Anti‐Tumor‐Initiating Effects of Spiro‐biflavonoids from Abies sachalinensis

Cancer chemoprevention, the prevention of cancer by ingestion of chemical agents that reduce the risk of carcinogenesis, is one of the potent ways to reduce morbidity and mortality. We have been searching for cancer chemopreventive agents from the leaves and barks of coniferous trees that have been treated as waste in the forestry industry. We have previously reported the isolation of spiro‐biflavonoids, named as abiesinols, and a neolignan from the MeOH extract of the bark of Abies sachalinensis. These compounds were tested for their inhibitory effects on the activation of (±)‐(E)‐methyl‐2‐[(E)‐hydroxyimino]‐5‐nitro‐6‐methoxyhex‐3‐enamide (NOR 1), a nitric oxide (NO) donor, as a primary screening test for anti‐tumor initiators. All compounds tested exhibited potent inhibitory effects on NOR 1 activation. Furthermore, abiesinol A, bearing a spiro‐biflavonoid skeleton, showed remarkable anti‐tumor‐initiating activity in the in vivo two‐stage mouse skin carcinogenesis test using peroxynitrite (ONOO^?; PN) as the initiator and 12‐O‐tetradecanoylphorbol‐13‐acetate (TPA) as the promoter.     

Immune modulation by interleukin-12 in tumor-bearing mice receiving vitamin D3 treatments to block induction of immunosuppressive granulocyte/macrophage progenitor cells

 Lewis lung carcinoma (LLC-LN7) tumors stimulate myelopoiesis and increase the presence of granulocyte/macrophage (GM) progenitor cells having natural suppressor activity. Treatment of these tumor-bearing mice with interleukin-12 (IL-12) resulted in minimal immune modulation. The objective of this study was to determine whether eliminating natural suppressor activity would allow for immune stimulation by IL-12. Treatment of LLC-LN7 tumor-bearing mice with vitamin D₃ eliminated natural suppressor activity. In mice that were first treated with vitamin D₃ and then also with IL-12, there was stimulation of splenic T cell proliferation in response to immobilized anti-CD3 plus IL-2. In addition, spleen and lymph node cells from vitamin-D₃/IL-12-treated tumor-bearing mice became stimulated in response to autologous tumor to produce interferon γ (IFNγ), although IL-2 production was not stimulated. A prominent effect of the combined vitamin-D₃/IL-12 treatment regimen was the synergistic augmentation of autologous tumor-specific cytolytic activity within the regional lymph nodes. The generation of these tumor-specific effector cells required the presence of the tumor mass since such activity was not elicited in the lymph nodes of mice from which the tumors had been surgically excised. The results of this study show that, after treatment of tumor bearers with vitamin D₃ to eliminate GM-suppressor cells, IL-12 can induce select regional antitumor immune responses, particularly IFNγ production and cytolysis by regional lymph node cells of autologous tumor. Received: 15 December 1995 / Accepted: 22 March 1996     

Calcium signaling and cellular senescence

Cellular senescence is a stable cell proliferation arrest induced by a variety of stresses including telomere shortening, oncogene activation and oxidative stress. This process plays a crucial role in many physiopathological contexts, especially during aging when cellular senescence favors development of age-related diseases, shortening lifespan. However, the molecular and cellular mechanisms controlling senescence are still a matter of active research. In the last decade, there has been emerging literature indicating a key involvement of calcium signaling in cellular senescence. In this review we will initially give an account of the direct evidence linking calcium and the regulation of senescence. We will then review our current knowledge on the role of calcium in some senescence-associated features and physiopathological conditions, which will shed light on additional ways in which calcium signaling is implicated in cellular senescence.     

miRNA参与肿瘤基因表达调控研究进展

调查表明,我国城乡居民恶性肿瘤死亡率属于世界较高水平,而且呈持续的增长趋势。近年来的研究发现在肿瘤的发生与发展过程中涉及到多种因素,其中mi RNA可能扮演了重要的作用。mi RNA是一种长度约为22 nt的非编码短序列RNA,通过介导特异性的基因沉默导致靶m RNA降解,促使相应蛋白质的转译受阻而失去原有编码蛋白质的功能。mi RNA在细胞分裂周期中影响着基因的表达调控,在此过程中基因表达的失控就可能导致疾病的发生。而肿瘤的发生是以细胞恶变为基础,细胞恶变则是与细胞周期调控因素失衡相关,由此提示了一些mi RNA可能参与了肿瘤的发生、发展过程并在其中发挥了重要作用。随着研究的深入,mi RNA逐渐成为肿瘤诊治的新研究方向。本文主要讨论mi RNA在肿瘤基因表达调控方面的研究进展。     

Development of a versatile DNMT and HDAC inhibitor C02S modulating multiple cancer hallmarks for breast cancer therapy

DNMT and HDAC are closely related to each other and involved in various human diseases especially cancer. These two enzymes have been widely recognized as antitumor targets for drug discovery. Besides, research has indicated that combination therapy consisting of DNMT and HDAC inhibitors exhibited therapeutic advantages. We have reported a DNMT and HDAC dual inhibitor 15a of which the DNMT enzymatic inhibitory potency needs to be improved. Herein we reported the development of a novel dual DNMT and HDAC inhibitor C02S which showed potent enzymatic inhibitory activities against DNMT1, DNMT3A, DNMT3B and HDAC1 with IC₅₀ values of 2.05, 0.93, 1.32, and 4.16 µM, respectively. Further evaluations indicated that C02S could inhibit DNMT and HDAC at cellular levels, thereby inversing mutated methylation and acetylation and increasing expression of tumor suppressor proteins. Moreover, C02S regulated multiple biological processes including inducing apoptosis and G0/G1 cell cycle arrest, inhibiting angiogenesis, blocking migration and invasion, and finally suppressing tumor cells proliferation in vitro and tumor growth in vivo.     

Design,synthesis and biological evaluation of coumarin-3-carboxamides as selective carbonic anhydrase IX and XII inhibitors

A series of novel 7-hydroxycoumarin-3-carboxamides was synthesized by the reaction of 7-hydroxy-2-oxo-2H-chromene-3-carboxylic acid with various substituted aromatic amines. The newly synthesized compounds were evaluated for their inhibitory activity against the four physiologically relevant human carbonic anhydrase (hCA, EC 4.2.1.1) isoforms CA I, CA II, CA IX and CA XII. The CA inhibition results show that the newly synthesized 7-hydroxycoumarin-3-carboxamides (4a-n) exhibited selective inhibition of the tumor associated isoforms, CA IX and CA XII over CA I and II isoforms. The inhibition constants ranged from sub micromolar to low micromolar. Amongst all the compounds tested, compound 4m was the most effective inhibitor exhibiting sub micromolar potency against both hCA IX and hCA XII, with a K_i of 0.2 µM. Therefore, it can be anticipated that compound 4m can serve as a lead for development of anticancer therapy by exhibiting a novel mechanism of action. The binding modes of the most potent compounds within hCA IX and XII catalytic clefts were investigated by docking studies.     

MicroRNA-155 Regulates Cell Survival,Growth, and Chemosensitivity by Targeting FOXO3a in Breast Cancer

Breast cancer is the second leading cause of cancer death in women. Despite improvement in treatment over the past few decades, there is an urgent need for development of targeted therapies. miR-155 (microRNA-155) is frequently up-regulated in breast cancer. In this study, we demonstrate the critical role of miR-155 in regulation of cell survival and chemosensitivity through down-regulation of FOXO3a in breast cancer. Ectopic expression of miR-155 induces cell survival and chemoresistance to multiple agents, whereas knockdown of miR-155 renders cells to apoptosis and enhances chemosensitivity. Further, we identified FOXO3a as a direct target of miR-155. Sustained overexpression of miR-155 resulted in repression of FOXO3a protein without changing mRNA levels, and knockdown of miR-155 increases FOXO3a. Introduction of FOXO3a cDNA lacking the 3′-untranslated region abrogates miR-155-induced cell survival and chemoresistance. Finally, inverse correlation between miR-155 and FOXO3a levels were observed in a panel of breast cancer cell lines and tumors. In conclusion, our study reveals a molecular link between miR-155 and FOXO3a and presents evidence that miR-155 is a critical therapeutic target in breast cancer.     

细胞穿膜肽在肿瘤靶向治疗及疾病诊断中的应用

近年来细胞穿膜肽(cell-penetrating peptides,CPP)在生物医药领域被广泛应用,它为生物分子的胞内递送提供了有效的策略。关注CPP在肿瘤治疗及疾病诊断中的作用,并重点介绍其在肿瘤靶向治疗和医学影像诊断中的应用及优势。同时,根据CPP在药物传递系统中的特点,改进CPP存在的不足,扩大其联合用药的可能性,这也成为CPP研究的热点。对CPP及其在肿瘤等疾病的诊断及治疗中的应用作一综述,并简述其优化及改进策略,以期促进CPP在临床中的应用。     

早期子宫颈恶性肿瘤腹腔镜手术中两种示踪剂前哨淋巴结活检结果的对比分析

目的:通过在早期子宫颈恶性肿瘤患者中应用吲哚箐绿(ICG)及纳米炭混悬液为示踪剂行腹腔镜下前哨淋巴结(sentinel lymph node,SLN)切除术,对比两种示踪剂的示踪效果,寻找临床更适宜普遍使用的示踪剂。方法:选取仁济医院妇瘤科2016.8～2019.10期间诊断明确的122例早期子宫颈恶性肿瘤患者为研究对象。随机采用ICG或纳米炭为前哨示踪剂。对两种示踪剂的显影情况和SLN的示踪效果进行分析。结果:在122例子宫颈恶性肿瘤病例中,宫颈注射ICG64例,检出SLN385枚,平均每个患者检出6.02枚SLN,检出率100%(64/64),特异度96.77%,敏感度75%。宫颈注射纳米炭混悬液58例,检出SLN265枚,平均每个患者检出4.57枚SLN,检出率96.9%(56/58),特异度96.36%,敏感度66.67%。两种示踪剂都有较好的示踪效果(P=0.9356)。结论:早期子宫颈恶性肿瘤行宫颈注射ICG或纳米炭混悬液,腹腔镜下显影的SLN均具有较高的检出率与准确率,是一种较为可行的方法,可普遍开展,值得推广。