cancers because its ability to kill tumor cells with limited toxicity to normal cells.
METHODS: In this study, the morphophical changes and apoptosis induction of WEHI 3B leukemia cell line treated with NDV strain AF2240 were studied by scanning electron microscopes and transmission electron microscopes techniques.
RESULT: Electron microscopy indicated that NDV strain AF 2240 significantly altered cell morphology and reduced cell viability. Furthermore, early apoptosis was observed 6 h post-inoculation by fluorescence microscope.
CONCLUSION: Our results suggest that NDV has ability to induce significant apoptoic structural changes in WEHI 3B leukemia cell line. These findings provide new insights into the mechanism of action of NDV virotherapy and could lead to the development of more effective treatments for leukemia.

Matched MeSH terms: Oncolytic Virotherapy/methods
Newcastle diseases virus strain V4UPM displayed oncolytic ability against experimental human malignant glioma

Zulkifli MM, Ibrahim R, Ali AM, Aini I, Jaafar H, Hilda SS, et al.

Neurol Res, 2009 Feb;31(1):3-10.
PMID: 18937888 DOI: 10.1179/174313208X325218

Newcastle disease virus (NDV) is a virus of paramyxovirus family and lately has been studied for the treatment of cancer in human. In this study, we successfully determined the oncolysis potential of NDV vaccine, V4UPM tested on the human glioblastoma multiform cell line (DBTRG.05MG) and human glioblastoma astrocytoma cell line (U-87MG) in vitro and in vivo. The V4UPM strain is a modified V4 strain developed as thermostable feed pellet vaccine for poultry.

Matched MeSH terms: Oncolytic Virotherapy/methods*
Evaluation of Ultra-Microscopic Changes and Proliferation of Apoptotic Glioblastoma Multiforme Cells Induced by Velogenic Strain of Newcastle Disease Virus AF2240

Ali- Saeed R, Alabsi AM, Ideris A, Omar AR, Yusoff K, Ali AM

Asian Pac J Cancer Prev, 2019 Mar 26;20(3):757-765.
PMID: 30909682

Aim: Newcastle disease virus (NDV) is a member of genus Avulavirus within the family Paramyxoviridae. Interest
of using NDV as an anticancer agent has arisen from its ability to kill tumor cells with limited toxicity to normal cells.
Methods: In this investigation, the proliferation of brain tumor cell line, glioblastoma multiform (DBTRG.05MG)
induced by NDV strain AF2240 was evaluated in-vitro, by using MTT proliferation assay. Furthermore, Cytological
observations were studied using fluorescence microscopy and transmission electron microscopy, DNA laddering in
agarose gel electrophoresis assay used to detect the mode of cell death and analysis of the cellular DNA content by
flowcytometery. Results: MTT proliferation assay, Cytological observations using fluorescence microscopy and
transmission electron microscopy show the anti-proliferation effect and apoptogenic features of NDV on DBTRG.05MG.
Furthermore, analysis of the cellular DNA content showed that there was a loss of treated cells in all cell cycle phases
(G1, S and G2/M) accompanied with increasing in sub-G1 region (apoptosis peak). Conclusion: It could be concluded
that NDV strain AF2240 is a potent antitumor agent that induce apoptosis and its cytotoxicity increasing while increasing
of time and virus titer.

Matched MeSH terms: Oncolytic Virotherapy/methods*
Turning cold tumours hot: oncolytic virotherapy gets up close and personal with other therapeutics at the 11th Oncolytic Virus Conference

Dyer A, Baugh R, Chia SL, Frost S, Iris, Jacobus EJ, et al.

Cancer Gene Ther, 2019 03;26(3-4):59-73.
PMID: 30177818 DOI: 10.1038/s41417-018-0042-1

The 11th International Oncolytic Virus Conference (IOVC) was held from April 9-12, 2018 in Oxford, UK. This is part of the high-profile academic-led series of meetings that was started back in 2002 by Steve Russell and John Bell, with most of the previous meetings being held in North America (often in Banff). The conference brought together many of the major players in oncolytic virotherapy from all over the world, addressing all stages of research and development-from aspects of basic science and cellular immunology all the way through to early- and late-phase clinical trials. The meeting welcomed 352 delegates from 24 countries. The top seven delegate countries, namely, the UK, US, Canada, The Netherlands, Germany, Japan and South Korea, contributed 291 delegates while smaller numbers coming from Australia, Austria, Bulgaria, China, Finland, France, Iraq, Ireland, Israel, Italy, Latvia, Malaysia, Poland, Slovenia, Spain, Sweden and Switzerland. Academics comprised about half of the attendees, industry 30% and students 20%. The next IOVC is scheduled to be held on Vancouver Island in autumn 2019. Here we share brief summaries of the oral presentations from invited speakers and proffered papers in the different subtopics presented at IOVC 2018.

Matched MeSH terms: Oncolytic Virotherapy/methods*
Fulltext Safety and clinical usage of newcastle disease virus in cancer therapy

Lam HY, Yeap SK, Pirozyan MR, Omar AR, Yusoff K, Suraini AA, et al.

J Biomed Biotechnol, 2011;2011:718710.
PMID: 22131816 DOI: 10.1155/2011/718710

Newcastle disease virus (NDV) is an avian virus that causes deadly infection to over 250 species of birds, including domestic and wild-type, thus resulting in substantial losses to the poultry industry worldwide. Many reports have demonstrated the oncolytic effect of NDV towards human tumor cells. The interesting aspect of NDV is its ability to selectively replicate in cancer cells. Some of the studies have undergone human clinical trials, and favorable results were obtained. Therefore, NDV strains can be the potential therapeutic agent in cancer therapy. However, investigation on the therapeutic perspectives of NDV, especially human immunological effects, is still ongoing. This paper provides an overview of the current studies on the cytotoxic and anticancer effect of NDV via direct oncolysis effects or immune stimulation. Safety of NDV strains applied for cancer immunotherapy is also discussed in this paper.

Matched MeSH terms: Oncolytic Virotherapy/methods*
Effects of HSV-G47Δ Oncolytic Virus on Telomerase and Telomere Length Alterations in Glioblastoma Multiforme Cancer Stem Cells Under Hypoxia and Normoxia Conditions

Vazifehmand R, Ali DS, Homaie FM, Jalalvand FM, Othman Z, Deming C, et al.

Curr Cancer Drug Targets, 2024;24(12):1262-1274.
PMID: 38357955 DOI: 10.2174/0115680096274769240115165344

BACKGROUND: Due to the existence of tumor stem cells with tumorigenicity properties and resistance patterns, treatment of glioblastoma is not easy. Hypoxia is a major concern in glioblastoma therapy. Telomerase activity and telomere length alterations have been known to play a critical role in glioblastoma progression and invasion.
OBJECTIVE: This study aimed to investigate the effects of HSV-G47Δ oncolytic virus on telomerase and telomere length alterations in U251GBMCSCs (U251-Glioblastoma cancer stem cells) under hypoxia and normoxia conditions.
METHODS: U251-CSCs were exposed to the HSV-G47Δ virus in optimized MOI (Multiplicity of infection= 1/14 hours). An absolute telomere length and gene expression of telomerase subunits were determined using an absolute human telomere length quantification PCR assay. Furthermore, a bioinformatics pathway analysis was carried out to evaluate physical and genetic interactions between dysregulated genes with other potential genes and pathways.
RESULTS: Data revealed that U251CSCs had longer telomeres when exposed to HSV-G47Δ in normoxic conditions but had significantly shorter telomeres in hypoxic conditions. Furthermore, hTERC, DKC1, and TEP1 genes were significantly dysregulated in hypoxic and normoxic microenvironments. The analysis revealed that the expression of TERF2 was significantly reduced in both microenvironments, and two critical genes from the MRN complex, MER11 and RAD50, were significantly upregulated in normoxic conditions. RAD50 showed a significant downregulation pattern in the hypoxic niche. Our results suggested that repair complex in the telomeric structure could be targeted by HSV-G47Δ in both microenvironments.
CONCLUSION: In the glioblastoma treatment strategy, telomerase and telomere complex could be potential targets for HSV-G47Δ in both microenvironments.

Matched MeSH terms: Oncolytic Virotherapy/methods
Fulltext Evaluation of a Recombinant Newcastle Disease Virus Expressing Human IL12 against Human Breast Cancer

Mohamed Amin Z, Che Ani MA, Tan SW, Yeap SK, Alitheen NB, Syed Najmuddin SUF, et al.

Sci Rep, 2019 Sep 30;9(1):13999.
PMID: 31570732 DOI: 10.1038/s41598-019-50222-z

The Newcastle disease virus (NDV) strain AF2240 is an avian avulavirus that has been demonstrated to possess oncolytic activity against cancer cells. However, to illicit a greater anti-cancer immune response, it is believed that the incorporation of immunostimulatory genes such as IL12 into a recombinant NDV backbone will enhance its oncolytic effect. In this study, a newly developed recombinant NDV that expresses IL12 (rAF-IL12) was tested for its safety, stability and cytotoxicity. The stability of rAF-IL12 was maintained when passaged in specific pathogen free (SPF) chicken eggs from passage 1 to passage 10; with an HA titer of 29. Based on the results obtained from the MTT cytotoxic assay, rAF-IL12 was determined to be safe as it only induced cytotoxic effects against normal chicken cell lines and human breast cancer cells while sparing normal cells. Significant tumor growth inhibition (52%) was observed in the rAF-IL12-treated mice. The in vivo safety profile of rAF-IL12 was confirmed through histological observation and viral load titer assay. The concentration and presence of the expressed IL12 was quantified and verified via ELISA assay. In summary, rAF-IL12 was proven to be safe, selectively replicating in chicken and cancer cells and was able to maintain its stability throughout several passages; thus enhancing its potential as an anti-breast cancer vaccine.

Matched MeSH terms: Oncolytic Virotherapy/methods*
Cytolytic effects and apoptosis induction of Newcastle disease virus strain AF2240 on anaplastic astrocytoma brain tumor cell line

Ali R, Alabsi AM, Ali AM, Ideris A, Omar AR, Yusoff K, et al.

Neurochem Res, 2011 Nov;36(11):2051-62.
PMID: 21671106 DOI: 10.1007/s11064-011-0529-8

Newcastle disease virus (NDV) is a member of genus Avulavirus within the family Paramyxoviridae. Interest of using NDV as an anticancer agent has arisen from its ability to kill tumor cells with limited toxicity to normal cells. In this investigation, the cytotolytic properties of NDV strain AF2240 were evaluated on brain tumor cell line, anaplastic astrocytoma (U-87MG), by using MTT assay. Cytological observations were studied using fluorescence microscopy and transmission electron microscopy to show the apoptogenic features of NDV on U-87MG. DNA laddering in agarose gel electrophoresis and terminal deoxyribonucleotide transferase-mediated dUTP-X nick end-labeling staining assay confirmed that the mode of cell death was by apoptosis. However, analysis of the cellular DNA content by flowcytometery showed that there was a loss of treated U-87MG cells in all cell cycle phases (G1, S and G2/M) accompanied with increasing in sub-G1 region (apoptosis peak). Early apoptosis was observed 6 h post-inoculation by annexin-V flow-cytometry method. It could be concluded that NDV strain AF2240 is a potent antitumor agent that induce apoptosis and its cytotoxicity increasing while increasing of time and virus titer.

Matched MeSH terms: Oncolytic Virotherapy/methods*
Fulltext Immunomodulatory effects of Newcastle disease virus AF2240 strain on human peripheral blood mononuclear cells

Lam HY, Yusoff K, Yeap SK, Subramani T, Abd-Aziz S, Omar AR, et al.

Int J Med Sci, 2014;11(12):1240-7.
PMID: 25317070 DOI: 10.7150/ijms.8170

Immunotherapy has raised the attention of many scientists because it hold promise to be an attractive therapeutic strategy to treat a number of disorders. In this study, the immunomodulatory effects of low titers of Newcastle disease virus (NDV) AF2240 on human peripheral blood mononuclear cells (PBMC) were analyzed. We evaluated cytokine secretion and PBMC activation by cell proliferation assay, immunophenotyping and enzyme linked immunosorbent assay. The proliferation of the human PBMC was measured to be 28.5% and 36.5% upon treatment with 8 hemaglutinin unit (HAU) and 2 HAU of NDV respectively. Interestingly, the percentage of cells with activating markers CD16 and CD56 were increased significantly. Furthermore, the intracellular perforin and granzyme levels were also increased upon virus infection. Human PBMC treated with NDV titer 8 HAU was found to stimulate the highest level of cytokine production including interferon-γ, interleukin-2 and interleukin-12. The release of these proteins contributes to the antitumor effect of PBMC against MCF-7 breast cancer cells. Based on the 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide assay, activated human PBMC showed high cytolytic efficiency towards human breast tumor cells. In summary, NDV was able to stimulate PBMC proliferation, cytokine secretion and cytolytic activity.

Matched MeSH terms: Oncolytic Virotherapy/methods*
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.

Matched MeSH terms: Oncolytic Virotherapy/methods*
Fulltext Regression of solid breast tumours in mice by Newcastle disease virus is associated with production of apoptosis related-cytokines

Raihan J, Ahmad U, Yong YK, Eshak Z, Othman F, Ideris A

BMC Cancer, 2019 Apr 04;19(1):315.
PMID: 30947706 DOI: 10.1186/s12885-019-5516-5

BACKGROUND: Different strains of Newcastle disease virus (NDV) worldwide proved to have tumouricidal activity in several types of cancer cells. However, the possible anti-cancer activity of Malaysian NDV AF2240 strain and its mechanism of action remains unknown. The ability of cytokine-related apoptosis-inducing NDV AF2240 to treat breast cancer was investigated in the current study.
METHODS: A total of 90 mice were used and divided into 15 groups, each group comprising of 6 mice. Tumour, body weight and mortality of the mice were determined throughout the experiment, to observe the effect of NDV and NDV + tamoxifen treatments on the mice. In addition, the toxic effect of the treatments was determined through liver function test. In order to elucidate the involvement of cytokine production induced by NDV, a total of six cytokines, i.e. IL-6, IFN-γ, MCP-1, IL-10, IL12p70 and TNF-α were measured using cytometric bead array assay (plasma) and enzyme-linked immunosorbent spot (isolated splenocytes).
RESULTS: The results demonstrated that 4 T1 breast cancer cells in allotransplanted mice treated with AF2240 showed a noticeable inhibition of tumour growth and induce apoptotic-related cytokines.
CONCLUSIONS: NDV AF2240 suppression of breast tumour growth is associated with induction of apoptotic-related cytokines. It would be important to further investigate the molecular mechanism underlaying cytokines production by Newcastle disease virus.

Matched MeSH terms: Oncolytic Virotherapy/methods*
Fulltext The oncolytic activity of Newcastle disease virus in clear cell renal carcinoma cells in normoxic and hypoxic conditions: the interplay between von Hippel-Lindau and interferon-β signaling

Ch'ng WC, Stanbridge EJ, Yusoff K, Shafee N

J Interferon Cytokine Res, 2013 Jul;33(7):346-54.
PMID: 23506478 DOI: 10.1089/jir.2012.0095

Viral-mediated oncolysis is a promising cancer therapeutic approach offering an increased efficacy with less toxicity than the current therapies. The complexity of solid tumor microenvironments includes regions of hypoxia. In these regions, the transcription factor, hypoxia inducible factor (HIF), is active and regulates expression of many genes that contribute to aggressive malignancy, radio-, and chemo-resistance. To investigate the oncolytic efficacy of a highly virulent (velogenic) Newcastle disease virus (NDV) in the presence or absence of HIF-2α, renal cell carcinoma (RCC) cell lines with defective or reconstituted wild-type (wt) von Hippel-Lindau (VHL) activity were used. We show that these RCC cells responded to NDV by producing only interferon (IFN)-β, but not IFN-α, and are associated with increased STAT1 phosphorylation. Restoration of wt VHL expression enhanced NDV-induced IFN-β production, leading to prolonged STAT1 phosphorylation and increased cell death. Hypoxia augmented NDV oncolytic activity regardless of the cells' HIF-2α levels. These results highlight the potential of oncolytic NDV as a potent therapeutic agent in the killing of hypoxic cancer cells.

Matched MeSH terms: Oncolytic Virotherapy/methods*

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