“…Given the increased prevalence of colorectal cancer, and its poor response to current treatments, targeted therapeutic approaches are required [41]. OVs have the ability to selectively replicate in cancer cells and exhibit antitumor effects using a variety of mechanisms; further- more, many engineered viruses are undergoing different phases of clinical trials; for example, a specific form of herpes simplex virus for the treatment of melanoma has been approved by the US Food and Drug Administration [42]. Oncolytic reovirus is one of the most attractive anticancer agents for clinical trial [43,44].…”
<b><i>Background:</i></b> Colorectal cancer is the third most common cancer all over the world, so in the battle to fight this hurdle, new therapeutic approaches such as oncolytic viruses (OV) have attracted much attention because of the fact that they can inherently kill cancer cells. Oncolytic reovirus is one of the candidates for treatment as a nonpathogenic species specially reovirus type 3 Dearing (T3D), which can induce apoptosis. To speed up the entry and function of the reovirus, low-intensity ultrasound, which is a safe system for damage to the cells and tissues, is a promising approach to be used in combination with other therapeutic approach. <b><i>Methods:</i></b> L929 and CT26 cells were infected with reovirus T3D and were exposed to ultrasonic irradiation (1 MHz, 1 W/cm<sup>2</sup>, and 20% duty factor) for 10 s. The viruses’ titer level of both groups was calculated in 2 types of cells by using the CCID<sub>50</sub> method and compared with each other. Apoptosis, after 24 h, was measured by the flow cytometry method. <b><i>Result:</i></b> The results of CCID<sub>50</sub> in infected cells were exposed to low-intensity ultrasound showed an increased virus titer compared with unexposed infected cells. Moreover, according to the results of the flow cytometry test, it was found that the amount of apoptosis in infected cells that are exposed to low-intensity ultrasound waves is higher than those infected cells. <b><i>Conclusion:</i></b> Due to the results of CCID<sub>50</sub> and flow cytometry tests, low-intensity ultrasound increases the cytotoxicity level of reovirus in CT26 cells of the cellular colorectal cancer model.
“…Given the increased prevalence of colorectal cancer, and its poor response to current treatments, targeted therapeutic approaches are required [41]. OVs have the ability to selectively replicate in cancer cells and exhibit antitumor effects using a variety of mechanisms; further- more, many engineered viruses are undergoing different phases of clinical trials; for example, a specific form of herpes simplex virus for the treatment of melanoma has been approved by the US Food and Drug Administration [42]. Oncolytic reovirus is one of the most attractive anticancer agents for clinical trial [43,44].…”
<b><i>Background:</i></b> Colorectal cancer is the third most common cancer all over the world, so in the battle to fight this hurdle, new therapeutic approaches such as oncolytic viruses (OV) have attracted much attention because of the fact that they can inherently kill cancer cells. Oncolytic reovirus is one of the candidates for treatment as a nonpathogenic species specially reovirus type 3 Dearing (T3D), which can induce apoptosis. To speed up the entry and function of the reovirus, low-intensity ultrasound, which is a safe system for damage to the cells and tissues, is a promising approach to be used in combination with other therapeutic approach. <b><i>Methods:</i></b> L929 and CT26 cells were infected with reovirus T3D and were exposed to ultrasonic irradiation (1 MHz, 1 W/cm<sup>2</sup>, and 20% duty factor) for 10 s. The viruses’ titer level of both groups was calculated in 2 types of cells by using the CCID<sub>50</sub> method and compared with each other. Apoptosis, after 24 h, was measured by the flow cytometry method. <b><i>Result:</i></b> The results of CCID<sub>50</sub> in infected cells were exposed to low-intensity ultrasound showed an increased virus titer compared with unexposed infected cells. Moreover, according to the results of the flow cytometry test, it was found that the amount of apoptosis in infected cells that are exposed to low-intensity ultrasound waves is higher than those infected cells. <b><i>Conclusion:</i></b> Due to the results of CCID<sub>50</sub> and flow cytometry tests, low-intensity ultrasound increases the cytotoxicity level of reovirus in CT26 cells of the cellular colorectal cancer model.
“…The potential use of an oncolytic reovirus created by Reolysin®, (pelareorep; wild-type reovirus; Serotype 3 Dearing; Oncolytics Biotech Inc.), for the treatment of various tumor cells was examined in several clinical trials [ 224 ]. Reolysin®, a novel systemically administered promising anti-cancer drug for pancreatic, ovarian, and malignant glioma tumors, received FDA approval in 2015 [ 225 , 226 ]. The oncolytic reovirus's anti-cancer effect against the glioblastoma multiforme (GBM) cell line may be enhanced by AD-MSCs, which are a vulnerable host for the virus [ 227 ].…”
Section: Msc-based Delivery Of Oncolytic Reovirusmentioning
Oncolytic viruses (OVs) infect, multiply, and finally remove tumor cells selectively, causing no damage to normal cells in the process. Because of their specific features, such as, the ability to induce immunogenic cell death and to contain curative transgenes in their genomes, OVs have attracted attention as candidates to be utilized in cooperation with immunotherapies for cancer treatment. This treatment takes advantage of most tumor cells' inherent tendency to be infected by certain OVs and both innate and adaptive immune responses are elicited by OV infection and oncolysis. OVs can also modulate tumor microenvironment and boost anti-tumor immune responses. Mesenchymal stem cells (MSC) are gathering interest as promising anti-cancer treatments with the ability to address a wide range of cancers.
MSCs exhibit tumor-trophic migration characteristics, allowing them to be used as delivery vehicles for successful, targeted treatment of isolated tumors and metastatic malignancies. Preclinical and clinical research were reviewed in this study to discuss using MSC-released OVs as a novel method for the treatment of cancer.
“…T3wt is in clinical trials as a therapy for numerous cancers (8), in conjunction with other traditional therapies such as immunotherapies, chemotherapeutics, and radiation (9)(10)(11). In 2015, T3wt received orphan drug designation from FDA for malignant glioma, ovarian cancer, and pancreatic cancer (12).…”
Wild type reovirus serotype 3 ‘Dearing PL strain’ (T3wt) is being heavily evaluated as an oncolytic and immunotherapeutic treatment for cancers. Mutations that promote reovirus entry into tumor cells were previously reported to enhance oncolysis; herein we aimed to discover mutations that enhance the post-entry steps of reovirus infection in tumor cells. Using directed evolution, we identified that reovirus variant T3v10M1 exhibited enhanced replication relative to T3wt on a panel of cancer cells. T3v10M1 contains an alanine-to-valine substitution (A612V) in the core-associated μ2, which was previously found to have NTPase activities in virions and to facilitate virus factory formation by association with μNS. Paradoxically, the A612V mutation in μ2 from T3v10M1 was discovered to impair NTPase activities and RNA synthesis, leading to five-fold higher probability of abortive infection for T3v10M1 relative to T3wt. The A612V mutation resides in a previously uncharacterized C-terminal region that juxtaposes the template entry site of the polymerase μ2; our findings thus support an important role for this domain during virus transcription. Despite crippled onset of infection, T3v10M1 exhibited greater accumulation of viral proteins and progeny during replication, leading to increased overall virus burst size. Both Far-Western and co-immunoprecipitation approaches corroborated that the A612V mutation in μ2 increased association with the non-structural virus protein μNS and enhances burst size. Altogether the data supports that mutations in the C-terminal loop domain of μ2 inversely regulate NTPase and RNA synthesis versus interactions with μNS, but with a net gain of replication in tumorigenic cells.
SIGNIFICANCE
Reovirus is a model system for understanding virus replication but also a clinically relevant virus for cancer therapy. We identified the first mutation that increases reovirus infection in tumorigenic cells by enhancing post-entry stages of reovirus replication. The mutation is in a previously uncharacterized c-terminal region of the M1-derived μ2 protein, which we demonstrated affects multiple functions of μ2; NTPase, RNA synthesis, inhibition of antiviral immune response and association with the virus replication factory-forming μNS protein. These findings promote a mechanistic understanding of viral protein functions. In the future, the benefits of μ2 mutations may be useful for enhancing reovirus potency in tumors.
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