Bcl-2 and LMP1 expression in nasopharyngeal carcinomas

Saraç, Sarp; Akyol, Muammer; Kanbur, Bilge; Poyraz, Aylar; Akyol, Gülen; Yılmaz, Taner; Sungur, Arzu

doi:10.1053/ajot.2001.28071

Cited by 41 publications

(42 citation statements)

References 16 publications

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“…However, Bcl-2 is overexpressed in the majority of NPC tumors (61-89%), even in the absence of detectable LMP1 expression, and it is postulated that Bcl-2 may play a critical role in promoting cell survival and mediating resistance to chemotherapeutic agents in NPC. [6][7][8][9][10][11][12] Thus, Bcl-2 represents a rational therapeutic target in NPC.…”

Section: Discussionmentioning

confidence: 99%

“…5 Although a direct link between LMP-1 expression, Bcl-2 upregulation and cell survival in NPC is unclear, the majority of NPC tumors overexpress Bcl-2, even in the absence of LMP-1 expression. [6][7][8][9][10][11][12] Given the antiapoptotic function of Bcl-2 and its role in conferring resistance to chemotherapy, it represents a rational target for modulation using antisense strategies in NPC.…”

Section: Epstein-barr Virus (Ebv) Is Causally Linked To Undifferentiamentioning

confidence: 99%

“…Animals were injected with 5 million C666-1 and randomized to CDDP (diamonds), CDDP 1 2 base mismatch control oligo MM (triangles) or CDDP 1 G3139 (squares) (n 5 5-6 per arm). Treatment with oligo was initiated on day 7 at a dose of 25 mg/kg every 3 days 3 5 doses (days [7][8][9][10][11][12][13][14][15][16][17][18][19][20]. CDDP was administered on day 14 (8 mg/kg 3 1).…”

Section: G3139 Inhibits C666-1 Growth and Enhances Sensitivity To Cddmentioning

confidence: 99%

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Systemic Bcl‐2 antisense oligodeoxynucleotide in combination with cisplatin cures EBV⁺ nasopharyngeal carcinoma xenografts in SCID mice

Lacy

Loomis

Grill

et al. 2006

Intl Journal of Cancer

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Nasopharyngeal carcinoma (NPC) is causally linked to Epstein‐Barr virus (EBV), and the EBV oncoprotein, latent membrane protein 1 (LMP‐1), is expressed in the majority of NPCs. LMP‐1 upregulates antiapoptotic genes, including bcl‐2, and Bcl‐2 protein is overexpressed in NPC. Given the antiapoptotic and chemoprotective effects of Bcl‐2, it represents a rational therapeutic target in NPC. We have investigated the antitumor and chemosensitizing effects of the Bcl‐2 antisense oligodeoxynucleotide G3139 (oblimersen, Genasense) in NPC. For these studies, we used the C666‐1 line, a stably infected NPC‐derived line that co‐expresses LMP‐1 and Bcl‐2. We have shown that G3139 treatment of C666‐1 in vitro caused sequence‐dependent suppression of Bcl‐2 protein, inhibition of cell growth and enhanced sensitivity to cisplatin (CDDP), as measured by increased antiproliferative and apoptotic effects. In vivo, G3139 treatment (25 mg/kg every 3 days × 5 doses) delayed engraftment and significantly inhibited growth of established C666‐1 xenografts in SCID mice compared to control oligo‐treated animals. However, G3139 alone did not prevent engraftment or cure established tumors in any animals. In contrast, G3139 treatment (25 mg/kg every 3 days × 5 starting on day 7) in combination with CDDP (8 mg/kg on day 14) completely abrogated tumor engraftment in 80% of animals compared to CDDP (0%) or CDDP + control oligo (0%). When treatment was delayed until tumor was established, G3139 in combination with CDDP significantly inhibited tumor growth compared to CDDP or CDDP + control oligo, and cured 69% animals with established tumors. No animals treated with G3139, CDDP or CDDP + control oligo were cured. Tumor burden and response to treatment correlated with EBV DNA load in serum, measured by real‐time PCR. Western blots of tumor extracts obtained during oligo treatment showed that Bcl‐2 levels were significantly decreased in G3139‐treated animals. Our studies have demonstrated that the Bcl‐2 antisense oligodeoxynucleotide, G3139, has proapoptotic effects in C666‐1, and in combination with CDDP, is curative in C666‐1 NPC xenograft tumors in vivo. The sequence‐dependency of these effects is consistent with an antisense mechanism. These studies suggest that Bcl‐2 may represent a biologically relevant target for the development of novel combinatorial therapies for NPC. © 2006 Wiley‐Liss, Inc.

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Section: Discussionmentioning

confidence: 99%

Section: Epstein-barr Virus (Ebv) Is Causally Linked To Undifferentiamentioning

confidence: 99%

Section: G3139 Inhibits C666-1 Growth and Enhances Sensitivity To Cddmentioning

confidence: 99%

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Systemic Bcl‐2 antisense oligodeoxynucleotide in combination with cisplatin cures EBV⁺ nasopharyngeal carcinoma xenografts in SCID mice

Lacy

Loomis

Grill

et al. 2006

Intl Journal of Cancer

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“…In support of this argument, several reports have demonstrated that Bcl-2 protein expression cannot be activated by LMP-1 in human epithelial cell lines (Rowe et al, 1994) or in fibroblasts (Henderson et al, 1993). The finding supported that nasopharyngeal carcinoma (NPC) Bcl-2 expression can be independent of LMP-1 (Sarac et al, 2001), and that EBV up-regulation of apoptosis has no relation to Bcl-2 expression. In EBVassociated non-Hodgkin lymphomas, the T cell type is predominant (Takano et al, 1997), which corresponds to the finding (Kim et al, 2004) that EBV does not induce the up-regulation of Bcl-2 expression in classical Hodgkin's lymphoma.…”

Section: Lmp-1 Specifically Up-regulates Bcl-2 Expressionmentioning

confidence: 93%

Epstein-Barr virus interactions with the Bcl-2 protein family and apoptosis in human tumor cells

Mao

2013

J. Zhejiang Univ. Sci. B

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Epstein-Barr virus (EBV), a human gammaherpesvirus carried by more than 90% of the world's population, is associated with malignant tumors such as Burkitt's lymphoma (BL), Hodgkin lymphoma, post-transplant lymphoma, extra-nodal natural killer/T cell lymphoma, and nasopharyngeal and gastric carcinomas in immune-compromised patients. In the process of infection, EBV faces challenges: the host cell environment is harsh, and the survival and apoptosis of host cells are precisely regulated. Only when host cells receive sufficient survival signals may they immortalize. To establish efficiently a lytic or long-term latent infection, EBV must escape the host cell immunologic mechanism and resist host cell apoptosis by interfering with multiple signaling pathways. This review details the apoptotic pathway disrupted by EBV in EBV-infected cells and describes the interactions of EBV gene products with host cellular factors as well as the function of these factors, which decide the fate of the host cell. The relationships between other EBV-encoded genes and proteins of the B-cell leukemia/lymphoma (Bcl) family are unknown. Still, EBV seems to contribute to establishing its own latency and the formation of tumors by modifying events that impact cell survival and proliferation as well as the immune response of the infected host. We discuss potential therapeutic drugs to provide a foundation for further studies of tumor pathogenesis aimed at exploiting novel therapeutic strategies for EBV-associated diseases.

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“…Otro indicador específico de la presencia del VEB en el CNF es la expresión de EBER, debido a que no se detecta en epitelios respiratorio y nasofaríngeo normales, ni en tejido adyacente al tumor (45 Las LMP-1 y -2 también se han identificado en CNF, aunque existe controversia con respecto a su expresión por la marcada variabilidad entre los resultados de diversos estudios (47,48). La expresión de LMP-1 es más uniforme en etapas tempranas del CNF y en carcinoma in situ, lo que sugiere que esta proteína puede facilitar la progresión de la enfermedad (49), debido a que concentraciones bajas de la proteína son suficientes para inducir cambios morfológicos y fenotipos invasivos en células de CNF in vitro (50,51).…”

Section: Veb Y Carcinoma Nasofaríngeo (Cnf)unclassified

Virus de Epstein-Barr y su relación con el desarrollo del cáncer

Medina-Ortega

López-Valencia

Mosquera-Monje

et al. 2017

iatreia

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RESUMENEl virus de Epstein-Barr (VEB) es un agente infeccioso que tiene tropismo por células linfoides y ocasionalmente por células epiteliales. La Agencia Internacional para la Investigación sobre Cáncer (IARC, por su sigla en inglés) lo clasificó hace 20 años como carcinógeno de tipo I, porque durante la infección latente expresa diferentes proteínas o micro-ARN con capacidad oncogénica, por lo que las células infectadas tendrían el potencial de desarrollar cáncer. Esto se ha demostrado en algunos tipos de cáncer como linfomas, carcinoma nasofaríngeo y cán-cer gástrico, mientras que la asociación no es completamente clara en los cánceres de mama y pulmón. La presente revisión describe, profundiza y analiza la relación del VEB con dichos tipos de cáncer, así como los métodos diagnósticos empleados para su detección. Finalmente, se plantean preguntas cuyas respuestas podrían contribuir al conocimiento de los mecanismos moleculares involucrados en la relación VEB-cáncer. PALABRAS CLAVE

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Bcl-2 and LMP1 expression in nasopharyngeal carcinomas

Cited by 41 publications

References 16 publications

Systemic Bcl‐2 antisense oligodeoxynucleotide in combination with cisplatin cures EBV⁺ nasopharyngeal carcinoma xenografts in SCID mice

Systemic Bcl‐2 antisense oligodeoxynucleotide in combination with cisplatin cures EBV⁺ nasopharyngeal carcinoma xenografts in SCID mice

Epstein-Barr virus interactions with the Bcl-2 protein family and apoptosis in human tumor cells

Virus de Epstein-Barr y su relación con el desarrollo del cáncer

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Bcl-2 and LMP1 expression in nasopharyngeal carcinomas

Cited by 41 publications

References 16 publications

Systemic Bcl‐2 antisense oligodeoxynucleotide in combination with cisplatin cures EBV+ nasopharyngeal carcinoma xenografts in SCID mice

Systemic Bcl‐2 antisense oligodeoxynucleotide in combination with cisplatin cures EBV+ nasopharyngeal carcinoma xenografts in SCID mice

Epstein-Barr virus interactions with the Bcl-2 protein family and apoptosis in human tumor cells

Virus de Epstein-Barr y su relación con el desarrollo del cáncer

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Product

Resources

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Systemic Bcl‐2 antisense oligodeoxynucleotide in combination with cisplatin cures EBV⁺ nasopharyngeal carcinoma xenografts in SCID mice

Systemic Bcl‐2 antisense oligodeoxynucleotide in combination with cisplatin cures EBV⁺ nasopharyngeal carcinoma xenografts in SCID mice