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Zhao F.,Xuzhou Medical College | Wang H.,Poten Biomedical Institute for Cancer Immunotherapy | Kunda P.,Poten Biomedical Institute for Cancer Immunotherapy | Chen X.,Poten Biomedical Institute for Cancer Immunotherapy | And 3 more authors.
Oncology Reports | Year: 2013

Retinoblastoma (RB) is an intraocular cancer that affects young children. There is an ongoing effort to find new agents for RB management that are effective, specific and with few side-effects. In the present study, we tested artesunate (ART), a synthetic derivative from the herbal drug artemisinin, used in the clinic for the treatment of malaria. We analyzed ART cytotoxicity in an RB cell line (RB-Y79) and in a retinal epithelial cell line (hTERT-RPE1) by flow cytometric analysis (FCM). We related the effect of ART to the expression of transferrin receptor 1 (TfR-1, also known as CD71) by knocking down CD71 with RNAi and analyzing cell cycle variables by FCM. We found that the cytotoxic action of ART is specific for RB cells in a dose-dependent manner, with low toxicity in normal retina cells. ART is more effective in RB than carboplatin with a markedly strong cytotoxic effect on carboplatin-resistant RB cells. RB had higher CD71 levels at the membrane compared to normal retinal cells. We showed that ART internalization in RB cells is dependent upon the expression of the CD71. In addition, ART blocked the cell cycle progression at the G1 phase, even at low doses, and decreased the proportion of RB cells in the S phase. In conclusion, we showed that ART is a promising drug exhibiting high selective cytotoxicity even against multidrug-resistant RB cells. Thus, we suggest that ART could be used in the treatment of RB. Source

Wang Y.-F.,Xinxiang Medical University | Kunda P.E.,Poten Biomedical Institute for Cancer Immunotherapy | Lin J.-W.,Poten Biomedical Institute for Cancer Immunotherapy | Wang H.,Poten Biomedical Institute for Cancer Immunotherapy | And 3 more authors.
Oncology Reports | Year: 2013

Retinoblastoma (RB) is a challenging disease that affects mostly young children. Chemical therapy has been shown to have limitations during clinical practice, principally because of the ability of RB to become resistant to the treatment. Nevertheless, chemotherapy is still the main treatment for RB, and immunotherapy has become a promising treatment for most solid tumors with fewer side effects than traditional therapies. In this study, we explored the antitumor effects of cytokine-induced killer (CIK) cells co-cultured with dendritic cells (DCs) pulsed with complete tumor antigens (DC-Ag). Cytotoxicity and specificity were evaluated on an RB cell line (RB-Y79), on a human normal retina cell line (hTERT-RPE1) and a carboplatin-resistant RB cell line. Our results showed that CIK differentiation and cytotoxicity were enhanced by co-culturing CIKs with DC-Ag. Moreover, the co-culture improved the CIK proliferation rate by increasing IL-6 and decreasing IL-10 levels in the culture medium. Furthermore, the use of DC-Ag-CIK cells had little effect on normal retinal cells but high cytotoxicity on RB cells even on carboplatin-resistant retinoblastoma cells. This is the first study showing that DC cells pulsed with the complete tumor antigen improve proliferation, differentiation and cytotoxic activity of CIKs specific not only for RB but also for the chemotherapy- resistant form of the malady. Thus highly efficient immunotherapy based on DC-Ag-CIK cells may be a potential effective and safe mean of treating RB especially to patients where traditional chemical therapy has failed. Source

Liu Q.,General Hospital of the Chinese Peoples Armed Police Forces | Wang Y.,General Hospital of the Chinese Peoples Armed Police Forces | Wang Y.,Xinxiang Medical University | Wang H.,Poten Biomedical Institute for Cancer Immunotherapy | And 3 more authors.
Journal of Cancer Research and Clinical Oncology | Year: 2013

Purpose: The goal of this study was to provide an experimental basis for the clinical application of cell immunotherapy on RB in combination with chemotherapy treatment and to explore the mechanism of their combined cytotoxicity. Methods: We investigated the antitumor effect of cytokine-induced killer cells (CIK), co-cultivated with dendritic cells pulsed with tumor antigens (DC-Ag) and/or with carboplatin. Cytotoxicity was evaluated on a retinoblastoma cell line (RB-Y79) by FCM and immunofluorescence microscopy. Time-lapse video microscopy was used to follow the sequence of events during the carboplatin and CIK cytotoxicity. Results: Our results showed that a small proportion of RB-Y79 cells died after a low-dose carboplatin application. The cell population recovered 5 days after carboplatin was removed from the culture medium. Three times fewer normal epithelium retina cell lines (hTERT-RPE1) died at the same carboplatin dose. CIK achieved 5 times more cytotoxicity against RB cells pre-treated with low dose of carboplatin, showing the highest antitumor activity in the tandem carboplatin-DC-Ag-CIK-carboplatin treatment. Time-lapse video microscopy revealed that carboplatin-preconditioned RB cells are more avidly engaged by CIK cells, increasing RB mortality and resulting in an overall increment in apoptosis. Conclusion: This study provides evidence that carboplatin combined with cell immunotherapy is superior to carboplatin alone to kill RB cells in vitro. We propose that a primary application of a low dose of a chemotherapeutic drug that is able to attack the tumor, and a subsequent treatment with highly effective immunotherapy based on DC-Ag-CIK cells could be a safe and selective treatment for RB. © 2013 Springer-Verlag Berlin Heidelberg. Source

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