Adenovirus-mediated p53 gene therapy in osteosarcoma cell lines: sensitization to cisplatin and doxorubicin

Ganjavi, Hooman; Gee, Matthew F.W.; Narendran, Aru; Parkinson, Nicole; Krishnamoorthy, M; Freedman, Melvin H.; Malkin, David

doi:10.1038/sj.cgt.7700909

Cited by 41 publications

(36 citation statements)

References 8 publications

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“…However, the antitumor activity of replication-deficient Ad-p53 is limited in some human osteosarcoma cells (47). Ad-p53-mediated p53 overexpression increases the sensitivity of human osteosarcoma cells to the chemotherapeutic drugs, cisplatin and doxorubicin (48). A synergistic antitumor effect between doxorubicin and roscovitine was also associated with autophagy induction in human osteosarcoma U2OS cells (49).…”

Section: Mol Cancer Ther; 12(3) March 2013mentioning

confidence: 88%

Dual Programmed Cell Death Pathways Induced by p53 Transactivation Overcome Resistance to Oncolytic Adenovirus in Human Osteosarcoma Cells

Hasei

Sasaki

Tazawa

et al. 2013

Molecular Cancer Therapeutics

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Tumor suppressor p53 is a multifunctional transcription factor that regulates diverse cell fates, including apoptosis and autophagy in tumor biology. p53 overexpression enhances the antitumor activity of oncolytic adenoviruses; however, the molecular mechanism of this occurrence remains unclear. We previously developed a tumor-specific replication-competent oncolytic adenovirus, OBP-301, that kills human osteosarcoma cells, but some human osteosarcoma cells were OBP-301-resistant. In this study, we investigated the antitumor activity of a p53-expressing oncolytic adenovirus, OBP-702, and the molecular mechanism of the p53-mediated cell death pathway in OBP-301-resistant human osteosarcoma cells. The cytopathic activity of OBP-702 was examined in OBP-301-sensitive (U2OS and HOS) and OBP-301-resistant (SaOS-2 and MNNG/ HOS) human osteosarcoma cells. The molecular mechanism in the OBP-702-mediated induction of two cell death pathways, apoptosis and autophagy, was investigated in OBP-301-resistant osteosarcoma cells. The antitumor effect of OBP-702 was further assessed using an orthotopic OBP-301-resistant MNNG/HOS osteosarcoma xenograft tumor model. OBP-702 suppressed the viability of OBP-301-sensitive and -resistant osteosarcoma cells more efficiently than OBP-301 or a replication-deficient p53-expressing adenovirus (Adp53). OBP-702 induced more profound apoptosis and autophagy when compared with OBP-301 or Ad-p53. E1A-mediated miR-93/106b upregulation induced p21 suppression, leading to p53-mediated apoptosis and autophagy in OBP-702-infected cells. p53 overexpression enhanced adenovirus-mediated autophagy through activation of damage-regulated autophagy modulator (DRAM). Moreover, OBP-702 suppressed tumor growth in an orthotopic OBP-301-resistant MNNG/HOS xenograft tumor model. These results suggest that OBP-702-mediated p53 transactivation is a promising antitumor strategy to induce dual apoptotic and autophagic cell death pathways via regulation of miRNA and DRAM in human osteosarcoma cells.

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Section: Mol Cancer Ther; 12(3) March 2013mentioning

confidence: 88%

Dual Programmed Cell Death Pathways Induced by p53 Transactivation Overcome Resistance to Oncolytic Adenovirus in Human Osteosarcoma Cells

Hasei

Sasaki

Tazawa

et al. 2013

Molecular Cancer Therapeutics

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“…Polychemotherapy of osteosarcoma relies on methotrexate, ifosfamide, doxorubicin, and cisplatin regimens, some of these drugs being well-known to induce apoptosis in cancer cells through the mitochondrial apoptotic pathway (4,32,33). OSM also sensitized OSRGA cells to cell death induced by doxorubicin or cisplatin as revealed by the enhanced caspase-3 activity (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Oncostatin M Induces Bone Loss and Sensitizes Rat Osteosarcoma to the Antitumor Effect of MidostaurinIn vivo

Brounais

Chipoy

Mori

et al. 2008

Clinical Cancer Research

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Purpose: In cultures, the cytokine oncostatin M (OSM) reduces the growth and induces differentiation of osteoblasts and osteosarcoma cells into glial/osteocytic cells. Moreover, OSM sensitizes these cells to apoptosis driven by various death inducers such as the kinase inhibitor staurosporine. Here, we asked whether OSM would have similar effects in vivo. Experimental Design: Adenoviral gene transfer of OSM (AdOSM) was done in naive and osteosarcoma-bearing rats, alone or in combination with Midostaurin (PKC412), a derivative of staurosporine currently used in cancer clinical trials. Bone variables were analyzed by microcomputed tomography scanner, by histology, and by the levels of various serum bone markers. Osteosarcoma progression was analyzed by the development of the primary bone tumor, evolution of pulmonary metastasis, histology (necrosis and fibrosis), and animal survival. Results: In naive rats, AdOSM reduced serum osteoblastic and osteoclastic markers in correlation with a reduced trabecular bone volume. In an osteosarcoma rat model, the combination of AdOSM with PKC412 reduced the progression of the primary bone tumor, pulmonary metastatic dissemination, and increased overall survival, whereas these agents alone had no antitumor effect. Increased tumor necrosis and tissue repair (fibrosis) were observed with this combination. Conclusion: These in vivo experiments confirm that systemic OSM overexpression alters osteoblast/osteosarcoma activity. Because OSM sensitizes rat osteosarcoma to apoptosis/necrosis, the use of kinase inhibitors such as Midostaurin in association with OSM could represent new adjuvant treatments for this aggressive malignancy.Osteosarcomas are rare bone-forming tumors that affect primarily young adults. These cancer cells arise from osteoblasts, the cells responsible for bone apposition. Rather than a unique gene alteration, multiple deregulations of the proteins controlling the G 1 -S-phase cell cycle checkpoint (p53, Rb, p16INK4A , MDM2, etc.) are involved in the pathogenesis and chemoresistance of osteosarcomas (1, 2). Although the prognosis and chemotherapies of patients with osteosarcoma were improved significantly in the seventies, the survival rate after 5 years is only 60% to 70% and as low as 30% when pulmonary metastases are detected at diagnosis. These survival rates were not further ameliorated during the past decades (3, 4).Thus, new therapies that inhibit the growth or metastasis of these tumors will have a significant effect on patient survival. Cytokines of the interleukin-6 (IL-6) family, such as oncostatin M (OSM), are recognized as pleiotropic factors influencing many pathophysiologic events in several organs, including bone (5 -8). These cytokines have all been reported to stimulate osteoclastogenesis and, in some cases, to stimulate osteoblast differentiation in cell cultures. However, recent in vivo and genetic data have challenged these concepts (reviewed in refs. 5 -8). For example, transgenic mice overexpressing IL-6 showed a decrease in osteobla...

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“…The sarcoma cell lines were treated with various doses of Adwtp53. From our previous studies, 54 doses of the chemotherapeutic agents cisplatin and doxorubicin were also chosen that, by themselves, would have a limited effect (20-30% cell death).…”

Section: Adenovirus-mediated P53 Gene Therapy In Pediatric Stsmentioning

confidence: 99%

Adenovirus-mediated p53 gene therapy in pediatric soft-tissue sarcoma cell lines: sensitization to cisplatin and doxorubicin

et al. 2004

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Sarcomas, or tumors of connective tissue, represent roughly 20% of childhood cancers. Although the cure rate for sarcomas in general has significantly improved in the last 10 years, there continue to be subgroups that are difficult to treat. High-grade or metastatic soft-tissue sarcomas and rhabdomyosarcomas (RMS) of the extremities remain therapeutic challenges and their prognosis is often poor. The future of sarcoma therapy will likely include molecular approaches including gene/protein expression profiling and gene-based therapy. Most sarcomas harbor defects in the p53 or pRb pathways. The tumor suppressor p53 is central to regulation of cell growth and tumor suppression and restoring wild-type p53 function in pediatric sarcomas may be of therapeutic benefit. Studies with adenoviral-mediated p53 gene transfer have been conducted in many cancer types including cervical, ovarian, prostatic and head and neck tumors. Studies of this approach, however, remain limited in pediatric cancers, including sarcomas. Using three viral constructs containing cDNA for wild-type p53, mutant p53 (C135S) and lacZ, we studied the effect of adenoviralmediated gene therapy in four pediatric sarcoma cell lines, RD and Rh4 (RMS), Rh1 (Ewing's sarcoma) and A204 (undifferentiated sarcoma). Using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay, we have shown a dose-dependent decrease in cell viability 72 h post-treatment that occurs with Ad-wtp53 but not with Ad-mutp53. Cells treated with Ad-wtp53 show upregulation of the p53 downstream targets, p21 CIP1/WAF1 and bax. Growth curves demonstrate suppression of cell growth over a period of 4 days and cells treated with Ad-wtp53 demonstrate a significant increase in sensitivity to the chemotherapeutic agents, cisplatin and doxorubicin. Our results indicate that restoration of wild-type p53 function in pediatric sarcoma cells could provide a basis for novel approaches to treatment of this disease.

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Adenovirus-mediated p53 gene therapy in osteosarcoma cell lines: sensitization to cisplatin and doxorubicin

Cited by 41 publications

References 8 publications

Dual Programmed Cell Death Pathways Induced by p53 Transactivation Overcome Resistance to Oncolytic Adenovirus in Human Osteosarcoma Cells

Dual Programmed Cell Death Pathways Induced by p53 Transactivation Overcome Resistance to Oncolytic Adenovirus in Human Osteosarcoma Cells

Oncostatin M Induces Bone Loss and Sensitizes Rat Osteosarcoma to the Antitumor Effect of MidostaurinIn vivo

Adenovirus-mediated p53 gene therapy in pediatric soft-tissue sarcoma cell lines: sensitization to cisplatin and doxorubicin

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