Validation of Enhancing Effects of Curcumin on Radiotherapy with F98/FGT Glioblastoma-Bearing Rat Model
姜黄素对 F98/FGT 胶质母细胞瘤大鼠模型放疗增强作用的验证
- 作者列表："Wei-Hsun Wang","Chao-Yu Shen","Yi-Chun Chien","Wen-Shin Chang","Chia-Wen Tsai","Yi-Hsien Lin","Jeng-Jong Hwang
Glioblastoma, the most common and aggressive brain tumor with low survival rate, is difficult to be cured by neurosurgery or radiotherapy. Mounting evidence has reported the anti-inflammatory and anticancer effects of curcumin on several types of cancer in preclinical studies and clinical trials. To our knowledge, there is no platform or system that could be used to effectively and real-timely evaluate the therapeutic efficacy of curcumin for glioblastoma multiforme (GBM). In this study, we constructed a lentivirus vector with triple-reporter genes (<i>Fluc</i>/<i>GFP</i>/<i>tk</i>) and transduced into rat F98 glioblastoma cells to establish an orthotopic F98/<i>FGT</i> glioma-bearing rat model. In the model, the therapeutic efficacies for curcumin alone, radiation alone, and their combination were evaluated via noninvasive bioluminescent imaging and overall survival measurements. At the cell level, curcumin is capable of causing a G2/M cell cycle arrest and sensitizing the F98 cells to radiation. In animal model, curcumin synergistically enhances the effects of radiotherapy on suppressing the growth of both transplanted glioma cells and in situ brain tumors, and extending the overall survival periods longer than those of curcumin alone and radiation alone treatments. In conclusion, we have demonstrated that curcumin may serve as a novel radiosensitizer to combine with radiotherapy using the triple-reporter F98/<i>FGT</i> animal model for effective and simultaneous evaluation of therapeutic efficacy.
胶质母细胞瘤是最常见、最具侵袭性的脑肿瘤，生存率低，很难通过神经外科手术或放疗治愈。越来越多的证据报道了姜黄素在临床前研究和临床试验中对几种类型的癌症的抗炎和抗癌作用。据我们所知，目前尚无平台或系统可用于有效、实时评价姜黄素对多形性胶质母细胞瘤 (GBM) 的治疗效果。在这项研究中,我们构建了一个含有三个报告基因的慢病毒载体 (<i>Fluc</i>/<i>GFP</i>/<i>tk</i>) 并转导入大鼠 F98 胶质母细胞瘤细胞，建立原位 F98/<i>FGT</i> 荷胶质瘤大鼠模型。在模型中，通过无创生物发光成像和总生存测量评价姜黄素单独、单独放疗及其联合的治疗效果。在细胞水平上，姜黄素能够引起 G2/M 期细胞周期阻滞，并使 F98 细胞对辐射敏感。在动物模型中，姜黄素协同增强放疗对抑制移植胶质瘤细胞和原位脑肿瘤生长的作用,延长总生存期比单独使用姜黄素和放射治疗更长。总之,我们已经证明姜黄素可以作为一种新的放射增敏剂与放疗结合，使用三重报告 F98/<i>FGT</i> 动物模型来有效和同时评价治疗疗效。
METHODS::Chimeric antigen receptor (CAR) T cells are a novel class of anti-cancer therapy in which autologous or allogeneic T cells are engineered to express a CAR targeting a membrane antigen. In Europe, tisagenlecleucel (Kymriah™) is approved for the treatment of refractory/relapsed acute lymphoblastic leukemia in children and young adults as well as relapsed/refractory diffuse large B-cell lymphoma, while axicabtagene ciloleucel (Yescarta™) is approved for the treatment of relapsed/refractory high-grade B-cell lymphoma and primary mediastinal B-cell lymphoma. Both agents are genetically engineered autologous T cells targeting CD19. These practical recommendations, prepared under the auspices of the European Society of Blood and Marrow Transplantation, relate to patient care and supply chain management under the following headings: patient eligibility, screening laboratory tests and imaging and work-up prior to leukapheresis, how to perform leukapheresis, bridging therapy, lymphodepleting conditioning, product receipt and thawing, infusion of CAR T cells, short-term complications including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, antibiotic prophylaxis, medium-term complications including cytopenias and B-cell aplasia, nursing and psychological support for patients, long-term follow-up, post-authorization safety surveillance, and regulatory issues. These recommendations are not prescriptive and are intended as guidance in the use of this novel therapeutic class.
METHODS:The aim of the present study was to explore the possible mechanisms of phosphatase and tensin homolog (PTEN) in the pathogenesis of Burkitt's lymphoma, and provide novel information that can be used in the targeted treatment of this disease. PTEN lentiviral overexpression vector and short‑hairpin PTEN silencing vectors were constructed. The effect of PTEN on the growth and proliferation of CA46 and RAJI cells was analyzed using a Cell Counting Kit‑8 assay. Apoptosis was detected by Hoechst 33342 and propidium iodide double staining. Flow cytometry was used to analyze the cell cycle. A Transwell chamber was used to detect cell migration and invasion abilities. Western blot analysis was used to detect related protein changes. The mechanism of the effect of PTEN on the biological characteristics of Burkitt's lymphoma cells was subsequently analyzed. The results revealed that PTEN inhibited the proliferation of CA46 and RAJI cells by downregulating the expression of p‑AKT, It was indicated that the upregulation of proapoptotic proteins (including Bad and Bax) induced apoptosis, regulated cyclin (including P53, P21, CDK4, CDK6, cyclin D3 and cyclin H) to inhibit cell cycle progression, and mediated epithelial‑mesenchymal transition‑like cell markers (including E‑cadherin, N‑cadherin, β‑catenin, TCF‑8, vimentin, Slug and Snail) to inhibit cell migration and invasion. In conclusion, the tumor‑suppressor gene PTEN inhibited the phosphoinositide 3‑kinase/protein kinase B (PI3K/AKT) signaling pathway and inhibited the proliferation and migration of Burkitt's lymphoma cells, induced apoptosis and cell cycle arrest, thus playing a crucial role in the pathogenesis of Burkitt's lymphoma.
METHODS:Melatonin (Mel) has been shown to involve in many essential cell functions via modulating many signaling pathways. We for the first time investigated that Mel exerted anti-tumor activities in Hodgkin lymphoma (HL) via inhibiting cell proliferation and promoting cell apoptosis. Further study revealed that Mel treatment increased expression of LC3-II and decreased p62 proteins with the enhanced production of autolysosome, indicating it induced activation of autophagy. Nevertheless, Mel treatment together with autophagy inhibitors 3-MA or CQ exacerbated the damage effect of Mel in HL cells, which means autophagy plays a protective role in this process. Furthermore, we found Mel treatment increased the expression of G protein-coupled receptors MT2 and retinoic acid-related orphan receptors (RORs), eg. RORA, RORB and RORC. While RORC has the highest increase in Mel treated HL cells. In addition, RORC overexpression induced autophagy activation. Therefore, Mel showed tumor-suppressive role due to an increased level of RORC induced autophagy in HL.