Potent antitumor effects of the conditioned medium of bone marrow-derived mesenchymal stem cells via IGFBP-4

Cell transfer therapy using mesenchymal stem cells (MSCs) has pronounced therapeutic potential, but concerns remain about immune rejection, emboli formation, and promotion of tumor progression. Because the mode of action of MSCs highly relies on their paracrine effects through secretion of bioactive molecules, cell-free therapy using the conditioned medium (CM) of MSCs is an attractive option. However, the effects of MSC-CM on tumor progression have not been fully elucidated. Herein, we addressed this issue and investigated the possible underlying molecular mechanisms. The CM of MSCs derived from human bone marrow greatly inhibited the in vitro growth of several human tumor cell lines and the in vivo growth of the SCCVII murine squamous cell carcinoma cell line with reduced neovascularization. Exosomes in the MSC-CM were only partially involved in the inhibitory effects. The CM contained a variety of cytokines including insulin-like growth factor binding proteins (IGFBPs). Among them, IGFBP-4 greatly inhibited the in vitro growth of these tumors and angiogenesis, and immunodepletion of IGFBP-4 from the CM significantly reversed these effects. Of note, the CM greatly reduced the phosphorylation of AKT, ERK, IGF-1 receptor beta, and p38 MAPK in a partly IGFBP4-dependent manner, possibly through its binding to IGF-1/2 and blocking the signaling. The CM depleted of IGFBP-4 also reversed the inhibitory effects on in vivo tumor growth and neovascularization. Thus, MSC-CM has potent inhibitory effects on tumor growth and neovascularization in an IGFBP4-dependent manner, suggesting that cell-free therapy using MSC-CM could be a safer promising alternative for even cancer patients.     

复发性卵巢癌的药物治疗及进展

卵巢癌在女性妇科肿瘤中死亡率第一,且复发率高.复发性卵巢癌无法治愈,目前复发性卵巢癌的治疗以改善患者生活质量,延长患者无进展生存期及总生存期为目的.分子靶向治疗复发性卵巢癌是研究热点,靶向药物包括抗血管生成药物、聚二磷酸腺苷核糖聚合酶抑制剂及免疫检查点抑制剂.该文重点对复发性卵巢癌的药物治疗进展进行综述.     

An in silico comparative study of curcumin and 2-deoxyuridine nucleoside derivatives: Reveals the role of angiogenin in ER stress-induced apoptosis signaling

Angiogenin (ANG) protein plays a crucial role in angiogenesis, neovascularization, and cancer metastasis in NSCLC (non-small cell lung cancer) via non-coding tiRNA. It protects the cell under ER (endoplasmic reticulum) stress-induced apoptosis through the translational reprogramming process. Although B82 (Curcumin derivatives) induces ER stress-induced apoptosis, its mechanism of action was not studied. Therefore, it was hypothesized that the ribonucleolytic activity of ANG may be regulated by B82, resulting in modulated ER stress signaling for apoptosis. Hence, we designed and proposed a synthesis scheme for RNA-based anti-angiogenic derivatives of 2-deoxyuridine nucleoside forming peptide bond with amino acids like serine (Ser-3) and para-hydroxy-phenyl glycine (Normtyr-1) and compared B82 with them to know the binding affinity with ANG, anti-angiogenic potential, and its probable mechanism of anti-RNase activity through MD simulation study. Therefore, using Gromos96 43a1 and 43a2 force fields, MD simulation was performed to investigate binding affinity, ligand-induced molecular surface area change, conformational change, and dynamics of catalytic site residues to predict ligand binding to ANG in this study. The obtained binding free energy (∆G_bind) result showed the total average ∆G_bind as −113.480 ± 1.682 (Normtyr-1) > −53.038 ± 33.069 (B82) > −27.909 ± 16.438 (Ser-3) kJ/mole specify role of B82 in regulating ER stress signaling induced apoptosis through ANG ribonucleolytic activity inhibition, suitability of 43a2 force fields and methodology in ligand screening. It shows the crucial role of Leu115 and His13 residue involvement in total ∆G_bind contribution. Hence, based on the MD result, novel conformation of catalytic residues, and ∆G_bind, a promising combination candidate could be proposed for metastatic NSCLC therapy.