Rituximab inhibits p38 MAPK activity in 2F7 B NHL and decreases IL-10 transcription: Pivotal role of p38 MAPK in drug resistance

Vega, Mario I.; Huerta-Yepaz, Sara; Garbán, Hermes; Jazirehi, Ali R.; Emmanouilides, Christos; Bonavida, Benjamin

doi:10.1038/sj.onc.1207336

Cited by 128 publications

(120 citation statements)

References 42 publications

(41 reference statements)

Supporting

Mentioning

105

Contrasting

Unclassified

Order By: Relevance

“…Subsequent investigations have confirmed synergy of rituximab with fludarabine, doxorubicin and other anticancer drugs (Alas et al, 2000;Alas and Bonavida, 2001;Ghetie et al, 2001). In one hypothesis, this synergism is mediated, at least in part, via downregulation of interleukin-10 (IL-10) by rituximab, which in turn causes downregulation of the antiapoptotic protein bcl2 and increased sensitivity to apoptosis (Vega et al, 2004). Another mechanism involves the inhibition of the activity of P-glycoprotein and, thus, the efflux of drugs like doxorubicin or vincristine (Ghetie et al, 2006).…”

Section: Mechanisms Of Action Of Rituximabmentioning

confidence: 96%

Rituximab therapy in malignant lymphoma

2007

View full text Add to dashboard Cite

Section: Mechanisms Of Action Of Rituximabmentioning

confidence: 96%

Rituximab therapy in malignant lymphoma

2007

View full text Add to dashboard Cite

“…Elevated levels of activated MAP kinase have been observed in a variety of solid tumors and hematologic malignancies, and MAP kinases may be important in the development of new therapeutic approaches (2,20). The anti-CD20 monoclonal antibody rituximab triggers and modifies various intracellular signaling pathways in NHL B-cell lines, resulting in the induction of apoptosis and chemosensitization (2,21,22). Alas et al (18) reported that rituximab downregulated tumor-derived IL-10 transcription and subsequently down-regulated Bcl-2 gene expression.…”

Section: Discussionmentioning

confidence: 99%

“…The standard treatment for NHL is chemotherapy. However, relapse eventually occurs and subsequent failure of chemotherapy to control cancer has prompted the development of alternative therapies (2). Mounting evidence shows that adoptive immunotherapy with genetically modified T cells expressing chimeric T-cell receptors targeting lymphoma-associated antigens is a promising approach for treating this group of diseases.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of p38 MAPK activity in B-NHL Raji cells by treatment with engineered CD20-specific T cells

Jiang

Kang

et al. 2011

Oncology Letters

View full text Add to dashboard Cite

Abstract. Adoptive immunotherapy with T cells expressing CD20-specific chimeric T-cell receptors is a promising approach to lymphoma therapy. However, modification of the cellular signaling pathways in target tumor cells by treatment with engineered CD20-specific T cells has yet to be fully elucidated. In this study, the non-Hodgkin's lymphoma Raji cell line was co-cultured with T cells that were genetically modified with anti-CD20scFvFc/CD28/CD3ζ or anti-CD20scFvFc gene. The cytolytic activity of engineered CD20-specific T cells and IL-10 secretion was quantitated by Cytotoxicity and ELISA assays, respectively. The engineered CD20-specific T cells and Raji cells were sorted using flow cytomety for the Western blot analysis. Treatment of Raji cells with T cells genetically modified with anti-CD20scFvFc/CD28/CD3ζ chimera (compared to anti-CD20scFvFc) yielded a higher cytotoxicity against Raji cells in vitro. Additionally, we found that engineered CD20-specific T cells caused a decrease in IL-10 secretion and inhibition of phosphor-STAT3 and Bcl-2 expression in Raji cells, possibly through the down-regulation of p38 MAPK and NF-κB activity. These results indicate that the treatment of Raji cells with engineered CD20-specific T cells inhibited the cellular p38 MAPK signaling pathways, which enhanced its antitumor activities against CD20-positive tumor cells.

show abstract

“…The observed upregulation of proapoptotic RKIP in situ during rituximab therapy is likely to represent the direct intracellular signalling properties of rituximab (Vega et al, 2004;Jazirehi and Bonavida, 2005). RKIP belongs to the family of the metastasis suppressor genes, which inhibit cellular proliferation, growth and metastatic spread and induce apoptosis (Keller et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, the relapsed CBCL in our patient cohort responded to other subsequent treatment modalities despite upregulation of bcl-2. Sensitisation to subsequent therapy may be conveyed by a counteracting downregulation of other antiapoptotic proteins by rituximab signalling; in this context, the observed increased expression of RKIP may be of importance, as it also functions as a negative regulator of antiapoptotic bcl-xL (Vega et al, 2004;Jazirehi and Bonavida, 2005). Hence, a complex network of interacting regulators of apoptosis is likely to be influenced by rituximab and the balance between pro-and antiapoptotic factors may determine the clinical outcome.…”

Section: Discussionmentioning

confidence: 99%

Bcl-2 expression in rituximab refractory cutaneous B-cell lymphoma

et al. 2007

View full text Add to dashboard Cite

Rituximab has been established as an effective and safe therapy for cutaneous B-cell lymphoma (CBCL). Different survival pathways, that is the Raf/MEK/Erk-or the p38MAPK cascade, have been suggested as downstream mediators of rituximab and may be involved in treatment failure. Biopsies from four patients, suffering from different subtypes of CBCL, which were obtained at various time points of relapse during or after therapy with 375 mg rituximab per m 2 of body surface area, were analysed for the expression of CD20, CD3, Ki-67, Raf-kinase inhibitory protein (RKIP) and bcl-2 by immunohistochemistry. No CD20-loss variants, that is the suggested main tumour escape mechanism to rituximab therapy, were observed in any specimen of relapsing CBCL. Notably, the expression of proapoptotic RKIP remained increased in these tumour samples. This was concomitated by a constant to slightly reduced proliferation status as demonstrated by Ki-67 staining. However, relapsing CBCL exhibited a strong upregulation of the antiapoptotic molecule bcl-2 in comparison to pretherapeutic levels. The immunohistochemical analyses of this case series of rituximab refractory CBCL suggest that upregulation of bcl-2 may play a major role in therapy resistance. The exact in vivo mechanisms of rituximab still remain elusive but likely include antibody-dependent cellular cytotoxicity (ADCC), complement-mediated lysis (CDC) and immune responses (Reff et al, 1994;Selenko et al, 2001). Furthermore, rituximab inhibits crucial survival pathways by upregulating the Raf-kinase inhibitory protein (RKIP), thus directly modifying the extracellular signal-regulated kinase1/2-and nuclear factor-k B, respectively (Jazirehi and Bonavida, 2005).Despite a high initial response rate, local or distant recurrence of CBCL is frequently observed in rituximab therapy. To delineate possible factors predicting or being associated with relapse, we scrutinised recurrent CBCL from four patients before, during and after systemic rituximab therapy. PATIENTS AND METHODS Patient characteristicsFour patients with multifocal CBCL (classified according to the WHO-EORTC classification for primary cutaneous lymphoma (Willemze et al, 2005)) were treated with rituximab intravenously at doses of 375 mg m À2 body surface area at

show abstract

Rituximab inhibits p38 MAPK activity in 2F7 B NHL and decreases IL-10 transcription: Pivotal role of p38 MAPK in drug resistance

Cited by 128 publications

References 42 publications

Rituximab therapy in malignant lymphoma

Rituximab therapy in malignant lymphoma

Inhibition of p38 MAPK activity in B-NHL Raji cells by treatment with engineered CD20-specific T cells

Bcl-2 expression in rituximab refractory cutaneous B-cell lymphoma

Contact Info

Product

Resources

About