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

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.

scholarly journals Oncolytic Viruses As Immunotherapeutic Agents for the Treatment of Malignant Tumors

2019 ◽  
Vol 74 (2) ◽  
pp. 108-117
Author(s):  
Alexander I. Glukhov ◽  
Dmitry A. Sivokhin ◽  
Daria A. Seryak ◽  
Tatyana S. Rodionova ◽  
Margarita I. Kamynina
Keyword(s):  
Cell Death ◽  
Antitumor Immunity ◽  
Randomized Clinical Trials ◽  
Tumor Antigens ◽  
Malignant Tumors ◽  
Oncolytic Viruses ◽  
Type I Interferons ◽  
Type I ◽  
Gm Csf ◽  
Cancer Cell Death

Oncolytic viruses (OVs) are novel and rapidly developing class of therapeutic agents for combating cancer, which can effectively infect and destroy tumor cells, leaving healthy tissues intact. Many viruses have a natural antitumor activity which causes cytolysis of cancer cells due to direct pathogenic action. Along with non-immunogenic cell death, oncolytic viruses have been shown to be capable of inducing immunogenic cancer cell death (necrosis, pyroptosis, etc.) accompanied by the release of OV-lysed tumor-associated antigens (TAAs). Releasing DAMPs and TAAs, in its turn, leads to the activation of adaptive antitumor immunity. In order to further enhance the antitumor immunity, OVs have been armed with immunostimulatory transgenes such as granulocyte-macrophage colony-stimulating factor (GM-CSF), type I interferons, interleukins (IL-2, 12, 15), costimulatory ligands (CD40, CD80), tumor antigens («prime-boost» vaccination), which further enhances the safety and effectiveness of oncolytic virotherapy. Preliminary results of randomized clinical trials of different approaches of oncolytic virotherapies in combination with immunotherapy confirm their high efficacy. However, there are some drawbacks, which necessitates their further study.

Epigenetic drugs for cancer treatment and prevention: mechanisms of action

2010 ◽  
Vol 1 (3-4) ◽  
pp. 239-251 ◽  
Author(s):  
Xiao-Dan Yu ◽  
Z. Sheng Guo
Keyword(s):  
Cell Death ◽  
Cancer Treatment ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Mechanisms Of Action ◽  
Mitotic Catastrophe ◽  
Epigenetic Therapy ◽  
Epigenetic Mechanisms ◽  
Epigenetic Drugs ◽  
Treatment And Prevention

AbstractThis review provides a brief overview of the basic principles of epigenetic gene regulation and then focuses on recent development of epigenetic drugs for cancer treatment and prevention with an emphasis on the molecular mechanisms of action. The approved epigenetic drugs are either inhibitors of DNA methyltransferases or histone deacetylases (HDACs). Future epigenetic drugs could include inhibitors for histone methyltransferases and histone demethylases and other epigenetic enzymes. Epigenetic drugs often function in two separate yet interrelated ways. First, as epigenetic drugs per se, they modulate the epigenomes of premalignant and malignant cells to reverse deregulated epigenetic mechanisms, leading to an effective therapeutic strategy (epigenetic therapy). Second, HDACs and other epigenetic enzymes also target non-histone proteins that have regulatory roles in cell proliferation, migration and cell death. Through these processes, these drugs induce cancer cell growth arrest, cell differentiation, inhibition of tumor angiogenesis, or cell death via apoptosis, necrosis, autophagy or mitotic catastrophe (chemotherapy). As they modulate genes which lead to enhanced chemosensitivity, immunogenicity or dampened innate antiviral response of cancer cells, epigenetic drugs often show better efficacy when combined with chemotherapy, immunotherapy or oncolytic virotherapy. In chemoprevention, dietary phytochemicals such as epigallocatechin-3-gallate and sulforaphane act as epigenetic agents and show efficacy by targeting both cancer cells and the tumor microenvironment. Further understanding of how epigenetic mechanisms function in carcinogenesis and cancer progression as well as in normal physiology will enable us to establish a new paradigm for intelligent drug design in the treatment and prevention of cancer.

The Important Role of Oncolytic Viruses in Common Cancer Treatments

2020 ◽  
Vol 16 (4) ◽  
pp. 292-305 ◽  
Author(s):  
Amir Mohamadi ◽  
Gilles Pagès ◽  
Mohammad S. Hashemzadeh
Keyword(s):  
Immune Response ◽  
Cell Death ◽  
Cancer Treatment ◽  
Cancer Cells ◽  
High Efficiency ◽  
Genetic Manipulation ◽  
Oncolytic Viruses ◽  
Tumor Cell Death ◽  
Cancer Treatments ◽  
Herpes Simplex Viruses

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.

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

Cells ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 207 ◽  
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.

scholarly journals Hyperthermia has Consistently Improved the Efficacy of Radiotherapy and Chemotherapy for Many Types of Cancers

2019 ◽  
Vol 1 (1) ◽  
pp. 01-05
Author(s):  
Kokkula Pavan Kumar ◽  
Prasad Garrepally
Keyword(s):  
Cancer Treatment ◽  
Cancer Cells ◽  
Mechanisms Of Action ◽  
Tumor Initiation ◽  
Large Role ◽  
Conventional Radiotherapy ◽  
Different Types

Cancer stem-like cells (CSCs) are a subset of cancer cells that are resistant to conventional radiotherapy and chemotherapy. As such, CSCs have been recognized as playing a large role in tumor initiation and recurrence. Although hyperthermia is broadly used in cancer treatment either alone or in combination with radio- or chemo-therapy, its potential to target CSCs is not well understood. In this review, we discuss different types of hyperthermia and potential mechanisms of action in cancer treatment, particularly in regards to killing CSCs.

scholarly journals Oncolytic Immunotherapy: Where Are We Clinically?

Scientifica ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Akseli Hemminki
Keyword(s):  
Antitumor Immunity ◽  
Clinical Work ◽  
Mechanisms Of Action ◽  
Oncolytic Viruses ◽  
Immunostimulatory Activity ◽  
Phase 3 ◽  
Safety And Efficacy ◽  
Relative Contribution ◽  
Added Benefit ◽  
Oncolytic Immunotherapy

Following a century of preclinical and clinical work, oncolytic viruses are now proving themselves in randomized phase 3 trials. Interestingly, human data indicates that these agents have potent immunostimulatory activity, raising the possibility that the key consequence of oncolysis might be induction of antitumor immunity, especially in the context of viruses harboring immunostimulatory transgenes. While safety and efficacy of many types of oncolytic viruses, including adenovirus, herpes, reo, and vaccinia seem promising, few mechanisms of action studies have been performed with human substrates. Thus, the relative contribution of “pure” oncolysis, the immune response resulting from oncolysis, and the added benefit of adding a transgene remain poorly understood. Here, the available clinical data on oncolytic viruses is reviewed, with emphasis on immunological aspects.

scholarly journals Recombinant Vaccinia Viruses Coding Transgenes of Apoptosis-Inducing Proteins Enhance Apoptosis But Not Immunogenicity of Infected Tumor Cells

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Olga Koval ◽  
Galina Kochneva ◽  
Anastasiya Tkachenko ◽  
Olga Troitskaya ◽  
Galina Sivolobova ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Antitumor Immunity ◽  
Cell Infection ◽  
Delay Tumor Growth ◽  
Gm Csf ◽  
Cell Death Pathways ◽  
Vaccinia Viruses ◽  
Caspase 7 ◽  
Double Recombinant

Genetic modifications of the oncolytic vaccinia virus (VV) improve selective tumor cell infection and death, as well as activation of antitumor immunity. We have engineered a double recombinant VV, coding human GM-CSF, and apoptosis-inducing protein apoptin (VV-GMCSF-Apo) for comparing with the earlier constructed double recombinant VV-GMCSF-Lact, coding another apoptosis-inducing protein, lactaptin, which activated different cell death pathways than apoptin. We showed that both these recombinant VVs more considerably activated a set of critical apoptosis markers in infected cells than the recombinant VV coding GM-CSF alone (VV-GMCSF-dGF): these were phosphatidylserine externalization, caspase-3 and caspase-7 activation, DNA fragmentation, and upregulation of proapoptotic protein BAX. However, only VV-GMCSF-Lact efficiently decreased the mitochondrial membrane potential of infected cancer cells. Investigating immunogenic cell death markers in cancer cells infected with recombinant VVs, we demonstrated that all tested recombinant VVs were efficient in calreticulin and HSP70 externalization, decrease of cellular HMGB1, and ATP secretion. The comparison of antitumor activity against advanced MDA-MB-231 tumor revealed that both recombinants VV-GMCSF-Lact and VV-GMCSF-Apo efficiently delay tumor growth. Our results demonstrate that the composition of GM-CSF and apoptosis-inducing proteins in the VV genome is very efficient tool for specific killing of cancer cells and for activation of antitumor immunity.

scholarly journals Vaccination with early ferroptotic cancer cells induces efficient antitumor immunity

2020 ◽  
Vol 8 (2) ◽  
pp. e001369 ◽  
Author(s):  
Iuliia Efimova ◽  
Elena Catanzaro ◽  
Louis Van der Meeren ◽  
Victoria D Turubanova ◽  
Hamida Hammad ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Antitumor Immunity ◽  
High Mobility ◽  
Adaptive Immune System ◽  
Immunogenic Cell Death ◽  
Term Survival ◽  
Atomic Force

BackgroundImmunotherapy represents the future of clinical cancer treatment. The type of cancer cell death determines the antitumor immune response and thereby contributes to the efficacy of anticancer therapy and long-term survival of patients. Induction of immunogenic apoptosis or necroptosis in cancer cells does activate antitumor immunity, but resistance to these cell death modalities is common. Therefore, it is of great importance to find other ways to kill tumor cells. Recently, ferroptosis has been identified as a novel, iron-dependent form of regulated cell death but whether ferroptotic cancer cells are immunogenic is unknown.MethodsFerroptotic cell death in murine fibrosarcoma MCA205 or glioma GL261 cells was induced by RAS-selective lethal 3 and ferroptosis was analyzed by flow cytometry, atomic force and confocal microscopy. ATP and high-mobility group box 1 (HMGB1) release were detected by luminescence and ELISA assays, respectively. Immunogenicity in vitro was analyzed by coculturing of ferroptotic cancer cells with bone-marrow derived dendritic cells (BMDCs) and rate of phagocytosis and activation/maturation of BMDCs (CD11c+CD86+, CD11c+CD40+, CD11c+MHCII+, IL-6, RNAseq analysis). The tumor prophylactic vaccination model in immune-competent and immune compromised (Rag-2−/−) mice was used to analyze ferroptosis immunogenicity.ResultsFerroptosis can be induced in cancer cells by inhibition of glutathione peroxidase 4, as evidenced by confocal and atomic force microscopy and inhibitors’ analysis. We demonstrate for the first time that ferroptosis is immunogenic in vitro and in vivo. Early, but not late, ferroptotic cells promote the phenotypic maturation of BMDCs and elicit a vaccination-like effect in immune-competent mice but not in Rag-2−/− mice, suggesting that the mechanism of immunogenicity is very tightly regulated by the adaptive immune system and is time dependent. Also, ATP and HMGB1, the best-characterized damage-associated molecular patterns involved in immunogenic cell death, have proven to be passively released along the timeline of ferroptosis and act as immunogenic signal associated with the immunogenicity of early ferroptotic cancer cells.ConclusionsThese results pave the way for the development of new therapeutic strategies for cancers based on induction of ferroptosis, and thus broadens the current concept of immunogenic cell death and opens the door for the development of new strategies in cancer immunotherapy.

scholarly journals First-in-class ruthenium anticancer drug (KP1339/IT-139) induces an immunogenic cell death signature in colorectal spheroids in vitro

Metallomics ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 1044-1048 ◽  
Author(s):  
Debora Wernitznig ◽  
Konstantinos Kiakos ◽  
Giorgia Del Favero ◽  
Nathalie Harrer ◽  
Herwig Machat ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cells ◽  
Anticancer Drug ◽  
Antitumor Immunity ◽  
3D Model ◽  
Ruthenium Complex ◽  
Immunogenic Cell Death ◽  
First Time

ICD enhances antigenicity from dying cancer cells, which leads to antitumor immunity. We show for the first time that a ruthenium-complex induces the ICD signature in a 3D model.

scholarly journals Lomitapide, a cholesterol-lowering drug, is an anticancer agent that induces autophagic cell death via inhibiting mTOR

2021 ◽  
Author(s):  
Boah Lee ◽  
Seung Ju Park ◽  
Seulgi Lee ◽  
Jinwook Lee ◽  
Eun Byeol Lee ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Death ◽  
Cancer Treatment ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Therapeutic Option ◽  
Cholesterol Lowering ◽  
Cellular Environment ◽  
Lowering Drug

Autophagy is a biological process that maintains cellular homeostasis and regulates the internal cellular environment. Hyperactivating autophagy to trigger cell death has been a suggested therapeutic strategy for cancer treatment. Mechanistic target of rapamycin (mTOR) is a crucial protein kinase that regulates autophagy; therefore, using a structure-based virtual screen analysis, we identified lomitapide, a cholesterol-lowering drug, as a potential mTOR complex 1 (mTORC1) inhibitor. Our results showed that lomitapide directly inhibits mTORC1 in vitro and induces autophagy-dependent cancer cell death by decreasing mTOR signaling, thereby inhibiting the downstream events associated with increased LC3 conversion in various cancer cells (e.g., HCT116 colorectal cancer cells) and tumor xenografts. Lomitapide also significantly suppresses the growth and viability along with elevated autophagy in patient-derived colorectal cancer organoids. Furthermore, a combination of lomitapide and immune checkpoint blocking antibodies synergistically inhibits tumor growth in murine MC-38 or B16-F10 pre-clinical syngeneic tumor models. These results elucidates the direct, tumor-relevant immune-potentiating benefits of mTORC1 inhibition by lomitapide, which complement the current immune checkpoint blockade. This study highlights the potential repurposing of lomitapide as a new therapeutic option for cancer treatment.

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