Progress of the mechanism of energy metabolism reprogramming regulated by long non-coding RNA in cancer / 肿瘤研究与临床

Although it is widely believed that abnormal energy metabolism exists in cancer cells and affects the biological behavior of cancers, the exact mechanism of energy metabolic reprogramming and specific mechanism of its effect on proliferation, invasion and metastasis of cancer cells have not been clarified. In recent years, studies have shown that long non-coding RNA (lncRNA) can affect energy metabolism, development and progression of cancer cells through binding to specific nucleic acids and proteins at the transcriptional and post-transcriptional stages, and specifically through transcriptional interference, epigenetic regulation of genes, changes in protein activity, competitive binding to microRNA (miRNA) and other related mechanisms. The further study on the mechanism of lncRNA regulating energy metabolism reprogramming of cancer cells is expected to find new markers and targets for diagnosis and treatment of cancer. This paper reviews the current research progress of the mechanism of lncRNA regulating metabolic reprogramming of glucose, fatty acid, protein and nucleotide in cancer, and provides a new idea of lncRNA's regulation of energy metabolism pathways for targeted anticancer therapy.

Research Progress of Targeting uPA-uPAR System in Tumor Therapy / 肿瘤防治研究

The uPA-uPAR system is highly expressed in various tumor tissues. This system can promote the degradation of extracellular matrix proteins, as well as combine with vitronectin and integrin to transmit intracellular signal transduction. Subsequently, it mediates the occurrence and development of tumors. In recent years, a series of therapeutic programs that target this system has achieved notable results in tumor treatment, and some of them have been under the clinical trial stage, thus providing new ideas for tumor targeted therapy. Therefore, this paper intends to provide a review of research progress on the gene therapy, drug therapy, and immunotherapy targeting uPA-uPAR system.

Anti-tumor activity of novel targeting HER2 antibody-drug conjugates / 药学学报

Antibody-drug conjugates (ADCs) are widely used in cancer treatment. Human epidermal growth factor receptor-2 (HER2) is overexpressed in various types of solid tumors and is a validated therapeutic target for cancers. To develop a more effective therapy, we generated a novel anti-HER2 humanized monoclonal antibody MIL40 and MIL40 drug conjugates as novel cancer therapies. The MIL40 was conjugated with small molecule cytotoxic agents DM1 [emtansine, N2'-deacetyl-N2'-(3-mercapto-1-oxopropyl)-maytansine] or monomethylauristatin E (MMAE) to generate ADCs, which were evaluated for their in vitro and in vivo anti-cancer activities. Experimental results show that MIL40-DM1 and MIL40-MMAE can effectively identify and bind to HER2-positive tumor cells. The binding capabilities of MIL40-DM1 and MIL40-MMAE with HER2 extracellular domain (ECD) antigens were not different after conjugation with DM1 or MMAE. The ADCs showed potent cytotoxicity in HER2-positive ovarian cancer cells SKOV3, breast cancer cells SKBR3 and stomach cancer cells N87 in vitro. MIL40-DM1 can effectively inhibit the volume and weight growth of SKOV3 transplant tumors in mice. The mice in this study were used and treated by following the international guidelines for the care and use of laboratory animals, and approved by Animal Ethics Committee of Institute of Military Cognitive and Brain Sciences.

Research progress of neutrophil extracellular traps and related targeted drugs for the treatment of inflammatory diseases / 药学学报

The inflammatory response is an essential role of innate immune cells such as neutrophils, which plays an important role in the occurrence and development of inflammatory diseases. Neutrophil extracellular traps (NETs) are responsible for killing microorganisms and inducing the inflammatory response. We review the function of NETs in inflammatory diseases based on research publications since 2016. In addition, the ability of drugs that target NETs to ameliorate inflammation-related diseases is summarized. This review suggests a new strategy of targeting NETs for the treatment of inflammation-related diseases.

Recent progress of non-viral vector polyethylenimine in the application of gene delivery / 药学学报

In recent years, non-viral gene vectors have attracted great attention for efficient gene delivery due to the advantages, including low toxicity, low immunogenicity and simple preparation. Polyethylenimine (PEI) is one of the typical non-viral gene carriers that have been widely utilized for gene delivery owing to its superior capabilities in gene compression and buffering capacity. This article discusses the processes of gene delivery and the barriers of PEI-based carrier during the gene delivery, such as low biocompatibility, cytotoxicity, lack of specific targeting and insufficient gene release, etc. Therefore, we summarize the multiple approaches for the modifications of PEI in terms of improved biocompatibility, degradability, specific targeting and buffering capacity. Furthermore, we also review on the recent impressive progresses of smart stimuli-responsive PEI carriers, including endogenous stimuli (pH, reactive oxygen species, glutathione, biomolecular, etc), exogenous stimuli (light, temperature, magnetic field, etc) and dual-responsive strategies, which might provide guidance for the development of more efficient and safer non-viral gene vectors.

Specific bone-targeting nanoscale drug delivery system: Advantages and clinical applicability / 中国组织工程研究

BACKGROUND: Specific bone-targeting drug delivery system is very important in the treatment of bone-related diseases. Development of nanotechnology provides a good platform and a new thought for preparation of specific bone-targeting nanoscale drug delivery system. OBJECTIVE: To review the current development and future prospects of specific bone-targeting drug delivery systems. METHODS: A computer-based online search of PubMed, Web of Science, and Medline databases was performed to retrieve studies regarding active targeting drug delivery system and nanoscale drug delivery system published between March 2014 and March 2019 with the search terms “Bone target therapy, Nanoparticles, Drug delivery system”. RESULTS AND CONCLUSION: The targeting group is an important component of the specific bone-targeting drug delivery system and it determines the targeting efficiency of the drug delivery system. Targeting bone tissue, osteoblasts, osteoblasts, and bone marrow mesenchymal stem cells have their own advantages and disadvantages. Specific bone-targeting nanoscale drug delivery systems have been widely used in various bone diseases, such as metastatic osteoporosis, osteomyelitis, multiple myeloma, osteosarcoma, and bone metastases. Specific bone-targeting drug delivery systems have advantages and challenges. Although many basic studies have shown good results of specific bone-targeting drug delivery systems in vivo, little is reported on successful clinical transformation of bone-targeting groups-modified nanoscale drug delivery systems.

Progress in targeting therapy of cancer metastasis by CCL21/CCR7 axis / 生物工程学报

Metastasis is the leading cause of mortality for cancer patients, and lymphatic metastasis is one of the main ways of tumor metastasis. The role of CCL21 and its receptor CCR7 in lymphatic metastasis has been increasingly concerned in recent years. CCR7 is mainly expressed by both dendritic cells and T cells for immune responses. CCL21, the chemokine ligand for CCR7, secreted from lymphatic endothelial cells binds CCR7 and recruits immune cells toward lymphatic vessels and lymphatic nodes. CCR7 expressed tumor cells can also metastasize to lymphatic system by the similar way as immune cells. Targeting CCL21/CCR7 axis to inhibit lymphatic metastasis but remain potent anti-tumor immune response has increasingly become a spot light of tumor immunotherapy. In this review, we summarize the role of CCL21/CCR7 axis in lymphatic metastasis, as well as preclinical trials and clinical trials in targeting CCL21/CCR7 axis for tumor metastasis therapy, hoping to accelerate the progress on tumor metastasis therapy by targeting CCL21/CCR7 axis.

Biologics for targeting inflammatory cytokines and their clinical application / 生物工程学报

Inflammatory cytokines can mediate many biological processes and are tightly regulated by the body. Loss of control can trigger a range of diseases such as autoimmune inflammation and cancer. Therefore, a number of biological agents that can effectively regulate the biological effects of inflammatory cytokines such as recombinant anti-inflammatory cytokines, cytokine receptors and neutralizing antibodies have been extensively used in the treatment of related diseases caused by the imbalance of inflammatory cytokines. In recent years, in particular, a number of new innovative biological agents for blocking and regulating cytokine activities are emerging. In this article, we review the recent development and clinical use of the biologics targeting TNF-α, IL-1, IL-6 and IL-17, and point out their inherent limitations and clinical risks. Finally, based on the research findings of our own and other scholars, we suggest some approaches and methods for reducing their side-effects and clinical risk. We consider that using modern biotechnology to improve the tissue specificity to inflammatory site and tumor will be an important development direction of such biologics.

Progress in chemotherapy for malignant melanoma / 实用肿瘤学杂志

Malignant melanoma( MM) is a very malignant solid tumor that is highly invasive and has a poor prognosis. Al-though the treatment of advanced melanoma has entered the era of targeting and immunotherapy,chemotherapy is still not to be aban-doned. Chemotherapy for malignant melanoma has undergone a development process from single-drug chemotherapy,combination of two or three or even four drugs,and biochemotherapy. This article reviews the progress of chemotherapy for malignant melanoma,com-pares the main chemotherapy regimens,and looks forward into the future direction of chemotherapy.

Chinese Medicine Amygdalin and β-Glucosidase Combined with Antibody Enzymatic Prodrug System As A Feasible Antitumor Therapy / 中国结合医学杂志

Amarogentin is an efficacious Chinese herbal medicine and a component of the bitter apricot kernel. It is commonly used as an expectorant and supplementary anti-cancer drug. β-Glucosidase is an enzyme that hydrolyzes the glycosidic bond between aryl and saccharide groups to release glucose. Upon their interaction, β-glucosidase catalyzes amarogentin to produce considerable amounts of hydrocyanic acid, which inhibits cytochrome C oxidase, the terminal enzyme in the mitochondrial respiration chain, and suspends adenosine triphosphate synthesis, resulting in cell death. Hydrocyanic acid is a cell-cycle-stage-nonspecific agent that kills cancer cells. Thus, β-glucosidase can be coupled with a tumor-specific monoclonal antibody. β-Glucosidase can combine with cancer-cell-surface antigens and specifically convert amarogentin to an active drug that acts on cancer cells and the surrounding antibodies to achieve a killing effect. β-Glucosidase is injected intravenously and recognizes cancer-cell-surface antigens with the help of an antibody. The prodrug amarogentin is infused after β-glucosidase has reached the target position. Coupling of cell membrane peptides with β-glucosidase allows the enzyme to penetrate capillary endothelial cells and clear extracellular deep solid tumors to kill the cells therein. The Chinese medicine amarogentin and β-glucosidase will become an important treatment for various tumors when an appropriate monoclonal antibody is developed.

Progress in biological treatment of osteosarcoma / 实用肿瘤学杂志

Osteosarcoma(OS)is a primary malignant bone tumor,characterized by a high degree of malignancy,prone to early metastasis,and poor prognosis. The survival rate of traditional surgical treatment is less than 20% . After the continuous improvement of the OS chemotherapy regimen,the 5-year survival rate of neoadjuvant chemotherapy combined with surgery-based treatment pro-gram is increased to 60% ~70% . However,the current chemotherapy regimen does not increase the survival rate of patients with OS, and the prognosis is extremely poor if patients have developed chemotherapy resistance. In order to solve the" bottleneck" problem of chemotherapy,in recent years,a comprehensive treatment plan combining immunotherapy,gene therapy,targeted therapy and chemo-therapy has been advocated. In this review,the progress of OS in the immunotherapy,gene therapy and targeted therapy is discussed in recent years,and summarized the treatment of OS.

JAK/STAT3 Signaling Pathway and Its Inhibitors in Tumor Therapy / 中国药学杂志

Signal transducers and activators of transcription 3 generally located in cytoplasm is a key intra-cellular transcription. So far, STAT3 has been known that could be activated by several different upstream kinase within cell, the most common one of which is Janus kinase. The aberrant activation of STAT3 induces tumorigenesis and promotes tumor development. Consequently, researchers have always been committed to developing novel anti-tumor drugs targeting JAK/STAT3 pathway signaling. In this review, researches as well as clinical trials of JAK/STAT3 inhibitors published over the past several years are collected and the targets, mechanism and pharmacological properties of certain inhibitors are summarized.

Significance of K-ras gene status and ras protein expression in immunophenotypic classification of gastric signet ring cell carcinoma / 重庆医学

Objective To investigate the significance of K-ras gene status and ras protein expression in immunophenotypic classification of gastric signet ring cell carcinoma.Methods The expression of ras protein in 180 cases of gastric signet-ring cell carcinoma was detected by tissue microarray immunohistochemistry.Meanwhile,the mutation in codon 12,13 of K-ras gene was determined by using PCR-based DNA direct sequencing analysis.Results The rate of ras protein expression was 27.8％.The rate of ras protein expression in intestinal phenotype was significantly higher than those in gastric and gastrointestinal phenotypes(P<0.05).The rate of ras protein expression in cases with lymph node metastasis was significantly higher than those in cases without nodal involvement(P<0.05).The rate of ras protein expression was significantly higher in cases with deeper invasion(P<0.05).The frequency of K-ras gene mutation was 22(12.2％).All of them were found in codon 12.The types of mutation included GGT→AGT(1 case),GGT→TGT(1 case),GGT→GCT(2 cases),GGT→GTT(8 cases)and GGT→GAT(10 cases).K-ras mutation was significantly associated with intestinal phenotype(P<0.05).The rates of ras protein expression in cases with mutational type of K-ras gene was higher than those in cases with wild type(P<0.05).The ras protein expression was positively associated with K-ras gene mutation(r=0.61,P<0.05).Conclusion The ras protein expression is correlated with nodal involvement and invasion.K-ras gene mutation and expression of ras protein is related to phenotypic classification,and they might influence the phenotypic transformation in gastric signet ring cell carcinoma.

Carcino-embryonic antigen targeted and drug loaded ultrasound nanoparticle agents inhibit growth of ovarian cancer cells in vitro / 中国医学影像技术

Objective To prepare carcino-embryonic antigen (CEA) targeted and paclitaxel loaded phase-shifting PLGA nanoparticles (Ab-PTX-NPs),and investigate the targeting capability and inhibition to the ovarian cancer cell in vitro.Methods Single-emulsion/solvent evaporation (O/W) and carbodiimide method were used to prepare the Ab-PTX-NPs.The size of nanoparticles was determined by Malvern analyzer.The encapsulation and drug loaded efficiency of paclitaxel were detected by high performance liquid chromatography.And the drug release characteristics was measured by dialysis method in constant temperature shaker.The targeting ability of Ab-PTX-NPs to the ovarian cancer SKOV3 cell was evaluated by the laser scanning confocal microscope and flow cytometry.And the inhibition ability of Ab-NPs was investigated by the CCK-8 assays.Results The size of Ab-PTX-NPs was (397.70±99.95)nm.The encapsulation efficiency and drug loading capacity of PTX were (67.26±4.15) ％ and (6.31±0.39) ％,respectively.The conjugating rate of Anti-CEA antibody was (92.74 ± 5.75) ％.The targeting study in vitro showed that such a number of contrast agents landed around the SKOV3 cells in targeting group,and the mean fluorescence intensity of ovarian cells in targeting group was significantly higher than other groups (P＜0.05).After 24 h,the viability rate of ovarian cells in targeting group was lower than the non-target group (P＜0.05),only higher than that of the pure PTX group (P＜0.05).But there was no significant difference between the targeting group and the pure PTX group (P＞0.05) at 48 h.Conclusion The CEA targeted and paclitaxel loaded phase-shifting PLGA nanoparticles are successfully prepared.It can enhance ultrasound imaging well after activated by LIFU.With high drug-loading efficiency and fast drug release velocity,the Ab-PTX-NPs appeares great targeted ability.

Preparation and Characterization of Tetracycline-Mediated Bone-Targeting Conjugate Micelles / 中国药学杂志

OBJECTIVE: To prepare atorvastatin-loaded tetracycline-PEG-PLGA(TC-PEG-PLGA/ATO) polymeric micelles, and investigate its pharmaceutical characteristics and targeting function in vitro. METHODS: The amphiphilic TC-PEG-PLGA conjugate was synthesized via an esterification reaction and identified by the 1H-NMR. Water insoluble atorvastatin was loaded on TC-PEG-PLGA conjugate micelles via dialysis method. The morphology of TC-PEG-PLGA/ATO micelles was observed under transmission electron microscope. The particle size distribution and Zeta potential of TC-PEG-PLGA/ATO micelles were determined by dynamic light scattering method. The drug loading and encapsulation efficiency were measured by HPLC, and in vitro release behavior was investigated via dialysis method. In vitro cytotoxicity was assessed via MTT assay, and bone-targeting activity was investigated via binding to the hydroxyapatite powder. RESULTS: TC-PEG-PLGA/ATO micelle was prepared successfully, and its particle size and Zeta potential were (47.2±4.7) nm and (-14.25±0.31) mV. The encapsulation efficiency and drug loading rate were(98.2±1.51)% and (8.71±0.23)%, respectively. Moreover, the accumulative release of ATO in vitro was about 70% in 48 h, which indicated that the drug was released slowly from the micelles. In vitro cell evaluation showed that TC-PEG-PLGA conjugate micelles were great biocompatibility with MC3T3-E1 cells within the concentration range of 100-500 μg·mL-1. In vitro targeting performance indicated that the proportion of the TC-PLGA NPs bound to Hap(87.94%) was greater than the bound proportion of PLGA NPs(18.59%). CONCLUSION: The TC-PEG-PLGA/ATO micelles exhibit small partical size and good stability, and significantly increased ATO content in aqueous solution. TC-PEG-PLGA/ATO micelles have good delayed release behavior, safety and binding efficacy to the hydroxyapatite powder.

Research progress on anticancer therapeutics targeting telomere/telomerase / 中国肿瘤临床

Telomeres are protective caps located at the ends of human chromosomes. Telomeres shorten with each successive cell di-vision in normal human cells, whereas they are continuously elongated by human telomerase in over 85%of tumors. This simple and attractive difference steers the development of anticancer drugs targeting telomeres and telomerase. Many promising current telo-mere/telomerase-targeting agents, such as GRN163L and GV1001, showed good therapeutic effect both in preclinical studies and phaseⅠ/Ⅱclinical trials. These agents have even entered phaseⅢclinical trials in patients with various tumors. Most therapeutics are more effective when used in combination with standard chemotherapies. Moreover, pharmacological interference with tumor-cell telomere biology to reduce telomere length and/or telomere stability could enhance the effectiveness and safety of radiotherapy. Therapeutics targeting telomere/telomerase may play a key role in radiotherapy in the era of personalized medicine in the future.

The inhibitory effect of OSTP-DDP on the growth of ovarian cancer A2780 cells / 中国药理学通报

Aim To study the growth inhibitory effect of the conjugate ( ovarian cancer specific targeting peptide and cisplatin, OSTP-DDP ) that targeting ovarian cancer cells A2780. Methods Using chemical method to syn-thesize OSTP-DDP, ovarian cancer cells A2780 were cul-tured in vitro, using CCK-8 method ( Cell Counting Kit-8) to detect the growth inhibitory effect of ovarian cancer A2780 cells, which were disposed by OSTP-DDP and DDP. Annexin V-FITC was used to detect the cycle and apoptosis effect of ovarian cancer A2780 cells which were disposed by OSTP-DDP and DDP. Results According to the mass spectrometry and the high performance liquid chromatography ( HPLC ) analysis, OSTP-DDP was proved to synthesize successfully. CCK-8 assay showed that both OSTP-DDP and DDP could play the growth in-hibitory effect and showed a concentration-dependent manner when cells were treated in different concentrations (10,20,40,80,160,320μmol·L-1 ) respectively after 24 h, 48 h, 72 h. And the effect of OSTP-DDP was stronger than DDP (P<0. 05), indicated OSTP-DDP had targeted cytostatic effect. The result of the flow cytometry showed that cell cycle was mostly arrested in G1 phase after 72h treated by OSTP-DDP and DDP, the inhibitory effect of OSTP-DDP was stronger than DDP (P<0. 05). The apop-tosis effect of OSTP-DDP was stronger than DDP ( P <0. 01),suggested that OSTP-DDP had a stronger targeting apoptosis-inducing effect. Conclusion OSTP-DDP has the targeting growth inhibitory effect on the ovarian cancer cell A2780, OSTP as a chemotherapeutic drug targeting vector has a great prospect to treat ovarian cancer.

Progress in human papilloma virus E6/E7 in cervical cancer / 肿瘤研究与临床

The occurrence of cervical cancer is the result of long-term synergy from a variety of carcinogenic factors.Human papilloma virus (HPV),the main biological cause of cervical cancer,is closely related to the occurrence of cervical cancer,while HPV E6/E7 protein plays an important role in the malignant transformation of cervical cancer.This article summarizes the carcinogenic mechanism of HPV E6/E7 and application in cervical cancer screening,and reviews the targeting therapy aiming at HPV E6/E7.

The relationship between DC-CIK and colorectal cancer prognoses and its influen-cing factors / 药学实践杂志

Objective To discuss dendritic cell-cytokine-induced killer (DC-CIK ) cell therapy effects and clinical out-comes in patients with colorectal cancer in order to have better clinical treatment .Methods A retrospective analysis of the data of 66 patients with colorectal cancer from the Biological Therapy Department of the Eastern Hepatobiliary Surgery Hospital was performed from January 2012 to January 2014 ,and then was followed up .Taking gender ,age ,degree of pathological differen-tiation ,TNM staging ,surgical methods ,and targeted therapy as the research basis ,by the Kaplan-Meier single factor and Cox multiple factors analysis we mainly discuss the DC-CIK cell treatment′s effect on the prognoses of patients .Results Kaplan-Meier single factor analysis results indicate :to a certain extent ,DC-CIK cell therapy can improve the prognoses of patients ;Cox multi-factor analysis results indicate whether accepting DC-CIK cell therapy is an independent factor influencing the prog-noses of patients .Conclusion DC-CIK cells therapy can improve the prognoses of patients with colorectal cancer .

Progress on drug therapy of neuropathic pain / 药学实践杂志

Neuropathic pain (NPP) is a chronic pain that caused by a series of infection and nerve damage events .It has high incidence ,complex etiology and seriously affects patients′life quality .Although clinic trials gradually increased ,the treat-ment of neuropathic pain is still insufficient .Recent research focuses on reasonably using drugs of different mechanisms and time of duration .The progress of NPP drugs was reviewed in this paper for providing basis for treatment of neuropathic pain .