Cocktail hepatocarcinoma therapy by a super-assembled nano-pill targeting XPO1 and ATR synergistically / 药物分析学报

Intensive cancer treatment with drug combination is widely exploited in the clinic but suffers from inconsistent pharmacokinetics among different therapeutic agents.To overcome it,the emerging nanomedicine offers an unparalleled opportunity for encapsulating multiple drugs in a nano-carrier.Herein,a two-step super-assembled strategy was performed to unify the pharmacokinetics of a pep-tide and a small molecular compound.In this proof-of-concept study,the bioinformatics analysis firstly revealed the potential synergies towards hepatoma therapy for the associative inhibition of exportin 1(XPO1)and ataxia telangiectasia mutated-Rad3-related(ATR),and then a super-assembled nano-pill(gold nano drug carrier loaded AZD6738 and 97-110 amino acids of apoptin(AP)(AA@G))was con-structed through camouflaging AZD6738(ATR small-molecule inhibitor)-binding human serum albumin onto the AP-Au supramolecular nanoparticle.As expected,both in vitro and in vivo experiment results verified that the AA@G possessed extraordinary biocompatibility and enhanced therapeutic effect through inducing cell cycle arrest,promoting DNA damage and inhibiting DNA repair of hepatoma cell.This work not only provides a co-delivery strategy for intensive liver cancer treatment with the clinical translational potential,but develops a common approach to unify the pharmacokinetics of peptide and small-molecular compounds,thereby extending the scope of drugs for developing the advanced com-bination therapy.

The Latest Research Progress of Selinexor in the Treatment of Non-Hodgkin Lymphoma --Review / 中国实验血液学杂志

Non-Hodgkin lymphoma (NHL) is a common lymphoid hematological malignancy, the treatment and prognosis of NHL have always been the focus of clinical attention. Chemotherapy is the main first-line treatment, but there is still no effective treatment for patients with poor response to chemotherapy, recurrence or progression within a short period of time after treatment, and new and effective drugs need to be developed clinically. As the only clinically validated oral selective inhibitor of nuclear export (SINE), Selinexor has been approved for the treatment of relapsed/refractory diffuse large B-cell lymphoma and multiple myeloma, clinical attempts are being made to apply it to the treatment of other hematological malignancies.This article reviews the anti-tumor mechanism of Selinexor and the latest research progress in its application in NHL, and provides ideas for a more diverse, standardized and effective applications of Selinexor in NHL.

Expression and clinical significance of DCAF8 gene in multiple myeloma / 中国肿瘤生物治疗杂志

@#［摘要］ 目的：寻找多发性骨髓瘤（MM）基因芯片数据集中的潜在致病基因、疾病诊断和预后相关因子并阐明其作用机制。 方法：获取基因芯片数据集GSE13591 和Zhan Myeloma，使用R 语言进行基因差异表达分析。对共同高表达基因进行Meta 分 析，得到P 值中位秩次TOP10 基因。CCLE 数据库分析TOP10 基因在各肿瘤细胞系中的mRNA表达情况，筛选出蛋白酶体通路 相关基因8（DCAF8）。cBioPortal 数据库中分析DCAF8 基因在各肿瘤细胞系的突变率。WB检测DCAF8 蛋白在骨髓瘤细胞系中 的表达情况。SPSS 和Graph Pad 软件分析DCAF8 表达量和MM患者临床特征之间的相关性，进行受试者工作特征曲线（ROC曲 线）绘制和生存分析。R语言Custer Profiler Package 和Metascape 数据库对DCAF8 互作蛋白基因和共表达基因进行GO和KEGG 功能富集分析。结果：数据集GSE13591 和Zhan Myeloma 的上调基因取交集得到477 个共同高表达基因。在合并数据集中对上 述基因进行Meta 分析，得到P 值中位秩次TOP10 基因，DCAF8 在MM细胞系中的平均表达水平最高。DCAF8 基因在浆细胞骨 髓瘤中的突变率位于各肿瘤细胞系的第一位。DCAF8 蛋白在多种MM细胞系中的表达量显著升高（P<0.01）。DCAF8 表达量与 MM患者的肿瘤负荷显著正相关，1q21 扩增阳性组的DCAF8 的表达量显著高于1q21 阴性组。ROC曲线显示DCAF8 的表达水平 可以很好地区分MM患者和正常人（P<0.01）。DCAF8 高表达组比DCAF8 低表达组中位生存时间显著缩短。蛋白互作网络显示 DCAF8 可与XPO1 蛋白直接相互作用。GO和KEGG功能富集分析结果表明，DCAF8 与蛋白酶体功能、剪切体活性、组蛋白乙酰 化酶活性、RNA转运等功能相关。结论：DCAF8 在MM中显著高表达，其表达水平可以很好地区分MM患者和正常人；其高表 达与MM患者的生存预后显著负相关，且与1q21 扩增和XPO1 蛋白相关。

Effects of XPO1 Inhibitor KPT-8602 on Proliferation and Apoptosis in U937 cells / 中山大学学报(医学科学版)

@#【Objective】To explore the effects and the possible mechanism of KPT- 8602，a novel selective inhibitor of nuclear export protein （XPO1），on proliferation，cell cycle and apoptosis in human histiocytic lymphoma cell line U937 cells.【Methods】U937 cells were treated with different concentrations of KPT- 8602. Cell viability was assessed by CCK-8 assay. The cell cycle distribution and the apoptosis rate were analyzed by flow cytometry. The proteins expression of XPO1，p-AKT，AKT，Cleaved Caspase-3，p21 were determined by Western blot. Fluorescence microscope was used in observing the intracellular location of XPO1. 【Results】 KPT- 8602 inhibited the growth of U937 cells in a dose- dependent（P<0.001）and time- dependent manner（P<0.001），but normal PBMC were unaffected. 48 h after treatment with KPT-8602，a higher proportion of cells in G1 phase was observed（P<0.001）and the apoptosis rate increased（P=0.016）with drug concentration in U937 cells. XPO1 protein expression of U937 cells was significantly higher than normal PBMC（P=0.003）. 48 h after treatment with KPT- 8602，the protein expression of XPO1 decreased（P=0.011），p-AKT decreased（P=0.011），and Cleaved Caspase- 3 increased（P=0.009）. In addition，the protein expression of p21，the cargo protein of XPO1，increased in both the nuclei and the cytoplasm（P<0.05）after treatment with KPT- 8602. XPO1 decreased in both the nuclei and the cytoplasm under the fluorescence microscope after treatment with KPT- 8602.【Conclusion】KPT- 8602 can inhibit the proliferation of U937 cells，block the cell cycle at G1 phase，and induce cell apoptosis，which may partially be attributed to the down-regulation of XPO1 and inhibition of PI3K/AKT signaling.