Autocrine production of interleukin-6 confers ovarian cancer cells resistance to tamoxifen via ER isoforms and SRC-1

Although 40–60% of ovarian cancer (OVCA)s express estrogen receptor (ER)α, only a minor proportion of patients respond to anti-estrogen treatment with ER antagonist tamoxifen (TAM). The mechanism underlying TAM resistance in the course of OVCA progression is incompletely understood. However, interleukin-6 (IL-6) plays a critical role in the development and progression of OVCA. Here we explore an association between IL-6 and TAM resistance. We demonstrate that both exogenous (a relatively short period of treatment with recombinant IL-6) and endogenous IL-6 (by transfecting with plasmid encoding for sense IL-6) induce TAM resistance in non-IL-6-expressing A2780 cells, while deleting of endogenous IL-6 expression in IL-6-overexpressing CAOV-3 cells (by transfecting with plasmid encoding for antisense IL-6) promotes the sensitivity of these cells to TAM. Further investigation indicates that TAM resistance caused by IL-6 is associated with the alteration of ERα, ERβ and steroid hormone receptor coactivator (SRC)-1 expression levels, the protein interactions between SRC-1 and ERα, but not ERβ, as well as blockage of estrogen-induced ER receptor nuclear translocation. These results show that IL-6 secreted by OVCA cells may contribute to the refractoriness of these cells to TAM via ER isoforms and SRC-1. Overexpression of IL-6 not only plays an important role in OVCA progression but also contributes to TAM resistance. Our studies suggest that TAM-IL-6-targeted adjunctive therapy may lead to a more effective intervention than TAM alone.     

Tumor associated macrophages and neutrophils in cancer

The tumor microenvironment is a complex framework, in which myeloid cells play important roles in sculpting cancer development from tumor initiation to metastasis. Immune cells are key participants of the tumor microenvironment where they can promote or inhibit cancer formation and development. Plasticity is a widely accepted hallmark of myeloid cells and in particular of the monocyte–macrophage lineage. It includes the ability to display a wide spectrum of activation states in response to distinct signals and classical M1 or alternative M2 macrophages represent a paradigm of this feature. Neutrophils have long been viewed as terminally differentiated effector cells, playing a major role during the acute phase of inflammation and resistance against microbes. Recent evidence questioned this limited point of view, indicating that neutrophils can interact with distinct cell populations and produce a wide number of cytokines and effector molecules. Therefore, macrophages and neutrophils are both integrated in the regulation of the innate and adaptive immune responses in various inflammatory situations, including cancer.     

Physiological organization of immune response based on the homeostatic mechanism of matrix reprogramming: Implication in tumor and biotechnology

It is accepted that the immune system responds to pathogens with activation of antigen-independent innate and antigen-dependent adaptive immunity. However many immune events do not fit or are even inconsistent with this notion. We developed a new homeostatic model of the immune response. This model consists of four units: a sensor, a regulator, an effector and a rehabilitator. The sensor, macrophages or lymphocytes, recognize pathogenic cells and generate alarm signals. The regulator, antigen-presenting cells, Тregs and myeloid-derived suppressor cells, evaluate the signals and together with sensor cells program the effector. The effector, programmed macrophages and lymphocytes, eliminate the pathogenic cells. The rehabilitator, M2 macrophages, restrict inflammation, provide angiogenesis and reparation of tissue damage, and restore the homeostasis. We suggest the terms “immune matrix” for a biological template of immune responses to pathogens and “matrix reprogramming” for the interdependent reprogramming of different cells in the matrix. In an adequate immune response, the matrix forms a negative feedback mechanism to support the homeostasis. We defined the cellular and phenotypic composition of a tumor immune matrix. A tumor reprograms the homeostatic negative feedback mechanism of matrix into a pathogenic positive feedback mechanism. M2 macrophages play a key role in this transformation. Therefore, macrophages are an attractive target for biotechnology. Based on our hypotheses, we are developing a cell biotechnology method for creation of macrophages with a stable antitumor phenotype. We have shown that such macrophages almost doubled the survival time of mice with tumor.     

Application of Box-Behnken Design in the Preparation,Optimization, and In Vitro Evaluation of Self-Assembly–Based Tamoxifen- and Doxorubicin-Loaded and Dual Drug–Loaded Niosomes for Combinatorial Breast Cancer Treatment

This study was developed with the objective to prepare self-assembled niosomes to support sufficient entrapment and sustained drug release of the drugs having different solubility and mechanisms. In the current work, Tamoxifen- and Doxorubicin-loaded niosomes were prepared for combinatorial breast cancer treatment with statistical optimization by Box-Behnken experimental design. Atomic force microscopy revealed a spherical shape morphology of the niosomes. The entrapment efficiencies for the drugs were found to be 74.3% and 72.7% for Tamoxifen and Doxorubicin, respectively. The drug release experiments at different pH values displayed a sustained release up to 3 days. Fourier transform infrared spectroscopy and differential scanning calorimetry showed a robust drug-excipient compatibility. The niosomes were stable over a period of 6 months with no significant changes. In vitro cytotoxicity studies on MCF-7 cell line showed a 15-fold improvement (0.01 μg per mL) and a better synergistic effect of the niosomes in comparison to the free drug combination (0.15 μg per mL). Moreover, the nanocarrier uptake studies by fluorescence microscopy and flow cytometry showed a good distribution and greater uptake of the niosomes throughout the cells. These results suggest a profound therapeutic application of the niosomes for a combinatorial breast cancer treatment.     

Photochemical and Pharmacokinetic Characterization of Orally Administered Chemicals to Evaluate Phototoxic Risk

This study aimed to verify the applicability of a proposed photosafety screening system based on a reactive oxygen species (ROS) assay and a cassette-dosing pharmacokinetic (PK) study to chemicals with wide structural diversity. The orally taken chemicals, erythromycin, gatifloxacin, 8-methoxypsoralen (MOP), pirfenidone (PFD), trifluoperazine (TFP), and voriconazole (VRZ), were selected as test compounds. The ROS assay was conducted to evaluate their photoreactivity, and all test compounds excluding erythromycin generated significant ROS under simulated sunlight exposure. According to the ROS data, TFP had potent photoreactivity, and the photoreactivity of 4 other compounds was judged to be moderate. Regarding the oral cassette-dosing PK test in rats, the skin deposition of MOP, PFD, and VRZ was relatively high, and gatifloxacin and TFP exhibited moderate skin deposition properties. Based on the ROS and PK data of test compounds, PFD and TFP were judged to be potent phototoxic compounds, and MOP and VRZ were deduced to have phototoxic risk. The predicted phototoxic risk of test compounds by proposed screening was mostly in agreement with observed in vivo phototoxicity in the rat skin. The proposed screening system could provide reliable photosafety information on orally administered compounds with wide structural diversity.     

三苯氧胺对人胰腺癌细胞mdr1基因表达逆转作用的实验研究

目的：研究三苯氧胺（TAM）对入胰腺癌细胞mdr1基因表达的逆转作用。方法：TAM和5-Fu作用于入胰腺癌细胞株（Capan-Ⅱ、SW1990），用MTT法测定细胞增殖的情况，流式细胞仪检测mdr1基因蛋白表达的变化，RT-PCR检测mdr1基因mRNA的变化。结果：高剂量的TAM对ERa阳性的Capan-Ⅱ细胞有抑制作用，TAM可以逆转Capan-Ⅱ细胞和T47D细胞中mdr1蛋白和mRNA表达。结论：高剂量的TAM对ERa阳性的Capan-Ⅱ细胞有抑制作用，可以逆转mdr1的表达。     

乳腺癌应用电化学合并三苯氧胺治疗(附37例报告)

目的　对乳腺恶性肿瘤不论是原发或复发转移失去手术机会、年老体弱不易手术或不愿接受手术的患者均可采用电化学治疗 (ECT)。方法　应用北京原子能科学院研制的WL -A型电化学治疗仪 ,在肿瘤部位插入阴、阳电极针分别连接到治疗仪通电治疗 ;11例原发乳腺癌自电化学治疗开始口服三苯氧胺 (TAM)三年。结果　本组ECT治疗乳腺恶性肿瘤 37例 ,按国际ECT协会评定疗效的标准 ;CR 2 6例、PR 6例 ,总有效率为 86 5 % (CR +PR 32 /37)。结论　乳腺癌应用电化学合并三苯氧胺治疗创伤小、操作简单、疗效满意     

经阴道超声监测服用TAM的乳腺癌患者子宫内膜病变的价值分析

目的:探讨经阴道超声监测服用他莫昔芬TAM的乳腺癌患者子宫内膜病变的有效方法。材料和方法:回顾分析2010年1月-2019年1月首都医科大学附属北京妇产医院和北京市大兴区人民医院共94例乳腺癌术后服用TAM病人,对可疑子宫内膜病变者实行诊刮或手术获得组织病理学结果,进行病理与经阴道超声结果对照分析。结果:94例乳腺癌病人中,子宫内膜病理良性组78例(包括正常内膜8例、增生及复杂增生32例、息肉及息肉样增生28例及萎缩内膜10例),恶性组16例(包括非典型增生5例,高分化腺癌2例,中低分化腺癌5例,浆液性癌2例,恶性中胚叶混合瘤1例,透明细胞癌1例)。两组病人经阴道超声资料比较,在子宫内膜回声,内膜是否出现小囊性改变,内膜是否出现息肉样变,内膜与肌层界限情况及出现宫腔积液情况等指标上存在明显差异。而在子宫内膜厚度上差异不明显。结论:乳腺癌术后服用TAM病人经阴道超声检查如出现子宫内膜回声不均、子宫内膜出现息肉样变、内膜与肌层界限不清及宫腔积液者要高度警惕子宫内膜发生恶变可能,应提示临床尽早刮宫行组织病理学检查,而子宫内膜出现小囊变则良性内膜发生几率高。单纯依靠子宫内膜厚度测量尚不能做为超声判断子宫内膜良恶性的指标。