Cell cycle arrest and apoptosis induced by O-acetyl-GD2-specific monoclonal antibody 8B6 inhibits tumor growth in vitro and in vivo

Cochonneau, Denis; Terme, Mickaël; Michaud, Alexis; Dorvillius, Mylène; Gautier, Nicolas; Frikeche, Jihane; Alvarez-Rueda, Nidia; Bougras, Gwenola; Aubry, Jacques; Pâris, François; Birklé, Stéphane

doi:10.1016/j.canlet.2013.01.032

Cited by 37 publications

(57 citation statements)

References 33 publications

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“…Moreover, the Aurora A kinase binding partners: P53, PHLDA1 and MYCN, were either upregulated as in case of P53 and PHLDA1, or downregulated (MYCN) in the 14G2a mAb-treated IMR-32 and CHP-134 human neuroblastoma cells contributing to the observed decrease in cell viability (9). Finally, Cochonneau et al, demonstrated that an O-acetyl-GD2 ganglioside specific mAb treatment inhibited tumor growth of IMR-5 neuroblastoma cells in vivo in a NOD/SCID mouse model in the absence of operating ADCC and CDC mechanisms (10).…”

Section: Introductionmentioning

confidence: 98%

GD2 ganglioside specific antibody treatment downregulates PI3K/Akt/mTOR signaling network in human neuroblastoma cell lines

Durbas

Horwacik

Boratyn

et al. 2015

International Journal of Oncology

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Abstract. Mechanisms leading to inhibitory effects of an anti-GD2 ganglioside (GD2) 14G2a mouse monoclonal antibody (mAb) and PI3K/Akt/mTOR pathway inhibitors on human neuroblastoma cell survival were studied in vitro. We have recently shown on IMR-32, CHP-134, and LA-N-1 neuroblastoma cells that targeting GD2 with the mAb decreases cell viability of the cell lines. In this study we used cytotoxicity assays, proteomic arrays and immunoblotting to evaluate the response of the three cell lines to the anti-GD2 14G2a mAb and specific PI3K/Akt/mTOR pathway inhibitors. We show here that the mAb modulates intracellular signal transduction through changes in several kinases and their substrates phosphorylation. More detailed analysis of the PI3K/Akt/ mTOR pathway showed significant decrease in activity of Akt, mTOR, p70 S6 and 4E-BP1 proteins and transient increase in PTEN (a suppressor of the pathway), leading to inhibition of the signaling network responsible for stimulation of translation and proliferation. Additionally, combining the GD2-specific 14G2a mAb with an Akt inhibitor (perifosine), dual mTOR/PI3K inhibitors (BEZ-235 and SAR245409), and a pan-PI3K inhibitor (LY294002) was shown to enhance cytotoxic effects against IMR-32, CHP-134 and LA-N-1 cells. Our study extends knowledge on mechanisms of action of the 14G2a mAb on the neuroblastoma cells. Also, it stresses the need for further delineation of molecular signal orchestration aimed at more reasonable selection of drugs to target key cellular pathways in quest for better cure for neuroblastoma patients.

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Section: Introductionmentioning

confidence: 98%

GD2 ganglioside specific antibody treatment downregulates PI3K/Akt/mTOR signaling network in human neuroblastoma cell lines

Durbas

Horwacik

Boratyn

et al. 2015

International Journal of Oncology

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“…Thus, GD2 positive and 8B6, 10B8-treated IMR-32, IMR-5, H82, EL4 cells were binding an Apo2.7-PE antibody, when analyzed by flow cytometry, and this correlated with a cycle arrest of the cells and increase in P21 protein levels [46]. Additionally, expression of apoptosis-associated proteins such as BAX, cytochrome c in a cytoplasm, active caspase-3, phospho-P38 was shown by western blotting in the 8B6, 10B8-treated EL4 cells [46].…”

Section: Characterization Of Cell Death Induced With Gangliosidespecimentioning

confidence: 85%

“…In animals treated with either PBS or control antibody 4F6 (IgG3) no therapeutic effects were measured. It should be highlighted that the NOD/SCID mice do not mount CDC and ADCC responses, as the animals do not have T and B cells, circulating complement and activity of NK cell, thus suggesting that the observed effects of 8B6 and 10B6 administration were operating without the immunological mechanisms [46]. Based on the above publications, we can conclude that there are numerous examples of ganglioside-binding antibodies that show inhibitory effects on tumor cells overexpressing the antigens.…”

Section: Targeting ''B''-series Gangliosides With Monoclonal Antibodiesmentioning

confidence: 85%

“…In 2013, Cochonneau et al proved that the two mAb inhibit cell proliferation of IMR-5, IMR-32 human neuroblastoma cells and H82 human SCLC cells [46]. Moreover, the authors reported that a single 500 lg dose of the 8B6 mAb administered intravenously to NOD/ SCID mice, bearing subcutaneously established IMR-5 tumors of ca.…”

Section: Targeting ''B''-series Gangliosides With Monoclonal Antibodiesmentioning

confidence: 97%

“…Marked shrinkage of cytoplasm was reported in cultures of the mAb-treated GD2-positive D-18, but not negative C-8 cells (40 lg/ml of the mAb was used for 12 h) [43]. Moreover, some researchers showed inhibition of growth or invasion [46][47][48], DNA laddering (a result of oligonucleosomal DNA fragmentation) [40,43] and activation of caspases [43][44][45][46]49] in the cells treated with ganglioside-specific mAbs (see Fig. 1).…”

Section: Characterization Of Cell Death Induced With Gangliosidespecimentioning

confidence: 99%

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Targeting of tumor-associated gangliosides with antibodies affects signaling pathways and leads to cell death including apoptosis

Horwacik

Rokita

2015

Apoptosis

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Gangliosides are a diverse group of sialic acid containing glycosphigolipids that are abundantly present in an outer plasma membrane of some cells. Biological roles of gangliosides and other lipids in cell fate regulation are being extensively studied. Gangliosides are well known to be involved in interactions between cells and in signal transduction to regulate growth, adhesion and motility. Moreover, many gangliosides are tumor-associated antigens over-expressed on several tumor types. As a result, monoclonal antibodies binding gangliosides can be used to diagnose, monitor and to treat cancer patients. In the review, we gather and discuss data of various research groups on direct cytotoxic effects elicited by several ganglioside-specific antibodies, which bind to GM2, N-acetyl-GM2, N-glycolyl-GM2, GM3, GD3, GD2, O-acetyl-GD2, without involvement of immunological mechanisms. Thus, in cultures of numerous human and mouse cancer cell lines, the antibodies were reported to cause morphological changes, aggregation and detachment of cells, inhibition of proliferation and cell death involving necrosis, apoptosis and oncosis-like mechanisms. Additionally, data on proteome alterations were reviewed that encompass, among others, changes in kinome (P38, JNK, c-MET, ERK1/2, PI3K, AKT, FAK, aurora A, B, C), protein levels of transcription factors (P53, MYCN, HSF1) and pro-apoptotic proteins (caspase 3, BAX). Next, we collected data on application of the antibodies to enhance cytotoxicity of chemotherapeutic drugs and small molecule inhibitors. Finally, further research perspectives on the topic are discussed.

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Gangliosides and Tumor-Associated Ganglioside (TAG) Modulate Receptor-Tyrosine Kinases (RTKs)

Kim

2020

Ganglioside Biochemistry

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Cell cycle arrest and apoptosis induced by O-acetyl-GD2-specific monoclonal antibody 8B6 inhibits tumor growth in vitro and in vivo

Cited by 37 publications

References 33 publications

GD2 ganglioside specific antibody treatment downregulates PI3K/Akt/mTOR signaling network in human neuroblastoma cell lines

GD2 ganglioside specific antibody treatment downregulates PI3K/Akt/mTOR signaling network in human neuroblastoma cell lines

Targeting of tumor-associated gangliosides with antibodies affects signaling pathways and leads to cell death including apoptosis

Gangliosides and Tumor-Associated Ganglioside (TAG) Modulate Receptor-Tyrosine Kinases (RTKs)

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