Viral oncoapoptosis of human tumor cells (original) (raw)
Related papers
Restoring apoptosis as a strategy for cancer gene therapy: focus on p53 and mda-7
Seminars in Cancer Biology, 2003
Understanding the molecular and genetic determinants of cancer will provide unique opportunities for developing rational and effective therapies. Malignant cells are frequently resistant to chemotherapy and radiation induced programmed cell death (apoptosis). This resistance can occur by mutations in the tumor suppressor gene p53. Strategies designed to replace this defective tumor suppressor protein, as well as forced expression of a novel cancer specific apoptosis inducing gene, melanoma differentiation associated gene-7 (mda-7), offer promise for restoring apoptosis in tumor cells. Conditional-replicating viruses that selectively induce cytolysis in tumor cells provides an additional means of targeting cancer cells for destruction. Although these approaches represent works in progress, future refinements will in all likelihood result in the next generation of cancer therapies.
Virus-mediated killing of cells that lack p53 activity
Drug Resistance Updates, 2001
A major goal of molecular oncology is to identify means to kill cells lacking p53 function. Most current cancer therapy is based on damaging cellular DNA by irradiation or chemicals. Recent reports 1,2 support the notion that, in the event of DNA damage, the p53 tumour-suppressor protein is able to prevent cell death by sustaining an arrest of the cell cycle at the G2 phase. We report here that adeno-associated virus (AAV) selectively induces apoptosis in cells that lack active p53. Cells with intact p53 activity are not killed but undergo arrest in the G2 phase of the cell cycle. This arrest is characterized by an increase in p53 activity and p21 levels and by the targeted destruction of CDC25C. Neither cell killing nor arrest depends upon AAV-encoded proteins. Rather, AAV DNA, which is single-stranded with hairpin structures at both ends 3,4 , elicits in cells a DNA damage response that, in the absence of active p53, leads to cell death. AAV inhibits tumour growth in mice. Thus viruses can be used to deliver DNA of unusual structure into cells to trigger a DNA damage response without damaging cellular DNA and to selectively eliminate those cells lacking p53 activity.
The modulation of apoptosis by oncogenic viruses
Virology Journal, 2013
Transforming viruses can change a normal cell into a cancer cell during their normal life cycle. Persistent infections with these viruses have been recognized to cause some types of cancer. These viruses have been implicated in the modulation of various biological processes, such as proliferation, differentiation and apoptosis. The study of infections caused by oncogenic viruses had helped in our understanding of several mechanisms that regulate cell growth, as well as the molecular alterations leading to cancer. Therefore, transforming viruses provide models of study that have enabled the advances in cancer research. Viruses with transforming abilities, include different members of the Human Papillomavirus (HPV) family, Hepatitis C virus (HCV), Human T-cell Leukemia virus (HTLV-1), Epstein Barr virus (EBV) and Kaposi’s Sarcoma Herpesvirus (KSHV). Apoptosis, or programmed cell death, is a tightly regulated process that plays an important role in development and homeostasis. Addition...
Cell Cycle, 2004
Recent findings showed that type I interferons (IFN-α/β) induce the transcription of tumor suppressor p53 and sensitize primary mouse embryonic fibroblasts (MEFs) to p53mediated apoptosis by oncolytic viruses. However, the ability of RNA viruses to induce a p53-mediated apoptotic response may differ between primary and tumor cells and may be dependent upon the virus type. We have investigated this hypothesis by analyzing the apoptotic effects of various oncolytic viruses on the human colon carcinoma HCT116 cells and their derivatives lacking either p53 or bax gene. We show that HCT116 cells are resistant to the apoptotic effects of vesicular stomatitis virus, reovirus or poliovirus but activate the p53/Bax apoptotic pathway after infection with Sendai virus. These data substantiate the role of p53 in virus-mediated apoptosis and show that, unlike primary cells, tumor cells may be more selective in the activation of p53 pathway in response to the infection with specific types of viruses.
Viral genes as oncolytic agents for cancer therapy
Cellular and Molecular Life Sciences, 2014
Many viruses have the ability to modulate the apoptosis, and to accomplish it; viruses encode proteins which specifically interact with the cellular signaling pathways. While some viruses encode proteins, which inhibit the apoptosis or death of the infected cells, there are viruses whose encoded proteins can kill the infected cells by multiple mechanisms, including apoptosis. A particular class of these viruses has specific gene(s) in their genomes which, upon ectopic expression, can kill the tumor cells selectively without affecting the normal cells. These genes and their encoded products have demonstrated great potential to be developed as novel anticancer therapeutic agents which can specifically target and kill the cancer cells leaving the normal cells unharmed. In this review, we will discuss about the viral genes having specific cancer cell killing properties, what is known about their functioning, signaling pathways and their therapeutic applications as anticancer agents. Keywords Apoptosis Á Anticancer genes Á Cancer Á Gene therapy Á Chicken infectious anemia Á Apoptin Á VP3 Á Parvovirus Á NS1 Á Adenovirus Á E4orf4 Á B19PV Á MVM Á H-1PV Á CPV
Self-deleting suicide vectors (SDSV): selective killing of p53-deficient cancer cells
Cancer research, 2001
A self-deleting retrovirus vector carrying a herpes simplex virus (HSV)-thymidine kinase suicide gene has been developed to selectively kill cancer cells expressing a dysfunctional p53 tumor suppressor protein. When cells containing functional p53 are infected with the virus, the integrated provirus and the HSV-thymidine kinase gene are deleted from the genome by site-specific recombination (Cre/loxP). In contrast, cells without p53 or cells expressing a DNA-binding mutant of p53 retain the provirus and become susceptible to killing by ganciclovir. This strategy provides a new concept for the selective killing of cancer cells that can be adapted to any other dysfunctional transcription factor expressed by different tumors.
Conditionally replicative adenovirus expressing p53 exhibits enhanced oncolytic potency
PubMed, 2002
Conditionally replicative adenoviruses (CRAds) hold promise as anticancer agents. Their potency depends on their replication efficiency in cancer cells and their capacity to destroy these cells by oncolysis. In this regard, a critical determinant is the capacity of CRAds to induce cell death at late stages of infection to release their progeny. One of the cell death pathways that are exploited by adenoviruses involves the tumor suppressor protein p53. Unfortunately, many cancer cells have a nonfunctional p53 pathway and thus do not effectively support CRAd-induced cell death. We hypothesized that restoration of the p53-dependent cell death pathway in cancer cells would promote CRAd-induced cell lysis. Exogenous expression of p53 in human cancer cells during adenovirus replication accelerated cell death by several days and augmented early virus progeny release. The p53-enhanced oncolysis occurred independent of E1A binding to pRb and independent of E3 functions. On the basis of these findings, we constructed a new CRAd, AdDelta24-p53. This virus expressed functional p53 while replicating in cancer cells. Most importantly, AdDelta24-p53 exhibited enhanced oncolytic potency on 80% of tested human cancer cell lines of various tissue origins and with different p53 status. CRAd potency was increased up to >100-fold by p53 expression. We conclude that CRAds expressing p53 are promising new agents for more effective treatment of many human cancers.
Induction and Prevention of Apoptosis in Human HEp-2 Cells by Herpes Simplex Virus Type 1
Journal of Virology
Cultured human epithelial cells infected with an ICP27 deletion strain of herpes simplex virus type 1 (HSV-1) show characteristic features of apoptotic cells including cell shrinkage, nuclear condensation, and DNA fragmentation. These cells do not show such apoptotic features when infected with a wild-type virus unless the infections are performed in the presence of a protein synthesis inhibitor. Thus, both types of virus induce apoptosis, but the ICP27-null virus is unable to prevent this process from killing the cells. In this report, we show that this ICP27-deficient virus induced apoptosis in human HEp-2 cells through a pathway which involved the activation of caspase-3 and the processing of the death substrates DNA fragmentation factor and poly(ADP-ribose) polymerase. The induction of apoptosis by wild-type HSV-1 occurred prior to 6 h postinfection (hpi), and de novo viral protein synthesis was not required to induce the process. The ability of the virus to inhibit apoptosis was shown to be effective between 3 to 6 hpi. Wild-type HSV-1 infection was also able to block the apoptosis induced in cells by the addition of cycloheximide, staurosporine, and sorbitol. While U S 3and ICP22-deficient viruses showed a partial prevention of apoptosis, deletion of either the U L 13 or vhs gene products did not affect the ability of HSV-1 to prevent apoptosis in infected cells. Finally, we demonstrate that in UV-inactivated viruses, viral binding and entry were not sufficient to induce apoptosis. Taken together, these results suggest that either gene expression or another RNA metabolic event likely plays a role in the induction of apoptosis in HSV-1-infected human cells.
Journal of Virology, 2001
We have recently shown that vesicular stomatitis virus (VSV) exhibits potent oncolytic activity both in vitro and in vivo (S. Balachandran and G. N. Barber, IUBMB Life 50: [135][136][137][138] 2000). In this study, we further demonstrated, in vivo, the efficacy of VSV antitumor action by showing that tumors that are defective in p53 function or transformed with myc or activated ras are also susceptible to viral cytolysis. The mechanism of viral oncolytic activity involved the induction of multiple caspase-dependent apoptotic pathways was effective in the absence of any significant cytotoxic T-lymphocyte response, and occurred despite normal PKR activity and eIF2␣ phosphorylation. In addition, VSV caused significant inhibition of tumor growth when administered intravenously in immunocompetent hosts. Our data indicate that VSV shows significant promise as an effective oncolytic agent against a wide variety of malignant diseases that harbor a diversity of genetic defects.