Microfluidics:Emerging prospects for anti-cancer drug screening

Cancer constitutes a heterogenic cellular system with a high level of spatio-temporal complexity.Recent discoveries by systems biologists have provided emerging evidence that cellular responses to anti-cancer modalities are stochastic in nature.To uncover the intricacies of cell-to-cell variability and its relevance to cancer therapy,new analytical screening technologies are needed.The last decade has brought forth spectacular innovations in the field of cytometry and single cell cytomics,opening new avenues for systems oncology and high-throughput real-time drug screening routines.The up-and-coming microfluidic Lab-on-a-Chip(LOC)technology and micrototal analysis systems(μTAS)are arguably the most promising platforms to address the inherent complexity of cellular systems with massive experimental parallelization and 4D analysis on a single cell level.The vast miniaturization of LOC systems and multiplexing enables innovative strategies to reduce drug screening expenditures while increasing throughput and content of information from a given sample.Small cell numbers and operational reagent volumes are sufficient for microfluidic analyzers and,as such,they enable next generation high-throughput and high-content screening of anticancer drugs on patient-derived specimens.Herein we highlight the selected advancements in this emerging field of bioengineering,and provide a snapshot of developments with relevance to anti-cancer drug screening routines.

HPLC Method Research of Picoplatin-a New Platinum Anti-cancer Drug and Its Impurities

Purpose: To establish a HPLC testing method of the content of bulk picoplatin and its impurities. Method: the separation was perform on a C18 column(4.6 mm×250 mm, 5 m) with potassium dihydrogen phosphate-aceton-itrile as the mobile phase at a flow rate of 1.0 mL/min. The detecting wavelength was set at 210 nm, and the column temperature was set at 30℃. Result: in the method validation, the linear relationship modulus of picoplatin is 0.9999, the systemic precision is 0.44%, the method precision is 0.74%, the average recovery rate is 99.62%, the LOD and LOQ of picoplatin is 0.2 ng and 1.0 ng. The average resolution of picoplatin and its impurities is more than 2. Conclusion: The established method is good specificity, high sensitivity, and good repeatability which could provide scientific evidence for the quality control of picoplatin and its impurities.

Carbohydrate-associated epitope-based anti-cancer drugs and vaccines

RP215 is one of the three thousand monoclonal antibodies (Mabs) which were generated against the OC-3-VGH ovarian cancer cell line. RP215 was shown to react with a carbohydrate-associated epitope located specifically on glycoproteins, known as CA215, from cancer cells. Further molecular analysis by matrix adsorption laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) revealed that CA215 consists mainly of immunoglobulin super-family (IgSF) proteins, including immunoglobulins, T-cell receptors, and cell adhesion molecules, as well as several other unrelated proteins. Peptide mappings and glycoanalysis were performed with CA215 and revealed high-mannose and complex bisecting structures with terminal sialic acid in N-glycans. As many as ten O-glycans, which are structurally similar to those of mucins, were also identified. In addition, two additional O-linked glycans were exclusively detected in cancerous immunoglobulins but not in normal B cell-derived immunoglobulins. Immunizations of mice with purified CA215 resulted in the predominant generation of RP215-related Mabs, indicating the immunodominance of this carbohydrate-associated epitope. Anti-idiotype (anti-id) Mabs of RP215, which were generated in the rat, were shown to contain the internal images of the carbohydrate-associated epitope. Following immunizations of these anti-id Mabs in mice, the resulting anti-anti-id (Ab3) responses in mice were found to be immunologically similar to that of RP215. Judging from these observations, anti-id Mabs, which carry the internal image of the RP215-specific epitope, may be suitable candidates for anticancer vaccine development in humans.

Control the Silver Content in the Preparation Process of Platinum Group Anti-cancer Drugs

In order to control the silver content in the preparation process of platinum group anti-cancer drugs, we put two kinds of color reagent to color in the production process of the platinum anti-cancer drugs by UV spectra measurement to control drugs production of platinum anticancer, thus we could control the silver content in the drugs so that it meets the pharmacopoeia standards of US and

Drug-Drug Interactions in Patients with Breast Cancer

The research paper investigates the intricate landscape of drug-drug interactions (DDIs) within the context of breast cancer treatment, with a particular focus on the elderly population and the use of complementary and alternative medicine (CAM). The study underscores the heightened susceptibility of elderly patients to DDIs due to the prevalence of polypharmacy and the widespread utilization of CAM among breast cancer patients. The potential ramifications of DDIs, encompassing adverse drug events and diminished treatment efficacy, are elucidated. The paper accentuates the imperative for healthcare providers to comprehensively understand both conventional and CAM therapies, enabling them to provide patients with informed guidance regarding safe and efficacious treatment options, culminating in enhanced patient outcomes.

Regulation of “Checkpoint Molecule” Sheds New Light on Anti-Cancer Drug Development

The rivalry between T cells and tumor cells somewhat mimics the scene of 'Tom and Jerry,' an animated series in which Tom (a house cat) rarely succeeds in catching Jerry (a mouse), mainly because of Jerry’s cleverness and cunning abilities. In a way, tumor cells are like Jerry, in terms of their crafty and sneaky features.

Bridging academic science and clinical research in the search for novel targeted anti-cancer agents

This review starts with a brief history of drug discovery & development, and the place of Asia in this worldwide effort discussed. The conditions and constraints of a successful translational R&D involving academic basic research and clinical research are discussed and the Singapore model for pursuit of open R&D described. The importance of well-characterized, validated drug targets for the search for novel targeted anti-cancer agents is emphasized, as well as a structured, high quality translational R&D. Furthermore, the characteristics of an attractive preclinical development drug candidate are discussed laying the foundation of a successful preclinical development. The most frequent sources of failures are described and risk management at every stage is highly recommended. Organizational factors are also considered to play an important role. The factors to consider before starting a new drug discovery & development project are described, and an example is given of a successful clinical project that has had its roots in local universities and was carried through preclinical development into phase I clinical trials.

Targeting SAMHD1: To overcome multiple anti-cancer drugs resistance in hematological malignancies

Sterile α motif and histidine/aspartic acid domain containing protein 1 (SAMHD1) is a deoxynucleoside triphosphate (dNTPs) triphosphohydrolase that can hydrolyze dNTPs into deoxynucleosides and triphosphates to keep the balance of the intracellular dNTPs pool. Moreover, it has been reported that SAMHD1 plays a role in regulating cell proliferation and the cell cycle, maintaining genome stability and inhibiting innate immune responses. SAMHD1 activity is regulated by phosphorylation, oxidation, SUMOylation, and O-GlcNAcylation. SAMHD1 mutations have been reported to cause diseases, including chronic lymphocytic leukemia and mantle cell lymphoma. SAMHD1 expression in acute myeloid leukemia predicts inferior prognosis. Recently, it has been revealed that SAMHD1 mediates the resistance to anti-cancer drugs. This review will focus on SAMHD1 function and regulation, the association between SAMHD1 and hematological malignancies and will provide updated information on SAMHD1 mediating resistance to nucleoside analogue antimetabolites, topoisomerase inhibitors, platinum-derived agents and DNA hypomethylating agents. Furthermore, histone deacetylase inhibitors and tyrosine kinase inhibitors indirectly increase anti-cancer drug resistance by increasing SAMDH1 activity. We herein highlight the importance of the development of novel agents targeting SAMHD1 to overcome treatment resistance of hematological malignancies, which would be an opportunity to improve the outcome of patients with refractory hematological malignancies.

Utilization of kinase inhibitors as novel therapeutic drug targets:A review

Kinase inhibitors are a significant and continuously developing division of target therapeutics.The drug discovery and improvement efforts have examined numerous attempts to target the signaling pathway of kinases.The Kinase inhibitors have been heralded as a game-changer in cancer treatment.For developing kinase inhibitors as a treatment for various non-malignant disorders like auto-immune diseases,is currently undergoing extensive research.It may be beneficial to investigate whether cell-specific kinase inhibitor administration enhances therapeutic efficacy and decreases adverse effects.The goal of the current review is to gain insight into the role of kinase inhibitors in facilitating effective target drug delivery for the treatment of various anti-inflammatory,auto-immune,and anticancer disorders.The aim of this review is also to shed light on drug discovery approaches for kinase inhibitors,their mode of action,and delivery approaches.The variation in the binding of kinases bestows different target approaches in drug design,which can be employed for designing the targeted molecules.Several target sites have been studied,exceeding the design of drugs for various diseases like cancer,Alzheimer’s,rheumatoid arthritis,etc.Diverse delivery approaches have also been studied for the targeted application of kinase inhibitors.

多靶点抗肿瘤药应用与评价

目的:多靶点抗肿瘤药临床合理应用概况。方法:收集国内外相关文献,从多靶点抗肿瘤药的作用机制、应用状况、不良反应等方面进行分析评价。结果及结论:多靶点抗肿瘤药目前已普遍应用于临床。

pLoc-mGpos: Incorporate Key Gene Ontology Information into General PseAAC for Predicting Subcellular Localization of Gram-Positive Bacterial Proteins

The basic unit in life is cell.?It contains many protein molecules located at its different organelles. The growth and reproduction of a cell as well as most of its other biological functions are performed via these proteins. But proteins in different organelles or subcellular locations have different functions. Facing?the avalanche of protein sequences generated in the postgenomic age, we are challenged to develop high throughput tools for identifying the subcellular localization of proteins based on their sequence information alone. Although considerable efforts have been made in this regard, the problem is far apart from being solved yet. Most existing methods can be used to deal with single-location proteins only. Actually, proteins with multi-locations may have some special biological functions that are particularly important for drug targets. Using the ML-GKR (Multi-Label Gaussian Kernel Regression) method,?we developed a new predictor called “pLoc-mGpos” by in-depth extracting the key information from GO (Gene Ontology) into the Chou’s general PseAAC (Pseudo Amino Acid Composition)?for predicting the subcellular localization of Gram-positive bacterial proteins with both single and multiple location sites. Rigorous cross-validation on a same stringent benchmark dataset indicated that the proposed pLoc-mGpos predictor is remarkably superior to “iLoc-Gpos”, the state-of-the-art predictor for the same purpose.?To maximize the convenience of most experimental scientists, a user-friendly web-server for the new powerful predictor has been established at http://www.jci-bioinfo.cn/pLoc-mGpos/, by which users can easily get their desired results without the need to go through the complicated mathematics involved.

The Heat Shock Protein Story—From Taking mTORC1,2 and Heat Shock Protein Inhibitors as Therapeutic Measures for Treating Cancers to Development of Cancer Vaccines

Heat shock proteins (HSPs) serve to correct proteins’ conformation, send the damaged proteins for degradation (quality control function). Heat shock factors (HSFs) are their transcription factors. The protein complexes mTOR1 and 2 (with the same core mTOR), the phosphoinositide-dependent protein kinase-1 (PDK1), the seine/threonine-specific protein kinase (Akt), HSF1, plus their associated proteins form a network participating in protein synthesis, bio-energy generation, signaling for apoptosis with the help of HSPs. A cancer cell synthesizes proteins at fast rate and needs more HSPs to work on quality control. Shutting down this network would lead to cell death. Thus inhibitors of mTOR (mTORI) and inhibitors of HSPs (HSPI) could drive cancer cell to apoptosis—a “passive approach”. On the other hand, HSPs form complexes with polypeptides characteristic of the cancer cells;on excretion from the cell, they becomes antigens for the immunity cells, eventually leading to maturation of the cytotoxic T cells, forming the basic principle of preparing cancer-specific, person-specific vaccine. Recent finding shows that HSP70 can penetrate cancer cell and expel its analog to extracellular region, giving the hope to prepare a non-person-specific vaccine covering a variety of cancers. Activation of anti-cancer immunity is the “active approach”. On the other hand, mild hyperthermia, with increase of intracellular HSPs, has been found to activate the immunity response, and demonstrate anti-cancer effects. There are certain “mysteries” behind the mechanisms of the active and passive approaches. We analyze the mechanisms involved and provide explanations to some mysteries. We also suggest future research to improve our understanding of these two approaches, in which HSPs play many roles.

Functionalized liposomes for targeted breast cancer drug delivery

Despite the exceptional progress in breast cancer pathogenesis,prognosis,diagnosis,and treatment strategies,it remains a prominent cause of female mortality worldwide.Additionally,although chemotherapies are effective,they are associated with critical limitations,most notably their lack of specificity resulting in systemic toxicity and the eventual development of multi-drug resistance(MDR)cancer cells.Liposomes have proven to be an invaluable drug delivery system but of the multitudes of liposomal systems developed every year only a few have been approved for clinical use,none of which employ active targeting.In this review,we summarize the most recent strategies in development for actively targeted liposomal drug delivery systems for surface,transmembrane and internal cell receptors,enzymes,direct cell targeting and dual-targeting of breast cancer and breast cancer-associated cells,e.g.,cancer stem cells,cells associated with the tumor microenvironment,etc.

在替代模型中基于“行为组学间”分析预测抗肿瘤药物联合用药(英文)

Development of drug resistance is a challenge to chemotherapeutic success but the mechanisms remain elusive.To study cellular resistance against doxorubicin,which is a widely employed chemotherapeutic agents in the clinic against solid tumors,lymphomas and leukemias,we employed fission yeast as a model to set up a synthetic lethality workflow to isolate 91 doxorubicin-resistance(DXR)genes.These DXR genes interlock to form a large network to ensure high viability when cells were exposure to doxorubicin.Interestingly,the gene network is,at least in part,conserved in the human cells and the understanding of how DXR genes are connected has enabled us to design a unique drug combination to sensitize in human cervical carcinoma cells to sub-lethal dose of doxorubicin through concomitant targeted inhibition of the multidrug resistance 1 protein and the proton pump vacuolar-ATPase.Further dissection of the DXR network showed a significant degree of overlap with that regulating resistance against other drugs with mechanistically varied modes of action.We will show evidence of how we took advantage of this′interactomic′platform to target differential overlap in drug resistance networks to destabilize gastric cancer cells in conjunction with an agent that modulates chromatin landscape.

Fucosylation is a common glycosylation type in pancreatic cancer stem cell-like phenotypes

AIM: To evaluate/isolate cancer stem cells(CSCs) from tissue or cell lines according to various definitions and cell surface markers. METHODS: Lectin microarray analysis was conducted on CSC-like fractions of the human pancreatic cancer cell line Panc1 by establishing anti-cancer drug-resistant cells. Changes in glycan structure of CSC-like cells were also investigated in sphere-forming cells as well as in CSC fractions obtained from overexpression of CD24 and CD44. RESULTS: Several types of fucosylation were increased under these conditions, and the expression of fucosylation regulatory genes such as fucosyltransferases, GDP-fucose synthetic enzymes, and GDP-fucose transporters were dramatically enhanced in CSC-like cells. These changes were significant in gemcitabineresistant cells and sphere cells of a human pancreatic cancer cell line, Panc1. However, downregulation of cellular fucosylation by knockdown of the GDP-fucose transporter did not alter gemcitabine resistance, indicating that increased cellular fucosylation is a result of CSC-like transformation. CONCLUSION: Fucosylation might be a biomarker of CSC-like cells in pancreatic cancer.

Effect of cigarette smoking on human health and promising remedy by mangroves

This article reviews the evils of cigarette smoking and the promise of mangroves to cure them.Chemicals in cigarette smoke are leading cause of death to both smokers and nonsmokers.Plant is the potential source to produce medicine for almost all the diseases.Mangroves are promising as a novel source of anti-cancer drugs in regulating the cancer pathways and stimulating immunity in the body system.Research on medicine from mangroves for the treatment of cancer has not only been shown to have an effect on cancer,but also provided important methods for the study of cancer therapy and mechanism.This report may help to explore the medicinal properties of the mangroves.

Non-Flat Bisbenzylisoquinoline Alkaloid Fangchinoline As a Class of Potent G-Quadruplex Stabilizer with Anti-cancer Activity

Compounds selectively binding and stabilizing G-quadruplex structures could inhibit the telomerase or down- regulate the oncogenes and may act as anti-cancer drugs. An alkaloid with non-flat structure, fangchinoline, showed to strongly stabilize the intermolecular and intramolecular parallel stranded G-quadruplex structure, increasing melting temperature by 20 and 23℃, respectively. The binding mode was investigated by using NMR and molec- ular modelling methods. Four human cell lines （HL-60, BGC-823, Be1-7402 and KB） were taken to test the an- ti-proliferation effects of fangchinoline and the IC50 values were ranged from 16 to 32 μmol/L. These results showed that the fangchinoline or related moiety derivatives may represent a class of telomere-targeted agents as po- tential anti-cancer drugs.

Merger of Ezetimibe and Statin:a Potential Dual Inhibitor

A potential dual inhibitor（4） for exogenous absorption and endogenic synthesis of cholesterol was designed based on the conjugation of the β-lactam pharmacophore of ezetimibe and the δ-lactone pharmacophore of statins. The merger of ezetimibe and statin 4 was synthesized from p-hydroxybenzaldehyde through a ten-step route. 1H NMR analysis showed existence of four pairs of enantiomers（5.7：5.7：1：1, molar ratio）. And compound 4 was found to lower total glucose（TG） level in rat serum via a high-cholesterol and high-fat feeding experiment.

Modern Multicomponent Multi-Targetel Drugs and Composite Drugs in Traditional Chinese Medicine

1 Results Current single-targeted drugs still cannot effectively treat many complex diseases such as cancer, diabetes, heart disease, arthritis, asthma, and depression. Increasing awareness that treatments must address all relevant causes of such diseases has promoted the development of multicomponent drugs. Thus, medical practitioners have turned to a multi-target approach, one similar to those used to develop composite materials. With this approach, tailoring treatment can enhance efficacy and suppres...

Recent advances in platelet engineering for anti-cancer therapies

Platelets contribute a major role in hemostasis by clumping and coagulation at the site of blood vessel injuries.In light of recent findings of a close relationship between platelets and immunological response,as well as interactions between platelets and cancer cells,novel engineering strategies have emerged for the integration of platelets or platelet membrane(PM)with anti-cancer therapeutics.In this review,we discuss several recent innovations that use platelets or their membranes to circumvent host immune responses and target tumor cells with high specificity to deliver a range of pharmacological,photothermal,or immunologic agents for eradication of recalcitrant tumor cells.More specifically,we compare the relative advantages of using whole platelets versus single or hybrid PM to coat nanoparticle cargoes.These cargoes range from well-established anti-tumor apoptosis-inducing agents,to relatively new photothermal agents that can induce a feedback cascade in which they induce vascular damage to the tumor which recruits more platelet-or membrane-encapsulated agents to induce further damage.We also discuss the use of engineered platelets to produce programmed cell death-inducing platelet derived microparticles.This review provides an overview and future directions for this promising platelet-based biomimetic approach to anti-cancer therapy.