The Important Role of Oncolytic Viruses in Common Cancer Treatments

Oncolytic viruses (OV) are considered as promising tools in cancer treatment. In addition to direct cytolysis, the stimulation of both innate and adaptive immune responses is the most important mechanism in oncolytic virotherapy that finally leads to the long-standing tumor retardations in the advanced melanoma clinical trials. The OVs have become a worthy method in cancer treatment, due to their several biological advantages including (1) the selective replication in cancer cells without affecting normal cells; (2) the lack of resistance to the treatment; (3) cancer stem cell targeting; (4) the ability to be spread; and (5) the immune response induction against the tumors. Numerous types of viruses; for example, Herpes simplex viruses, Adenoviruses, Reoviruses, Poliovirus, and Newcastle disease virus have been studied as a possible cancer treatment strategy. Although some viruses have a natural orientation or tropism to cancer cells, several others need attenuation and genetic manipulation to increase the safety and tumor-specific replication activity. Two important mechanisms are involved in OV antitumor responses, which include the tumor cell death due to virus replication, and also induction of immunogenic cell death as a result of the immune system responses against the tumor cells. Furthermore, the high efficiency of OV on antitumor immune response stimulation can finally lead to a significant tumor shrinkage.

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Oncolytic Viruses and Cancer, Do You Know the Main Mechanism?

Frontiers in Oncology ◽

10.3389/fonc.2021.761015 ◽

2021 ◽

Vol 11 ◽

Author(s):

Wesam Kooti ◽

Hadi Esmaeili Gouvarchin Ghaleh ◽

Mahdieh Farzanehpour ◽

Ruhollah Dorostkar ◽

Bahman Jalali Kondori ◽

...

Keyword(s):

Cell Death ◽

Cancer Treatment ◽

Cancer Cells ◽

Antitumor Immunity ◽

Malignant Tumors ◽

Mechanisms Of Action ◽

Oncolytic Viruses ◽

Global Rate ◽

Recent Developments ◽

Review Study

The global rate of cancer has increased in recent years, and cancer is still a threat to human health. Recent developments in cancer treatment have yielded the understanding that viruses have a high potential in cancer treatment. Using oncolytic viruses (OVs) is a promising approach in the treatment of malignant tumors. OVs can achieve their targeted treatment effects through selective cell death and induction of specific antitumor immunity. Targeting tumors and the mechanism for killing cancer cells are among the critical roles of OVs. Therefore, evaluating OVs and understanding their precise mechanisms of action can be beneficial in cancer therapy. This review study aimed to evaluate OVs and the mechanisms of their effects on cancer cells.

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A Novel Herpes Vector for the High-Efficiency Transduction of Normal and Malignant Human Hematopoietic Cells

Blood ◽

10.1182/blood.v89.1.119.119_119_127 ◽

1997 ◽

Vol 89 (1) ◽

pp. 119-127 ◽

Cited By ~ 2

Author(s):

Dagmar Dilloo ◽

Donna Rill ◽

Claire Entwistle ◽

Michael Boursnell ◽

Wanyun Zhong ◽

...

Keyword(s):

High Efficiency ◽

Genetic Manipulation ◽

Clinical Investigation ◽

Hematopoietic Cells ◽

Single Cycle ◽

Herpes Simplex Viruses ◽

Stromal Support ◽

Normal Human ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony

Herpes simplex viruses (HSVs) would offer numerous advantages as vectors for gene transfer, but as yet they have not proved capable of transducing hematopoietic cells. Using a genetically inactivated form of HSV that is restricted to a single cycle of replication (disabled single-cycle virus, [DISC-HSV]), we have transduced normal human hematopoietic progenitor cells and primary leukemia blasts with efficiencies ranging from 80% to 100%, in the absence of growth factors or stromal support. Toxicity was low, with 70% to 100% of cells surviving the transduction process. Peak expression of transferred genes occurred at 24 to 48 hours after transduction with the DISC-HSV vector, declining to near background levels by 14 days. Despite this limitation, sufficient protein is produced by the inserted gene to permit consideration of the vector for applications in which transient expression is adequate. One example is the transfer of immunostimulatory genes, to generate leukemia immunogens. Thus, murine A20 leukemia cells transduced with a DISC-HSV vector encoding granulocyte-macrophage colony-stimulating factor were able to stimulate a potent antitumor response in mice, even against pre-existing leukemia. The exceptional transducing ability of the DISC-HSV vector should therefore facilitate genetic manipulation of normal and malignant human hematopoietic cells for biological and clinical investigation.

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The Immuno-Modulatory Effects of Inhibitor of Apoptosis Protein Antagonists in Cancer Immunotherapy

Cells ◽

10.3390/cells9010207 ◽

2020 ◽

Vol 9 (1) ◽

pp. 207 ◽

Cited By ~ 3

Author(s):

Jessica Michie ◽

Conor J. Kearney ◽

Edwin D. Hawkins ◽

John Silke ◽

Jane Oliaro

Keyword(s):

Cell Death ◽

Cancer Cells ◽

Tumour Progression ◽

Mitochondrial Protein ◽

Immune Checkpoint Blockade ◽

Oncolytic Viruses ◽

Inhibitor Of Apoptosis ◽

T Cell Therapy ◽

Apoptosis Protein ◽

Smac Mimetics

One of the hallmarks of cancer cells is their ability to evade cell death via apoptosis. The inhibitor of apoptosis proteins (IAPs) are a family of proteins that act to promote cell survival. For this reason, upregulation of IAPs is associated with a number of cancer types as a mechanism of resistance to cell death and chemotherapy. As such, IAPs are considered a promising therapeutic target for cancer treatment, based on the role of IAPs in resistance to apoptosis, tumour progression and poor patient prognosis. The mitochondrial protein smac (second mitochondrial activator of caspases), is an endogenous inhibitor of IAPs, and several small molecule mimetics of smac (smac-mimetics) have been developed in order to antagonise IAPs in cancer cells and restore sensitivity to apoptotic stimuli. However, recent studies have revealed that smac-mimetics have broader effects than was first attributed. It is now understood that they are key regulators of innate immune signalling and have wide reaching immuno-modulatory properties. As such, they are ideal candidates for immunotherapy combinations. Pre-clinically, successful combination therapies incorporating smac-mimetics and oncolytic viruses, as with chimeric antigen receptor (CAR) T cell therapy, have been reported, and clinical trials incorporating smac-mimetics and immune checkpoint blockade are ongoing. Here, the potential of IAP antagonism to enhance immunotherapy strategies for the treatment of cancer will be discussed.

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Parvovirus H-1-Induced Tumor Cell Death Enhances Human Immune Response In Vitro via Increased Phagocytosis, Maturation, and Cross-Presentation by Dendritic Cells

Human Gene Therapy ◽

10.1089/hum.2005.16.ft-92 ◽

2005 ◽

Vol 0 (0) ◽

pp. 050701034702004

Author(s):

Markus H. Moehler ◽

Maja Zeidler ◽

Vanessa Wilsberg ◽

Jan J. Cornelis ◽

Thomas Woelfel ◽

...

Keyword(s):

Immune Response ◽

Cell Death ◽

Dendritic Cells ◽

Tumor Cell ◽

Tumor Cell Death ◽

Cross Presentation ◽

Human Immune Response ◽

Human Immune ◽

Immune Response In Vitro

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Dominant-negative ATF5 rapidly depletes survivin in tumor cells

Cell Death and Disease ◽

10.1038/s41419-019-1872-y ◽

2019 ◽

Vol 10 (10) ◽

Author(s):

Xiaotian Sun ◽

James M. Angelastro ◽

David Merino ◽

Qing Zhou ◽

Markus D. Siegelin ◽

...

Keyword(s):

Cell Death ◽

Tumor Cell ◽

Cancer Cells ◽

Dominant Negative ◽

Tumor Cell Death ◽

Cell Penetrating ◽

Selective Death ◽

Tumor Types

Abstract Survivin (BIRC5, product of the BIRC5 gene) is highly expressed in many tumor types and has been widely identified as a potential target for cancer therapy. However, effective anti-survivin drugs remain to be developed. Here we report that both vector-delivered and cell-penetrating dominant-negative (dn) forms of the transcription factor ATF5 that promote selective death of cancer cells in vitro and in vivo cause survivin depletion in tumor cell lines of varying origins. dn-ATF5 decreases levels of both survivin mRNA and protein. The depletion of survivin protein appears to be driven at least in part by enhanced proteasomal turnover and depletion of the deubiquitinase USP9X. Survivin loss is rapid and precedes the onset of cell death triggered by dn-ATF5. Although survivin downregulation is sufficient to drive tumor cell death, survivin over-expression does not rescue cancer cells from dn-ATF5-promoted apoptosis. This indicates that dn-ATF5 kills malignant cells by multiple mechanisms that include, but are not limited to, survivin depletion. Cell-penetrating forms of dn-ATF5 are currently being developed for potential therapeutic use and the present findings suggest that they may pose an advantage over treatments that target only survivin.

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A Novel Herpes Vector for the High-Efficiency Transduction of Normal and Malignant Human Hematopoietic Cells

Blood ◽

10.1182/blood.v89.1.119 ◽

1997 ◽

Vol 89 (1) ◽

pp. 119-127 ◽

Cited By ~ 43

Author(s):

Dagmar Dilloo ◽

Donna Rill ◽

Claire Entwistle ◽

Michael Boursnell ◽

Wanyun Zhong ◽

...

Keyword(s):

High Efficiency ◽

Genetic Manipulation ◽

Clinical Investigation ◽

Hematopoietic Cells ◽

Single Cycle ◽

Herpes Simplex Viruses ◽

Stromal Support ◽

Normal Human ◽

Macrophage Colony Stimulating Factor ◽

Macrophage Colony

Abstract Herpes simplex viruses (HSVs) would offer numerous advantages as vectors for gene transfer, but as yet they have not proved capable of transducing hematopoietic cells. Using a genetically inactivated form of HSV that is restricted to a single cycle of replication (disabled single-cycle virus, [DISC-HSV]), we have transduced normal human hematopoietic progenitor cells and primary leukemia blasts with efficiencies ranging from 80% to 100%, in the absence of growth factors or stromal support. Toxicity was low, with 70% to 100% of cells surviving the transduction process. Peak expression of transferred genes occurred at 24 to 48 hours after transduction with the DISC-HSV vector, declining to near background levels by 14 days. Despite this limitation, sufficient protein is produced by the inserted gene to permit consideration of the vector for applications in which transient expression is adequate. One example is the transfer of immunostimulatory genes, to generate leukemia immunogens. Thus, murine A20 leukemia cells transduced with a DISC-HSV vector encoding granulocyte-macrophage colony-stimulating factor were able to stimulate a potent antitumor response in mice, even against pre-existing leukemia. The exceptional transducing ability of the DISC-HSV vector should therefore facilitate genetic manipulation of normal and malignant human hematopoietic cells for biological and clinical investigation.

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Enhancement of Tumor Cell Death by Combining gef Gene Mediated Therapy and New 1,4-Benzoxazepin-2,6-Dichloropurine Derivatives in Breast Cancer Cells

Frontiers in Pharmacology ◽

10.3389/fphar.2018.00798 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 6

Author(s):

Alberto Ramírez ◽

Ana Conejo-García ◽

Carmen Griñán-Lisón ◽

Luisa C. López-Cara ◽

Gema Jiménez ◽

...

Keyword(s):

Breast Cancer ◽

Cell Death ◽

Tumor Cell ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Tumor Cell Death

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ERK: A Double-Edged Sword in Cancer. ERK-Dependent Apoptosis as a Potential Therapeutic Strategy for Cancer

Cells ◽

10.3390/cells10102509 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2509

Author(s):

Reiko Sugiura ◽

Ryosuke Satoh ◽

Teruaki Takasaki

Keyword(s):

Cell Proliferation ◽

Cell Death ◽

Tumor Cell Death ◽

Cancer Treatments ◽

Erk Activation ◽

Cellular Processes ◽

Dual Specificity ◽

Anti Cancer ◽

Dual Specificity Phosphatases

The RAF/MEK/ERK signaling pathway regulates diverse cellular processes as exemplified by cell proliferation, differentiation, motility, and survival. Activation of ERK1/2 generally promotes cell proliferation, and its deregulated activity is a hallmark of many cancers. Therefore, components and regulators of the ERK pathway are considered potential therapeutic targets for cancer, and inhibitors of this pathway, including some MEK and BRAF inhibitors, are already being used in the clinic. Notably, ERK1/2 kinases also have pro-apoptotic functions under certain conditions and enhanced ERK1/2 signaling can cause tumor cell death. Although the repertoire of the compounds which mediate ERK activation and apoptosis is expanding, and various anti-cancer compounds induce ERK activation while exerting their anti-proliferative effects, the mechanisms underlying ERK1/2-mediated cell death are still vague. Recent studies highlight the importance of dual-specificity phosphatases (DUSPs) in determining the pro- versus anti-apoptotic function of ERK in cancer. In this review, we will summarize the recent major findings in understanding the role of ERK in apoptosis, focusing on the major compounds mediating ERK-dependent apoptosis. Studies that further define the molecular targets of these compounds relevant to cell death will be essential to harnessing these compounds for developing effective cancer treatments.

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Graphene-Induced Hyperthermia (GIHT) Combined With Radiotherapy Fosters Immunogenic Cell Death

Frontiers in Oncology ◽

10.3389/fonc.2021.664615 ◽

2021 ◽

Vol 11 ◽

Author(s):

Malgorzata J. Podolska ◽

Xiaomei Shan ◽

Christina Janko ◽

Rabah Boukherroub ◽

Udo S. Gaipl ◽

...

Keyword(s):

Cell Death ◽

Tumor Cell ◽

Cancer Cells ◽

Combined Treatment ◽

Infrared Light ◽

Immunogenic Cell Death ◽

Tumor Cell Death ◽

Induced Hyperthermia ◽

B16f10 Cells ◽

Melanoma B16f10

Radiotherapy and chemotherapy are the standard interventions for cancer patients, although cancer cells often develop radio- and/or chemoresistance. Hyperthermia reduces tumor resistance and induces immune responses resulting in a better prognosis. We have previously described a method to induce tumor cell death by local hyperthermia employing pegylated reduced graphene oxide nanosheets and near infrared light (graphene-induced hyperthermia, GIHT). The spatiotemporal exposure/release of heat shock proteins (HSP), high group mobility box 1 protein (HMGB1), and adenosine triphosphate (ATP) are reported key inducers of immunogenic cell death (ICD). We hypothesize that GIHT decisively contributes to induce ICD in irradiated melanoma B16F10 cells, especially in combination with radiotherapy. Therefore, we investigated the immunogenicity of GIHT alone or in combination with radiotherapy in melanoma B16F10 cells. Tumor cell death in vitro revealed features of apoptosis that is progressing fast into secondary necrosis. Both HSP70 and HMGB1/DNA complexes were detected 18 hours post GIHT treatment, whereas the simultaneous release of ATP and HMGB1/DNA was observed only 24 hours post combined treatment. We further confirmed the adjuvant potential of these released DAMPs by immunization/challenge experiments. The inoculation of supernatants of cells exposed to sole GIHT resulted in tumor growth at the site of inoculation. The immunization with cells exposed to sole radiotherapy rather fostered the growth of secondary tumors in vivo. Contrarily, a discreet reduction of secondary tumor volumes was observed in mice immunized with a single dose of cells and supernatants treated with the combination of GIHT and irradiation. We propose the simultaneous release of several DAMPs as a potential mechanism fostering anti-tumor immunity against previously irradiated cancer cells.

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