Dataset Information

Neuroblastoma chemotherapy can be augmented by immunotargeting O-acetyl-GD2 tumor-associated ganglioside.

ABSTRACT: Despite recent advances in high-risk neuroblastoma therapy, the prognosis for patients remains poor. In addition, many patients suffer from complications related to available therapies that are highly detrimental to their quality of life. New treatment modalities are, thus, urgently needed to further improve the efficacy and reduce the toxicity of existing therapies. Since antibodies specific for O-acetyl GD2 ganglioside display pro-apoptotic activity against neuroblastoma cells, we hypothesized that combination of immunotherapy could enhance tumor efficacy of neuroblastoma chemotherapy. We demonstrate here that combination of anti-O-acetyl GD2 monoclonal antibody 8B6 with topotecan synergistically inhibited neuroblastoma cell proliferation, as shown by the combination index values. Mechanistically, we evidence that mAb 8B6 induced plasma cell membrane lesions, consistent with oncosis. Neuroblastoma tumour cells treated with mAb 8B6 indeed showed an increased uptake of topotecan by the tumor cells and a more profound tumor cell death evidenced by increased caspase-3 activation. We also found that the combination with topotecan plus monoclonal antibody 8B6 showed a more potent anti-tumor efficacy in vivo than either agent alone. Importantly, we used low-doses of topotecan with no noticeable side effect. Our data suggest that chemo-immunotherapy combinations may improve the clinical efficacy and safety profile of current chemotherapeutic modalities of neuroblastoma.

SUBMITTER: Faraj S

PROVIDER: S-EPMC5739551 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Neuroblastoma chemotherapy can be augmented by immunotargeting O-acetyl-GD2 tumor-associated ganglioside.

Faraj S S Bahri M M Fougeray S S El Roz A A Fleurence J J Véziers J J Leclair M D MD Thébaud E E Paris F F Birklé S S

Oncoimmunology 20170921 1

Despite recent advances in high-risk neuroblastoma therapy, the prognosis for patients remains poor. In addition, many patients suffer from complications related to available therapies that are highly detrimental to their quality of life. New treatment modalities are, thus, urgently needed to further improve the efficacy and reduce the toxicity of existing therapies. Since antibodies specific for O-acetyl GD2 ganglioside display pro-apoptotic activity against neuroblastoma cells, we hypothesized ...[more]

PMID: 29296527

Similar Datasets

Project description:BackgroundGanglioside GD2 is expressed on plasma membranes of various types of malignant cells. One of the most promising approaches for cancer immunotherapy is the treatment with monoclonal antibodies recognizing tumor-associated markers such as ganglioside GD2. It is considered that major mechanisms of anticancer activity of anti-GD2 antibodies are complement-dependent cytotoxicity and/or antibody-mediated cellular cytotoxicity. At the same time, several studies suggested that anti-GD2 antibodies are capable of direct induction of cell death of number of tumor cell lines, but it has not been investigated in details. In this study we investigated the functional role of ganglioside GD2 in the induction of cell death of multiple tumor cell lines by using GD2-specific monoclonal antibodies.MethodsExpression of GD2 on different tumor cell lines was analyzed by flow cytometry using anti-GD2 antibodies. By using HPTLC followed by densitometric analysis we measured the amount of ganglioside GD2 in total ganglioside fractions isolated from tumor cell lines. An MTT assay was performed to assess viability of GD2-positive and -negative tumor cell lines treated with anti-GD2 mAbs. Cross-reactivity of anti-GD2 mAbs with other gangliosides or other surface molecules was investigated by ELISA and flow cytometry. Inhibition of GD2 expression was achieved by using of inhibitor for ganglioside synthesis PDMP and/or siRNA for GM2/GD2 and GD3 synthases.ResultsAnti-GD2 mAbs effectively induced non-classical cell death that combined features of both apoptosis and necrosis in GD2-positive tumor cells and did not affect GD2-negative tumors. Anti-GD2 mAbs directly induced cell death, which included alteration of mitochondrial membrane potential, induction of apoptotic volume decrease and cell membrane permeability. This cytotoxic effect was mediated exclusively by specific binding of anti-GD2 antibodies with ganglioside GD2 but not with other molecules. Moreover, the level of GD2 expression correlated with susceptibility of tumor cell lines to cytotoxic effect of anti-GD2 antibodies.ConclusionsResults of this study demonstrate that anti-GD2 antibodies not only passively bind to the surface of tumor cells but also directly induce rapid cell death after the incubation with GD2-positive tumor cells. These results suggest a new role of GD2 as a receptor that actively transduces death signal in malignant cells.

Dataset Information

Neuroblastoma chemotherapy can be augmented by immunotargeting O-acetyl-GD2 tumor-associated ganglioside.

Publications

Neuroblastoma chemotherapy can be augmented by immunotargeting O-acetyl-GD2 tumor-associated ganglioside.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets