Effective combinations of anti-cancer and targeted drugs for pancreatic cancer treatment

Pancreatic cancer is highly aggressive and lethal.Due to the lack of effective methods for detecting the disease at an early stage,pancreatic cancer is frequently diagnosed late.Gemcitabine has been the standard chemotherapy drug for patients with pancreatic cancer for over 20 years,but its anti-tumor effect is limited.Therefore,FOLFIRINOX(leucovorin,fluorouracil,irinotecan,oxaliplatin)as well as combination therapies using gemcitabine and conventional agents,such as cisplatin and capecitabine,has also been administered;however,these have not resulted in complete remission.Therefore,there is a need to develop novel and effective therapies for pancreatic cancer.Recently,some studies have reported that combinations of gemcitabine and targeted drugs have had significant antitumor effects on pancreatic cancer cells.As gemcitabine induced DNA damage response,the proteins related to DNA damage response can be suitable additional targets for novel gemcitabine-based combination therapy.Furthermore,KRAS/RAF/MEK/ERK signaling triggered by oncogenic mutated KRAS and autophagy are frequently activated in pancreatic cancer.Therefore,these characteristics of pancreatic cancer are potential targets for developing effective novel therapies.In this minireview,combinations of gemcitabine and targeted drugs to these characteristics,combinations of targeted drugs,combinations of natural products and anti-cancer agents,including gemcitabine,and combinations among natural products are discussed.

Combination Activity of Standard Antituberculosis Drugs and Extracts of Medicinal Plants Commonly Used in Traditional Treatment of Tuberculosis in Uganda

Introduction: Resistance to antituberculosis drugs and adverse drug reactions remain the leading causes of tuberculosis therapeutic failure globally. Despite the increasing acceptance of medicinal plant use in combination with conventional antituberculosis drugs in treatment of tuberculosis (TB) in Uganda, there is paucity of knowledge on their combination effect. Aim: This research aimed to determine combination activity of standard antituberculosis drugs with extracts of Zanthoxylum leprieurii Guill. & Perr. and Rubia cordifolia L., the two common antituberculosis medicinal plants in Uganda, against pansensitive (H37Rv) and multi-drug resistant (MDR) Mycobacterium tuberculosis strains. Materials and Methods: Two reference MTB strains (H37Rv and MDR strain) were inoculated on Middlebrook 7H11 medium containing a combination of standard antituberculosis drugs and methanol extracts of Z. leprieurii and R. cordifolia at varying concentrations. The number of colonies on the plates was observed and counted weekly for up to 8 weeks. In vitro combination activity was determined using proportion method. Mean percentage inhibition was calculated for the reduction of number of colonies on drug-extract combination medium in relation to drug-extract-free control medium. Results: Drug-extract combinations showed good combination activity against Mycobacterium tuberculosis strains when compared with individual standard anti-TB drugs. This was more exhibited against MDR strain. There was however a reduction in percentage inhibition when extracts were combined with ethambutol and streptomycin against H37Rv strain. Conclusions: Zanthoxylum leprieurii and Rubia cordifolia in combination with standard anti-TB drugs exhibited increased in vitro activity against Mycobacterium tuberculosis, especially MDR-TB strain. This justifies the local use of these plants in traditional treatment of tuberculosis especially in resistant cases in Uganda.

Complex diseases demand novel treatment strategies: understanding drug combination

For many multigene or multifactorial diseases,the one-drug therapy for inhibiting a defined molecular target is often less effective than combined treatments.Typically,drug combination therapies are multitargeted,so the mechanisms or even interactions are often complementary.These drug-drug interactions may promote alteration of pharmacokinetic or pharmacodynamic activities of one drug by another drug.Other interactions may change the expected effect of medications through polymorphisms that alter the expression or activity of the drug-mediated enzyme and the cell signaling cascade,such as drug-gene interactions and drug-drug-gene interactions.The number of possible existing interactions requires appropriate methods of study.In this review,we summarized combination therapies for cancer,as well as for viral,cardiovascular,and neurological diseases.Here,we also highlight known methodologies,such as in vitro methods based on Loewe’s and Bliss’s pioneer models and in silico methods based on online available data.With more elaborate methods and reliable results,multitarget therapies through drug combinations may increasingly benefit patients suffering from complex diseases.

Advances in extracellular vesicle-based combination therapies for spinal cord injury

Spinal cord injury is a severe insult to the central nervous system that causes persisting neurological deficits.The currently available treatments involve surgical,medical,and rehabilitative strategies.However,none of these techniques can markedly reverse neurological deficits.Recently,extracellular vesicles from various cell sources have been applied to different models of spinal cord injury,thereby generating new cell-free therapies for the treatment of spinal cord injury.However,the use of extracellular vesicles alone is still associated with some notable shortcomings,such as their uncertainty in targeting damaged spinal cord tissues and inability to provide structural support to damaged axons.Therefore,this paper reviews the latest combined strategies for the use of extracellular vesicle-based technology for spinal cord injury,including the combination of extracellular vesicles with nanoparticles,exogenous drugs and/or biological scaffold materials,which facilitate the targeting ability of extracellular vesicles and the combinatorial effects with extracellular vesicles.We also highlight issues relating to the clinical transformation of these extracellular vesicle-based combination strategies for the treatment of spinal cord injury.

Nanotechnology-based combination therapy for overcoming multidrug-resistant cancer

Multidrug resistance(MDR) is a major obstacle to successful cancer treatment and is crucial to cancer metastasis and relapse.Combination therapy is an effective strategy for overcoming MDR. However, the different pharmacokinetic(PK) profiles of combined drugs often undermine the combination effect in vivo, especially when greatly different physicochemical properties(e.g.,those of macromolecules and small drugs) combine. To address this issue, nanotechnology-based codelivery techniques have been actively explored. They possess great advantages for tumor targeting, controlled drug release, and identical drug PK profiles. Thus,a powerful tool for combination therapy is provided, and the translation from in vitro to in vivo is facilitated. In this review, we present a summary of various combination strategies for overcoming MDR and the nanotechnology-based combination therapy.

The appliances and prospects of aurum nanomaterials in biodiagnostics, imaging, drug delivery and combination therapy

Aurum nanomaterials(ANM), combining the features of nanotechnology and metal elements, have demonstrated enormous potential and aroused great attention on biomedical applications over the past few decades. Particularly, their advantages, such as controllable particle size, flexible surface modification, higher drug loading, good stability and biocompatibility, especially unique optical properties, promote the development of ANM in biomedical field. In this review, we will discuss the advanced preparation process of ANM and summarize their recent applications as well as their prospects in diagnosis and therapy. Besides, multi-functional ANM-based theranostic nanosystems will be introduced in details, including radiotherapy(RT), photothermal therapy(PTT), photodynamic therapy(PDT), immunotherapy(IT), and so on.

Key factors and potential drug combinations of nonalcoholic steatohepatitis:Bioinformatic analysis and experimental validation-based study

Background:Nonalcoholic fatty liver disease and its advanced stage,nonalcoholic steatohepatitis(NASH),are the major cause of hepatocellular carcinoma(HCC)and other end-stage liver disease.However,the potential mechanism and therapeutic strategies have not been clarified.This study aimed to identify potential roles of mi RNA/m RNA axis in the pathogenesis and drug combinations in the treatment of NASH.Methods:Microarray GSE59045 and GSE48452 were downloaded from the Gene Expression Omnibus and analyzed using R.Then we obtained differentially expressed genes(DE-genes).DAVID database was used for Gene Ontology(GO)analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment pathway analysis.Protein-protein interaction(PPI)networks were used for the identification of hub genes.We found upstream regulators of hub genes using mi RTar Base.The expression and correlation of key mi RNA and its targets were detected by q PCR.Drug Pair Seeker was employed to predict drug combinations against NASH.The expression of mi RNA and hub genes in HCC was identified in the Cancer Genome Atlas database and Human Protein Atlas database.Results:Ninety-four DE-genes were accessed.GO and KEGG analysis showed that these predicted genes were linked to lipid metabolism.Eleven genes were identified as hub genes in PPI networks,and they were highly expressed in cells with vigorous lipid metabolism.hsa-mi R-335-5 p was the upstream regulator of 9 genes in the 11 hub genes,and it was identified as a key mi RNA.The hub genes were highly expressed in NASH models,while hsa-mi R-335-5 p was lowly expressed.The correlation of mi RNA-m RNA was established by q PCR.Functional verification indicated that hsa-mi R-335-5 p had inhibitory effect on the development of NASH.Finally,drug combinations were predicted and the expression of mi RNA and hub genes in HCC was identified.Conclusions:In the study,potential mi RNA-m RNA pathways related to NASH were identified.Targeting these pathways may be novel strategies against NASH.

Coptis,Pinellia,and Scutellaria as a promising new drug combination for treatment of Helicobacter pylori infection

BACKGROUND Helicobacter pylori(H.pylori)is the most important infectious agent and plays an important role in the progression of chronic gastritis and the development of gastric cancer.AIM To identify efficient therapeutic agents or strategies that can treat H.pylori infection.METHODS We performed literature analysis,experimental validation,and network pharmacology.First,traditional Chinese medicine(TCM)prescriptions for the treatment of H.pylori infection were obtained from the China National Knowledge Infrastructure,China Biology Medicine,China Science and Technology Journal Database,and WanFang databases.In addition,we conducted a relevant search by Reference Citation Analysis(RCA)(https://www.referencecitationanalysis.com).Next,we used TCM Inheritance Support System V2.5 to identify core drug combinations in the TCM prescriptions.Then,an H.pylori-associated chronic mouse model of gastritis was established.The antibacterial properties and antiinflammatory potential of the core drug combination were evaluated by the rapid urease test,modified Warthin-Starry silver staining,histopathological analysis,and enzyme linked immunosorbent assay.Finally,the active compounds,hub targets,and potential signaling pathways associated with the core drug combination were analyzed by network pharmacology.RESULTS The TCM treatment of H.pylori was mainly based on reinforcing the healthy Qi and eliminating pathogenic factors by simultaneously applying pungent dispersing,bitter descending,cold and warm drugs.The combination of Coptis,Pinellia,and Scutellaria(CPS)was identified as the core drug combination from 207 prescriptions and 168 herbs.This drug combination eradicated H.pylori,alleviated the gastric pathology induced by H.pylori infection,and reduced the expression levels of tumor necrosis factor-α(P=0.024)and interleukin-1β(P=0.001).Moreover,a total of 35 compounds and 2807 targets of CPS were identified using online databases.Nine key compounds(tenaxin I,neobaicalein,norwogonin,skullcapflavone II,baicalein,5,8,2'-trihydroxy-7-methoxyflavone,acacetin,panicolin,and wogonin)and nine hub target proteins(EGFR,PTGS2,STAT3,MAPK3,MAPK8,HSP90AA1,MAPK1,MMP9,and MTOR)were further explored.Seventy-seven signaling pathways were correlated with H.pylori-induced inflammation and carcinogenesis.CONCLUSION In summary,we showed that CPS is the core drug combination for treating H.pylori infection.Animal experiments demonstrated that CPS has bacteriostatic properties and can reduce the release of inflammatory cytokines in the gastric mucosa.Network pharmacology predictions further revealed that CPS showed complex chemical compositions with multi-target and multipathway regulatory mechanisms.Although the results derived from network pharmacology are not necessarily comprehensive,they still expand our understanding of CPS for treating H.pylori infection.

Combination therapy in cancer:effects of angiogenesis inhibitors on drug pharmacokinetics and pharmacodynamics

Validated preclinical studies have provided evidence that anti-vascular endothelial growth factor(VEGF) compounds enhance the activity of subsequent antitumor therapy, but the mechanism of this potentiation is far from clear. The most widespread explanation is enhanced delivery of therapeutics due to vascular remodeling, lower interstitial pressure, and increased blood flow. While the antiangiogenic efects on vascular morphology have been fairly consistent in both preclinical and clinical settings, the improvement of tumor vessel function is debated. This review focuses on the efect of anti-VEGF therapy on tumor microenvironment morphology and functions, and its therapeutic beneits when combined with other therapies. The uptake and spatial distribution of chemotherapeutic agents into the tumor after anti-VEGF are examined.

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.

Advances in drug delivery system for platinum agents based combination therapy

Platinum-based anticancer agents are widely used as first-line drugs in cancer chemotherapy for various solid tumors. However, great side effects and occurrence of resistance remain as the major drawbacks for almost all the platinum drugs developed. To conquer these problems, new strategies should be adopted for platinum drug based chemotherapy. Modern nanotechnology has been widely employed in the delivery of various therapeutics and diagnostic. It provides the possibility of targeted delivery of a certain anticancer drug to the tumor site, which could minimize toxicity and optimize the drug efficacy. Here, in this review, we focused on the recent progress in polymer based drug delivery systems for platinum-based combination therapy.

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

Hollow mesoporous polyaniline nanoparticles with high drug payload and robust photothermal capability for cancer combination therapy

In recent years,synergistic chemo-photothermal therapy has revealed promising potential in treatments against various kinds of cancer.However,the development of superb photothermal agents with high drug loading capacity is still highly required.In this work,a hollow mesoporous polyaniline nanoparticle(HPANI NP)has been developed for encapsulating chemotherapeutic drug doxorubicin(DOX)with an remarkable drug loading content as high as 37.5%.Additional PEG modification endowed the drugloaded HPANI NPs with improved water-dispersibility and bioavailability.Such PEG-HPANI-DOX NPs exhibited strong NIR absorbance and robust photothermal conversion capacity,exhibiting highly efficient synergistic cancer treatment.More interestingly,the responsively released DOX molecules could emit strong red fluorescence,which could be employed to monitor the cellular endocytosis and drug release profile of PEG-HPANI-DOX NPs.Finally,the as-fabricated NPs showed good biocompatibility and low toxicity,serving as a promising nanoagent for highly efficient drug delivery and cancer combination therapy.

Drug combination therapy:providing evidence of significant superiority of a combination of drugs compared to the single agents

Based on Jun-Chen-Zuo-Shi,traditional Chinese medicine has used mixtures of naturally occurring herbs for more than 2000 years.Since the last century,advances in omics and cell biology have greatly impacted on the increasing use of drug combination in modern medicine.The enhanced understanding of the biology of a disease as a disturbed system of interconnected molecular pathways which are more susceptible to the simultaneous action of several drugs,provides new opportunities for the rational development of combination therapies.Combination therapies exploit the chances for better efficacy,decreased toxicity,and reduced development of drug resistance and owing to these advantages,have become a standard for the treatment of several diseases and continue to represent a promising approach in indications of unmet medical need.

COMBINATION THERAPY OF DRUG-RESISTANT CHORIOCARCINOMA

From Jan. 1983 to June 1990, 35 drug-resistant choriocarcinoma treated in other hospitals were referred to our hospital. Among them, 88.6% of patients had already undergone more than 5 courses of chemotherapy, and the tumour showed resistance to at least 3 anti-choriocarcinoma drugs. PBA or PVBA regimen of chemotherapy as the main treatment was combined with irradiation or surgery. The 1, 2, and 3-year survival rates of PBA group were 60%, while 1 and 2-year survival rates of PVBA group were 73.3% and 75% respectively.The more the varieties of resistant drugs and the more the courses of previous chemotherapy had undergone,the worse the prognosis would be. The authors believe that the PVBA chemotherapy is very effective for drugresistant choriocarcinoma.

Assessment of the availability and rationality of unregistered fixed dose drug combinations in Nepal:a multicenter crosssectional study

Background:The medications that are registered and available in a country are meant for the prevention and treatment of ailments and diseases.However,a lack of effective regulatory bodies and operative control mechanisms,especially in developing countries,promotes irrational and inappropriate use of medicines.This study aims to evaluate the availability and rationality of unregistered fixed-dose drug combinations(FDCs)in Nepal.Methods:A snowball sampling method with visits to 20 retail pharmacies in each of five major cities in Nepal was used to assess the availability of unregistered FDCs.To justify the rationality of the FDCs obtained from these five cities,the toolkit developed by Health Action International Asia-Pacific(HAI-AP)was used.Results:Altogether,41 unregistered FDCs were obtained from the five cities.Among the total 41 FDCs,a majority were anti-inflammatory/analgesic/antipyretics.A maximum of eight drugs and a minimum of two drugs per combination were present among the total 41 FDCs,with a majority in the form of tablets followed by suspensions.The cost ranges from a minimum of 3.7 Nepalese Rupees(NRs)(=USD 0.05)to a maximum of 240 NRs(=USD 3.15).None of the FDCs fulfilled all the fundamental requirements as stated in the toolkit;thus,they were categorized as‘irrational’.Conclusions:Unregistered FDCs are available in the Nepalese pharmaceutical market.All the unregistered FDCs found in our study were‘irrational’as per the HAI-AP toolkit.Regulatory authorities should initiate strict monitoring and appropriate regulatory mechanisms to prohibit the use of unregistered and irrational FDCs.

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.

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.

Determination of Polynomial Degree in the Regression of Drug Combinations

Studies on drug combinations are becoming more and more popular in the past few decades, with the development of computer and algorithms. One of the most common methods in optimizing drug combinations is regression of a polynomial model based on certain number of experimental observations. In this paper, we study how to determine the degree of polynomials in different circumstances of drug combination optimization. Using cross-validation, we have found that in most cases, a high degree results in failures of accurate prediction, named overfitting. An anti-noise test has also revealed that polynomial model with high degree tends to be less resistant to random errors in the observations. © 2014 Chinese Association of Automation.

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.