Acquired resistance to reoviral oncolysis in Ras-transformed fibrosarcoma cells

Kim, M; Egan, Cay; Alain, Tommy; Urbanski, Stefan J.; Lee, P W; Forsyth, Peter; Johnston, Randal N.

doi:10.1038/sj.onc.1210189

Cited by 37 publications

(56 citation statements)

References 36 publications

(44 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The Dearing strain of reovirus serotype 3, purchased from the American Type Culture Collection (Manassas, VA), was propagated in L929 cells. The virus was purified as described elsewhere 19 and the viral titer was measured in plaque forming units (PFUs).…”

Section: Methodsmentioning

confidence: 99%

CUG2, a novel oncogene confers reoviral replication through Ras and p38 signaling pathway

Park

I-R

et al. 2010

Cancer Gene Ther

Self Cite

View full text Add to dashboard Cite

As we have recently found a novel oncogene, the cancer-upregulated gene 2 (CUG2), which was elevated in a variety of tumor tissues such as the ovary, liver, lung and pancreas, we examined whether reovirus could efficiently induce cytolysis in cancer cells expressing CUG2 and thus be used as a potential cancer therapeutic agent. In this study, we describe experiments in which we use reovirus to treat NIH3T3 cells stably expressing either CUG2 (NIH-CUG2) or vector only (NIH-Vec). NIH-CUG2 cells readily support reoviral proliferation and undergo apoptosis, whereas NIH-Vec cells are highly resistant to reoviral infection and virusinduced apoptosis. This notable result may be explained by the observation that CUG2 expression inhibits PKR activation, leading to reoviral proliferation in nonpermissive NIH3T3 cells. Furthermore, reovirus infection results in almost complete regression of tumorgenic NIH-CUG2 cells in transplanted nude mice. As we found that CUG2 enhances activation of MAPK (ERK, JNK and p38), Src kinase and Ras, we examined whether CUG2 confers reoviral replication independent of the Ras or p38 MAPK signaling pathway. From these experiments we found that either inhibition of p38 MAPK or Ras blocks reoviral proliferation even in the presence of CUG2 but inhibition of ERK, JNK and Src kinase does not, indicating that activation of p38 MAPK and Ras has critical roles in reoviral replication in CUG2-expressing tumor cells. Accordingly, we propose that reovirus can be useful in the treatment of transformed cells expressing CUG2, which is commonly detected in various tumor tissues.

show abstract

Section: Methodsmentioning

confidence: 99%

CUG2, a novel oncogene confers reoviral replication through Ras and p38 signaling pathway

Park

I-R

et al. 2010

Cancer Gene Ther

Self Cite

View full text Add to dashboard Cite

show abstract

“…Black foot syndrome was described as the discoloration and necrosis of feet, tails, distal legs, and ears in SCID/NOD mice several weeks after injection of reovirus intratumorally (48), again suggesting that virus replicating within the tumor serves as a source for systemic dissemination (49). The pathogenesis of black foot syndrome was characterized as due to venous vasculitis secondary to reovirus infection along with reovirus-induced myocarditis and heart failure (48,50) and typically, these symptoms developed weeks or months after the reovirus therapy into the tumor (48,49). We observed a variation of this syndrome in which tails of cyclophosphamide-treated mice became swollen, very sensitive, and, in a minority of cases, detached from the animal.…”

Section: Discussionmentioning

confidence: 99%

Cyclophosphamide Facilitates Antitumor Efficacy against Subcutaneous Tumors following Intravenous Delivery of Reovirus

Qiao¹,

Wang²,

Kottke³

et al. 2008

Clinical Cancer Research

158

155

View full text Add to dashboard Cite

Purpose: The purpose of the present study was to investigate whether it is possible to achieve truly systemic delivery of oncolytic reovirus, in immunocompetent hosts, using cyclophosphamide to overcome some of the barriers to effective intratumoral delivery and replication of i.v. injected virus. Experimental Design: I.v. delivery of reovirus was combined with different regimens of i.p. administered cyclophosphamide in C57Bl/6 mice bearing established s.c. B16 tumors. Intratumoral viral replication, tumor size, and survival were measured along with levels of neutralizing antibody (NAb) in the blood. Finally, differential toxicities of the virus/cyclophosphamide regimens were monitored through viral replication in systemic organs, survival, and cardiac damage. Results: Repeated i.v. injection of reovirus was poorly effective at seeding intratumoral viral replication/oncolysis. However, by combining i.v. virus with cyclophosphamide, viral titers of between 107 and 108 plaque-forming units per milligram were recovered from regressing tumors. Doses of cyclophosphamide that ablated NAb were associated with severe toxicities, characterized by viral replication in systemic organs—toxicities that are mirrored by repeated reovirus injections into B-cell knockout mice. Next, we restructured the dosing of cyclophosphamide and i.v. virus such that a dose of 3 mg cyclophosphamide was administered 24 h before reovirus injection, and this schedule was repeated every 6 days. Using this protocol, high levels of intratumoral viral access and replication (∼107 plaque-forming units per milligram tumor) were maintained along with systemically protective levels of NAb and only very mild, non–life-threatening toxicity. Conclusion: NAb to oncolytic viruses play a dual role in the context of systemic viral delivery; on one hand, they hinder repeated administration of virus but on the other, they provide an important safety mechanism by which virus released from vigorous intratumoral replication is neutralized before it can disseminate and cause toxicity. These data support the use of cyclophosphamide to modulate, but not ablate, patient NAb, in development of carefully controlled clinical trials of the systemic administration of oncolytic viruses.

show abstract

“…Although Ras signaling plays a critical role in dictating host cell permissiveness to reovirus (6), other signaling pathways may also contribute susceptibility to reoviral replication and oncolysis (9). Since it has been reported that reovirus efficiently kills many colon cancer cell lines (12) in vitro and in a rodent model in vivo (12,14,25), we wondered whether upregulation of ß-catenin might in some way enhance reovirus replication. However, we found that overexpression of ß-catenin as induced by exposure to the GSK-3ß inhibitor LiCl, did not enhance reoviral replication in HEK293 and HCT116 cells.…”

Section: Discussionmentioning

confidence: 99%

“…The Dearing strain of reovirus serotype 3 purchased from the ATCC (Manassas, VA) was propagated in L929 cells. The virus was purified as described elsewhere (24,25), and titer of virus was measured as plaque forming units (PFU).…”

Section: Cell Cultures and Virus Amplificationmentioning

confidence: 99%

Inhibition of GSK-3β enhances reovirus-induced apoptosis in colon cancer cells

Min

Koh²,

Cho³

et al. 2009

Int J Oncol

View full text Add to dashboard Cite

Abstract. Reovirus functions as an oncolytic agent for many types of cancer including colon cancer. Although most studies have emphasized the role of activated Ras signaling in enhancing reoviral oncolysis in susceptible cells, we note that many colon cancers also display elevated ß-catenin. Thus, it is possible that enhanced ß-catenin may augment reoviral susceptibility in colon cancer cells. To explore this hypothesis, HEK293 cells were treated with the glycogen synthase kinase (GSK)-3ß inhibitor LiCl, thereby inducing ß-catenin, followed by reoviral infection. Co-administration with LiCl indeed enhanced cell death compared to reovirus infection alone, but this was not associated with elevated reoviral replication. Similarly, HEK293 cells expressing the Frizzled-1 receptor in Wnt3a-conditioned medium also showed reovirus replication equivalent to that in cells in control medium, further suggesting that up-regulation of ß-catenin does not enhance the replication of reovirus. Instead, we observed that inhibition of GSK-3ß with LiCl decreased reovirus-induced NF-κB activation, leading to accelerated apoptosis via caspase 8 activation. We further found that colon cancer HCT116 cells were sensitized to apoptosis by co-treatment with reovirus and a GSK-3ß inhibitor, AR-A014418. Finally, we identified that inhibition of NF-κB sensitized apoptosis of HEK293 or HCT 116 cells during reovirus infection. Taken together, we propose that inhibition of GSK-3ß sensitizes reovirus-induced apoptosis of colon cancer cells by downregulation of NF-κB activity, offering a potentially improved therapeutic strategy for the treatment of colon cancer.

show abstract

Acquired resistance to reoviral oncolysis in Ras-transformed fibrosarcoma cells

Cited by 37 publications

References 36 publications

CUG2, a novel oncogene confers reoviral replication through Ras and p38 signaling pathway

CUG2, a novel oncogene confers reoviral replication through Ras and p38 signaling pathway

Cyclophosphamide Facilitates Antitumor Efficacy against Subcutaneous Tumors following Intravenous Delivery of Reovirus

Inhibition of GSK-3β enhances reovirus-induced apoptosis in colon cancer cells

Contact Info

Product

Resources

About