Oncolytic virus therapy is a new form of cancer treatment that uses viruses that preferentially infect and lyse cancer cells. Vesicular stomatitis virus (VSV) is a strong oncolytic virus candidate that infects multiple tumor cells, produces rapid viral replication in malignant cells and spreads quickly in the tumor. Defects in the interferon (IFN) antiviral pathway are common in tumor cells and such defects are accountable for the sensitivity to VSV infection and replication in several malignant cells. The intrinsic mitochondrial apoptotic pathway plays a crucial role in VSV-induced apoptosis and disturbance of this pathway is responsible for resistance to VSV oncolysis of cancer cells. The antiapoptotic protein B-cell lymphoma 2 (BCL-2) is commonly overexpressed in tumor cells, especially in hematological malignancies, and is strongly related to resistance to cancer therapy. Chronic lymphocytic leukemia (CLL) is an accumulative disease of mature-looking CD5+/CD19+ lymphocytes, caused by defects in apoptosis rather than increase in proliferation. CLL patients express high levels of the BCL-2 protein which correlates with poor treatment outcome. Small-molecule BCL-2 inhibitors showed promising anticancer properties in preclinical models. A phase I clinical trial demonstrated modest activity against CLL. Based on our observation that CLL cells are resistant to VSV-induced cell death due to overexpression of BCL-2, we hypothesized that inhibition of BCL-2 could restore VSV oncolytic potential in primary CLL cells. In fact, BCL-2 inhibitors EM20-25IVand obatoclax sensitized primary CLL cells to VSV-induced cell death. Mechanistically, while VSV infection triggered Phorbol-12-myristate-13-acetate-induced protein 1 (NOXA) upregulation, obatoclax blocked the ability of BCL-2 to dimerize with the proapoptotic BCL2-associated X protein (BAX). Together, NOXA expression and BAX release were able to efficiently induce apoptosis. Moreover, our data demonstrated a direct interaction between NOXA and BAX. Together, these data indicate that the use of BCL-2 inhibitors may improve VSV oncolysis in apoptosis-resistant hematological malignancies characterized by overexpression of anti-apoptotic proteins such as BCL-2. / Oncolytic virus therapy is a new form of cancer treatment that uses viruses that preferentially infect and lyse cancer cells. Vesicular stomatitis virus (VSV) is a strong oncolytic virus candidate that infects multiple tumor cells, produces rapid viral replication in malignant cells and spreads quickly in the tumor. Defects in the interferon (IFN) antiviral pathway are common in tumor cells and such defects are accountable for the sensitivity to VSV infection and replication in several malignant cells. The intrinsic mitochondrial apoptotic pathway plays a crucial role in VSV-induced apoptosis and disturbance of this pathway is responsible for resistance to VSV oncolysis of cancer cells. The antiapoptotic protein B-cell lymphoma 2 (BCL-2) is commonly overexpressed in tumor cells, especially in hematological malignancies, and is strongly related to resistance to cancer therapy. Chronic lymphocytic leukemia (CLL) is an accumulative disease of mature-looking CD5+/CD19+ lymphocytes, caused by defects in apoptosis rather than increase in proliferation. CLL patients express high levels of the BCL-2 protein which correlates with poor treatment outcome. Small-molecule BCL-2 inhibitors showed promising anticancer properties in preclinical models. A phase I clinical trial demonstrated modest activity against CLL. Based on our observation that CLL cells are resistant to VSV-induced cell death due to overexpression of BCL-2, we hypothesized that inhibition of BCL-2 could restore VSV oncolytic potential in primary CLL cells. In fact, BCL-2 inhibitors EM20-25IVand obatoclax sensitized primary CLL cells to VSV-induced cell death. Mechanistically, while VSV infection triggered Phorbol-12-myristate-13-acetate-induced protein 1 (NOXA) upregulation, obatoclax blocked the ability of BCL-2 to dimerize with the proapoptotic BCL2-associated X protein (BAX). Together, NOXA expression and BAX release were able to efficiently induce apoptosis. Moreover, our data demonstrated a direct interaction between NOXA and BAX. Together, these data indicate that the use of BCL-2 inhibitors may improve VSV oncolysis in apoptosis-resistant hematological malignancies characterized by overexpression of anti-apoptotic proteins such as BCL-2.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.96986 |
| Date | January 2011 |
| Creators | Tumilasci, Vanessa |
| Contributors | John Hiscott (Internal/Supervisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Microbiology & Immunology) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | Electronically-submitted theses. |
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