Induction of apoptosis and tumor regression by vesicular stomatitis virus in the presence of gemcitabine in lung cancer

Abstract

Key words: apoptosis; vesicular stomatitis virus; gemcitabine; lung cancer; chemotherapyLung cancer accounts for about 1.5 million cases worldwide and is the leading cause of cancer-related death in both males and females. Non small cell lung cancer (NSCLC) comprises approximately 75-80% of all lung cancers. Despite aggressive approaches made in the therapy of lung cancer in the past decades, the prognosis of NSCLC remains poor, with 5-year survival rates of 5-14%, even if treated with surgery, radiotherapy and/or chemotherapy. 1-3 Efforts are therefore continuing to develop new and less toxic therapeutic approaches for the treatment of lung cancer.Vesicular stomatitis virus (VSV) is an enveloped, negativesense RNA virus and prototypic member of the family rhabdoviridae. 4 -6 It has been shown to replicate rapidly in vitro and kill selectively a variety of tumor cell lines. An essential, dose-limiting site of chemotherapy is the bone marrow while VSV can selectively kill leukemia cells when cocultured with normal bone marrow cells. 4 Furthermore, VSV exhibits the antitumor activity in both human tumor xenografts in nude mice and syngeneic tumors in the immunocompetent mice. 4,5 Gemcitabine (2Ј,2Ј-diflurodeoxycytidine) is a new deoxycytidine analogue that inhibits DNA synthesis. After cellular uptake, gemcitabine is phosphorylated to its active metabolites, which competitively inhibits DNA chain elongation, leading to DNA fragmentation and cell death. Gemcitabine has shown cytotoxic activity against a wide range of cancer cell lines in vitro and a number of murine and human tumors in vivo. [7][8][9] Gemcitabine monotherapy produced objective response in 20 -25% of patients with advanced NSCLC and has similar efficacy to cisplatin plus etoposide. 10 -12 When combined with cisplatin and/or paclitaxel or vinorelbine, gemcitabine therapy shows an objective response rates in 28 -54% and the median survival durations ranged from 38 to 61.5 weeks. [13][14][15][16][17][18] However, the treatment of advanced lung cancer still remains a challenge to medical oncologists.Because of differences in mechanisms of action and toxicity profiles, the combination of the above 2 agents may have clinical potential. The present study was designed to determine whether gemcitabine potentiates the antitumor activity of VSV in vitro using both A549 (human lung adenocarcinoma) and LLC (murine Lewis lung carcinoma) cell lines and in vivo using A549 lung cancer xenografts and the murine syngeneic Lewis lung cancer, and if so, to examine the possible mechanism in the phenomenon, as well as to provide some potential implications for the treatment of human lung cancer. MATERIAL AND METHODS Cells lines and agentsLLC cells and A549 cells were purchased from American Type Culture Collection (Rockville, MD). They were maintained in monolayer cultures in DMEM and RPMI-1640, respectively, supplemented with 10% heat-inactivated fetal bovine serum (FBS), at 37°C in a humidified atmosphere containing 5% CO 2 . Human umbilical vein endothelial cells (HU...

Induction of apoptosis in pancreatic cancer cells by vesicular stomatitis virus

“…This result not only speaks to the potential of VSV-ΔM51-GFP as an oncolytic agent but also suggests it may also be useful as a sensitizer to chemotherapy. In several cancers, VSV-M51R infection improved doxorubicin treatment by facilitating degradation of the anti-apoptotic protein Mcl-1 (Schache et al, 2009), while another study showed that wt VSV in combination with gemcitabine increased apoptosis and increased killing of lung cancer cell lines in vitro and in vivo (Li et al, 2004). If successful, such combination therapies could allow for equal or greater efficacy at lower doses of chemotherapeutic drug, reducing side effects in patients.…”

Vesicular stomatitis virus matrix protein gene enhances the antitumor effects of radiation via induction of apoptosis

“…VSV exhibits antitumor activity in syngeneic tumors in immunocompetent mice and human tumor xenografts in nude mice via apoptosis [10][11][12][13][14][15]; however, the risks involved in its use prevent its clinical application. Matrix (M) protein is one of the products of VSV, and it plays a critical role in VSV-induced apoptosis.…”

Typhonium blumei extract inhibits proliferation of human lung adenocarcinoma A549 cells via induction of cell cycle arrest and apoptosis

“…More than difficult to cure, lung cancer also has a high incidence of recurrence (Khuri et al, 2001;Li et al, 2004;Molina et al, 2006). The non-small cell lung cancer (NSCLC) constitutes a majority of lung cancers.…”