Paynantheine more effectively reverses multidrug resistance in malignant EPG85.257RDB and MCF7MX cells than morphine and speciociliatine.

The possible interactions of morphine, paynantheine and speciociliatine alkaloids with ATP-binding cassette (ABC) transporters was investigated. The compounds were docked against ABCG2 and ABCB1 to predict the binding mode of alkaloids in active binding sites. The cytotoxicity of morphine, paynantheine and speciociliatine for EPG85.257RDB and MCF7MX cells was determined and ABCB1 and ABCG2 gene and protein expression were determined. The binding score of paynantheine to ABCB1 was higher in the docking studies. Paynantheine and speciociliatine had similar binding scores to ABCB1, but higher binding scores to ABCG2 than did morphine. Paynantheine and speciociliatine were more effective against MCF7MX and EPG85.257RDB cells and showed greater cyctotoxicity in the MTT assay. The effect of morphine and paynantheine on the ABCB1 gene and protein expression suggests these compounds can reduce resistance in cancer patients, but that speciociliatine may not be a suitable candidate because of its increased ABCB1 expression while speciociliatine decreased the expression of ABCG2 in MCF7MX cells. This indicates that speciociliatine is a better candidate for reducing drug resistance in this cell line. Structural modification, drug-metabolizing enzymes and differences in the binding sites could cause functional differences between these compounds.

Single-cell transcriptional signature-based drug repurposing and in vitro evaluation in colorectal cancer.

BACKGROUND: The need for intelligent and effective treatment of diseases and the increase in drug design costs have raised drug repurposing as one of the effective strategies in biomedicine. There are various computational methods for drug repurposing, one of which is using transcription signatures, especially single-cell RNA sequencing (scRNA-seq) data, which show us a clear and comprehensive view of the inside of the cell to compare the state of disease and health. METHODS: In this study, we used 91,103 scRNA-seq samples from 29 patients with colorectal cancer (GSE144735 and GSE132465). First, differential gene expression (DGE) analysis was done using the ASAP website. Then we reached a list of drugs that can reverse the gene signature pattern from cancer to normal using the iLINCS website. Further, by searching various databases and articles, we found 12 drugs that have FDA approval, and so far, no one has reported them as a drug in the treatment of any cancer. Then, to evaluate the cytotoxicity and performance of these drugs, the MTT assay and real-time PCR were performed on two colorectal cancer cell lines (HT29 and HCT116). RESULTS: According to our approach, 12 drugs were suggested for the treatment of colorectal cancer. Four drugs were selected for biological evaluation. The results of the cytotoxicity analysis of these drugs are as follows: tezacaftor (IC10 = 19 µM for HCT-116 and IC10 = 2 µM for HT-29), fenticonazole (IC10 = 17 µM for HCT-116 and IC10 = 7 µM for HT-29), bempedoic acid (IC10 = 78 µM for HCT-116 and IC10 = 65 µM for HT-29), and famciclovir (IC10 = 422 µM for HCT-116 and IC10 = 959 µM for HT-29). CONCLUSIONS: Cost, time, and effectiveness are the main challenges in finding new drugs for diseases. Computational approaches such as transcriptional signature-based drug repurposing methods open new horizons to solve these challenges. In this study, tezacaftor, fenticonazole, and bempedoic acid can be introduced as promising drug candidates for the treatment of colorectal cancer. These drugs were evaluated in silico and in vitro, but it is necessary to evaluate them in vivo.

Epigenetic disruption of histone deacetylase-2 accelerated apoptotic signaling and retarded malignancy in gastric cells.

Background: The objective of this research was to determine whether HDAC2 function is associated with gastric cancer progression. Methods: HDAC2 was knocked out in EPG85.257 cells using CRISPR/Cas9 and tumorigenesis pathways were evaluated. Results: Cell proliferation, colony formation, wound healing and transwell invasion were inhibited in ΔHDAC2:EPG85.257 cells. Quantitative analyses revealed a significant downregulation of MMP1, p53, Bax, MAPK1, MAPK3, pro-Caspase3, ERK1/2, p-ERK1/2, AKT1/2/3, p-AKT1/2/3, p-NF-κB (p65), Twist, Snail and p-FAK transcripts/proteins, while SIRT1, PTEN, p21 and Caspase3 were upregulated in ΔHDAC2:EPG85.257 cells. Conclusion: These results indicated that HDAC2 enhanced migration, colony formation and transmigration ability. HDAC2 inhibition may improve gastric cancer chemotherapy pathways.

DNA changes are the main causes of cancer. Therefore, finding easy ways to manipulate and correct DNA changes has been the biggest medical concern in cancer treatment. Researchers have introduced CRISPR/Cas9 as the newest technology for gene editing that precisely and easily changes the genome of any cell. In our study, histone deacetylase-2 was disrupted in gastric cancer cells using CRISPR technology. This modification reduced growth kinetics and invasion of cancer cells. On the other hand, cell death (also called apoptosis) was induced. Sensitization of the cancer cells to chemotherapeutic agents is noticeable in this research. This study needs to uncover more signaling pathways in vitro and in vivo.

Engineered mesoporous silica nanoparticles, new insight nanoplatforms into effective cancer gene therapy.

The use of nucleic acid to control the expression of genes relevant to tumor progression is a key therapeutic approach in cancer research. Therapeutics based on nucleic acid provide novel concepts for untreatable targets. Nucleic acids as molecular medications must enter the target cell to be effective and obstacles in the systemic delivery of DNA or RNA limit their use in a clinical setting. The creation of nucleic acid delivery systems based on nanoparticles in order to circumvent biological constraints is advancing quickly. The ease of synthesis and surface modification, biocompatibility, biodegradability, cost-effectiveness and high loading capability of nucleic acids have prompted the use of mesoporous silica nanoparticles (MSNs) in gene therapy. The unique surface features of MSNs facilitate their design and decoration for high loading of nucleic acids, immune system evasion, cancer cell targeting, controlled cargo release, and endosomal escape. Reports have demonstrated successful therapeutic outcomes with the administration of a variety of engineered MSNs capable of delivering genes to tumor sites in laboratory animals. This comprehensive review of studies about siRNA, miRNA, shRNA, lncRNA and CRISPR/Cas9 delivery by MSNs reveals engineered MSNs as a safe and efficient system for gene transfer to cancer cells and cancer mouse models.

DeeP4med: deep learning for P4 medicine to predict normal and cancer transcriptome in multiple human tissues.

BACKGROUND: P4 medicine (predict, prevent, personalize, and participate) is a new approach to diagnosing and predicting diseases on a patient-by-patient basis. For the prevention and treatment of diseases, prediction plays a fundamental role. One of the intelligent strategies is the design of deep learning models that can predict the state of the disease using gene expression data. RESULTS: We create an autoencoder deep learning model called DeeP4med, including a Classifier and a Transferor that predicts cancer's gene expression (mRNA) matrix from its matched normal sample and vice versa. The range of the F1 score of the model, depending on tissue type in the Classifier, is from 0.935 to 0.999 and in Transferor from 0.944 to 0.999. The accuracy of DeeP4med for tissue and disease classification was 0.986 and 0.992, respectively, which performed better compared to seven classic machine learning models (Support Vector Classifier, Logistic Regression, Linear Discriminant Analysis, Naive Bayes, Decision Tree, Random Forest, K Nearest Neighbors). CONCLUSIONS: Based on the idea of DeeP4med, by having the gene expression matrix of a normal tissue, we can predict its tumor gene expression matrix and, in this way, find effective genes in transforming a normal tissue into a tumor tissue. Results of Differentially Expressed Genes (DEGs) and enrichment analysis on the predicted matrices for 13 types of cancer showed a good correlation with the literature and biological databases. This led that by using the gene expression matrix, to train the model with features of each person in a normal and cancer state, this model could predict diagnosis based on gene expression data from healthy tissue and be used to identify possible therapeutic interventions for those patients.

CRISPR/Cas9 as precision and high-throughput genetic engineering tools in gastrointestinal cancer research and therapy.

Gastrointestinal cancer (GI) is one of the most serious and health-threatening diseases worldwide. Many countries have encountered an escalating prevalence of shock. Therefore, there is a pressing need to clarify the molecular pathogenesis of these cancers. The use of high-throughput technologies that allow the precise and simultaneous investigation of thousands of genes, proteins, and metabolites is a critical step in disease diagnosis and cure. Recent innovations have provided easy and reliable methods for genome investigation, including TALENs, ZFNs, and the CRISPR/Cas9 (clustered regularly interspaced palindromic repeats system). Among these, CRISPR/Cas9 has been revolutionary tool in genetic research. Recent years were prosperous years for CRISPR by the discovery of novel Cas enzymes, the Nobel Prize, and the development of critical clinical trials. This technology utilizes comprehensive information on genes associated with tumor development, provides high-throughput libraries for tumor therapy by developing screening platforms, and generates rapid tools for cancer therapy. This review discusses the various applications of CRISPR/Cas9 in genome editing, with a particular focus on genome manipulation, including infection-related genes, RNAi targets, pooled library screening for identification of unknown driver mutations, and molecular targets for gastrointestinal cancer modeling. Finally, it provides an overview of CRISPR/Cas9 clinical trials, as well as the challenges associated with its use.

Enzyme-sensitive nanoparticles, smart TAT and cetuximab conjugated immunoliposomes to overcome multidrug resistance in breast cancer cells.

Due to recent advances in the field of small molecule-based drugs, designing an efficient siRNA delivery system seems essential. Here, modified sets of lipids conjugated with cell-penetrating TAT peptide, MMP2 enzyme-sensitive moiety, and cetuximab antibodies against the EGF receptor were synthesized, purified and verified on HPLC, TLC, SEM, and DLS analyses. Different cellular and molecular experiments were designed to evaluate the transfection efficiency, targeting properties, and functions, including cytotoxicity assay, resensitization assessments, flow cytometry-based uptake assay, BCRP silencing efficiency, real-time PCR, and western blotting. The final targeted liposomes represented an average diameter of 160 nm; zeta-potential and siRNA encapsulation rates were respectively around -28.9 ± 3.16 mV and 88.3 ± 0.9 w/w. The siBCRP carried by the TAT+Cetuximab+ liposome led to an increase in the tumoricidal effect of mitoxantrone by a reduction in IC50 value by 4-fold (*** P < 0.001). Flow cytometry results showed that the cellular uptake rate of final immunoliposomes was significantly higher than the naked liposomes (*** P < 0.001). The Targeted siRNA encapsulating liposomes decreased BCRP transcript and protein levels in MCF7-MX cells by 0.24 and 0.2-fold after 48 h, respectively. Due to the silencing results of the BCRP by the encapsulated siRNA and the inhibitory effects of cetuximab on the EGFR, this formulation could widely be utilized as a carrier for tumor-directed gene delivery.

Silencing of α-N-acetylgalactosaminidase in the gastric cancer cells amplified cell death and attenuated migration, while the multidrug resistance remained unchanged.

Although the elevated level of the α-N-acetylgalactosaminidase enzyme (encoded by the NAGA gene) is a well-recognized feature of cancer cells; little research works have been undertaken on the cancer malignancy mechanisms. The effects of NAGA gene downregulation on cancer cells' features such as drug resistance, impaired programmed cell death, and migration were analyzed in this study. The cells grew exponentially with a doubling time of 30 h in an optimal condition. Toxicity of daunorubicin chemotherapy drug on NAGA-transfected EPG85.257RDB cells was evaluated in comparison to control cells and no significant change was recorded. Quantitative transcript analyses and protein levels revealed that the MDR1 pump almost remained unchanged during the study. Moreover, the NAGA gene downregulation enhanced the late apoptosis rate in EPG85.257RDB cells at 24 h posttransfection. The investigated expression level of genes and proteins involved in the TNFR2 signaling pathway, related to cancer cell apoptosis, showed considerable alterations after NAGA silencing as well. MAP3K14 and CASP3 genes were downregulated while IL6, RELA, and TRAF2 experienced an upregulation. Also, NAGA silencing generally diminished the migration ability of EPG85.257RDB cells and the MMP1 gene (as a critical gene in metastasis) expression decreased significantly. The expression of the p-FAK protein, which is located in the downstream of the α2 ß1 integrin signaling pathway, was reduced likewise. It could be concluded that despite drug resistance, NAGA silencing resulted in augmentative and regressive effects on cell death and migration.

siRNA delivery using intelligent chitosan-capped mesoporous silica nanoparticles for overcoming multidrug resistance in malignant carcinoma cells.

Although siRNA is a promising technology for cancer gene therapy, effective cytoplasmic delivery has remained a significant challenge. In this paper, a potent siRNA transfer system with active targeting moieties toward cancer cells and a high loading capacity is introduced to inhibit drug resistance. Mesoporous silica nanoparticles are of great potential for developing targeted gene delivery. Amino-modified MSNs (NH2-MSNs) were synthesized using a modified sol-gel method and characterized by FTIR, BET, TEM, SEM, X-ray diffraction, DLS, and 1H-NMR. MDR1-siRNA was loaded within NH2-MSNs, and the resulting negative surface was capped by functionalized chitosan as a protective layer. Targeting moieties such as TAT and folate were anchored to chitosan via PEG-spacers. The loading capacity of siRNA and the protective effect of chitosan for siRNA were determined by gel retardation assay. MTT assay, flow cytometry, real-time PCR, and western blot were performed to study the cytotoxicity, cellular uptake assay, targeting evaluation, and MDR1 knockdown efficiency. The synthesized NH2-MSNs had a particle size of ≈ 100 nm and pore size of ≈ 5 nm. siRNA was loaded into NH2-MSNs with a high loading capacity of 20% w/w. Chitosan coating on the surface of siRNA-NH2-MSNs significantly improved the siRNA protection against enzyme activity compared to naked siRNA-NH2-MSNs. MSNs and modified MSNs did not exhibit significant cytotoxicity at therapeutic concentrations in the EPG85.257-RDB and HeLa-RDB lines. The folate-conjugated nanoparticles showed a cellular uptake of around two times higher in folate receptor-rich HeLa-RDB than EPG85.257-RDB cells. The chitosan-coated siRNA-NH2-MSNs produced decreased MDR1 transcript and protein levels in HeLa-RDB by 0.20 and 0.48-fold, respectively. The results demonstrated that functionalized chitosan-coated siRNA-MSNs could be a promising carrier for targeted cancer therapy. Folate-targeted nanoparticles were specifically harvested by folate receptor-rich HeLa-RDB and produced a chemosensitized phenotype of the multidrug-resistant cancer cells.

Improvement of cytotoxicity of mitoxantrone and daunorubicin by candidone, tephrosin, and bavachinin.

BACKGROUND: Flavonoids have been demonstrated to have the ability of sensitizing cancer cells to chemotherapy and inverse multidrug resistance via various mechanisms, such as modulating of pumps. The therapeutic effect of candidone, tephrosin, and bavachinin in treatment of cancer, particularly to overcome multidrug resistance (MDR) is largely unknown. The capacity of these agents in sensitization of MDR cells is investigated in the current work. METHODS AND RESULTS: We analyzed the impact of candidone, tephrosin, and bavachinin, as chemosensitizer on cell cytotoxicity, P-gp and ABCG2 mRNA expression level on two multidrug resistant cells, ABCG2 overexpressing human epithelial breast cancer cell line (MCF7/MX), and P-gp overexpressing human gastric adenocarcinoma cell line (EPG85.257RDB). The inhibitory concentration of 50% (IC50) of daunorubicin in EPG85.257RDB cells in combination with IC10 of Bavachinin, Tephrosin, and Candidone were 6159 ± 948, 4186 ± 665, 730 ± 258 nM, and this data in MCF7/MX cell were 1773 ± 534, 7160 ± 405 and 3340 ± 622 nM respectively. These three flavonoids dose-dependently decreased the viability of MCF7/MX and EPG85.257RDB and significantly (p < 0.05) decreased IC50 of daunorubicin and mitoxantrone except Tephrosin in MCF7/MX cells. Candidone and Bavachinin were the most potent chemosensitizer in EPG85.257RDB and MCF7/MX cells respectively. Flavonoids did not reduce mRNA expression of P-gp and ABCG2 after 72 h treatment, except Candidone in EPG85.257RDB and Bavachinin in MCF7/MX cells. CONCLUSIONS: This effect is not time-dependent, and flavonoids have their own patterns that are cell-dependent. In general, tephrosin, candidone, and bavachinin had the potential of sensitizing MDR cells to mitoxantrone and daunorubicin.

Butylcycloheptylprodigiosin and undecylprodigiosin are potential photosensitizer candidates for photodynamic cancer therapy.

BACKGROUND: Prodiginines are bacterial red polypyrrole pigments and multifaceted secondary metabolites. These agents have anti-proliferative, immunosuppressive, antimicrobial, and anticancer effects. Recent analysis revealed that prodigiosin hypersensitizes Serratia marcescens to gamma radiation. In the present study, we report the cytotoxicity and genotoxicity properties of undecylprodigiosin and butylcycloheptylprodigiosin in the presence and absence of radiation through the MTT and alkaline comet experiments. METHODS AND RESULTS: Findings demonstrated that undecylprodigiosin was at least a fivefold more cytotoxic at low radiation doses (1 and 3 Gy) on both MCF7 and HDF lines rather than in the absence or high radiation doses (5 Gy) (P value < 0.05). Although butylcycloheptylprodigiosin toxicity on MCF7 and HDF was dose-dependent, it was not influenced by any radiation doses (P value > 0.05). Comet findings confirmed that these compounds' genotoxicity is only dose-dependent. Radiation had no significant effects on DNA damage on any of the cells (P value > 0.05). CONCLUSIONS: In general, it can be concluded that the prodiginines are cytotoxic agents that act as a double-edged sword, radiosensitizers and radio-protective, respectively at low and high radiation doses in cancer treatment process. As the results they could be used in antitumor therapies very soon.

Ecotypic Variations Affected the Biological Effectiveness of Thymus daenensis Celak Essential Oil.

Thymus (Lamiaceae) is famous for its pharmacological properties. Thymus daenensis Celak (Avishan-e-denaee in Persian) is an endemic Thymus species in Iran and is traditionally used for its digestive, carminative, antitussive, antispasmodic, and expectorant attributes in folk medicine. Ecotypic oils were extracted and analyzed with the GC-MS. Their biological properties in terms of antimicrobial, antioxidant, and antigenotoxic activities were evaluated using the minimal inhibitory concentration, minimal bactericidal concentration, and DPPH, ß-carotene, and comet assays. The GC-MS results for Thymus daenensis Celak oils revealed thymol (73.86%) and carvacrol (51.89%) as the most abundant components. Due to the results, reasonable bactericidal activity values range from 0.14 to 5.00 mg/ml, and fungicidal activity ranges from 0.17 to 0.58 mg/ml. The necessary oil free radical scavenging capacity (0.41-1.79 mg/ml), bleaching inhibitory activity (0.01-1.06 mg/ml), and genoprotective potential (1.04-7.78 mg/ml) indicated the dose-dependent activity. The results suggest that Thymus daenensis is an important antibacterial and antifungal bioresource. Additionally, the antioxidant and radical scavenging capacity suggests this species has a role as a natural preservative in oxidative diseases and in the prevention of food spoilage.

Pharmacodynamic mechanisms of anti-inflammatory drugs on the chemosensitization of multidrug-resistant cancers and the pharmacogenetics effectiveness.

Drug resistance as a remarkable issue in cancer treatment is associated with inflammation which occurs through complex chemical reactions in the tumor microenvironment. Recent studies have implicated that glucocorticoids and NSAIDs are mainly useful combinations for inflammatory response modulation in chemotherapeutic protocols for cancer treatment. Immunosuppressive actions of glucocorticoids and NSAIDs are mainly mediated by the transrepression or activation regulation of inflammatory genes with different DNA-bound transcription factors including AP-1, NFAT, NF-κB, STAT and also, varying functions of COX enzymes in cancer cells. Interestingly, many investigations have proved the benefits of these anti-inflammatory agents in the quenching of multidrug resistance pathways. Numerous analyses on the ABC transporter promoters showed conserved nucleotide sequences with several DNA response elements that participate in transcriptional regulation. Furthermore, genetic variations in nucleotide sequences of membrane transporters were strongly associated with changes in these transporters' expression or function and a substantial impact on systemic drug exposure and toxicity. It appeared that several polymorphisms in MDR transporter genes especially MDR1 have influenced the regulatory mechanisms and explained differences in glucocorticoid responses.

Synthetic Biology Based on Genetic Logic Circuit, Using the Expression of Drug Resistance, BCRP Pump in MCF-7 Cancer Cell Line.

Biological circuits are developed as biological parts within a cell to carry out logical functions resembling those studied in electronics circuits. These circuits can be performed as a method to vary cellular functions, to develop cellular responses to environmental conditions, or to regulate cellular developments. This research explored the possibility of synthetic biology based on the genetic logic circuit A and (not B) using the inducible expression of the both BCRP drug resistance pump and its specific shRNA in MCF-7 cancer cell line utilizing the third generation of lentiviral vectors. The accuracy of the output of the proposed circuit for living cells, was confirmed by the results of the Real-Time PCR and flow cytometry at the RNA and protein levels. At the RNA level, the effect of the inducers on the BCRP gene expression and silencing were investigated by real-time PCR. Furthermore, at the protein level, induction of the expression of the BCRP pump resulted in driving out of the substrate from inside the cells leading to the decrease of the fluorescent emission from the transfected cells. We successfully designed and implemented the genetic logic circuit A and (not B) using the inducible expression of the both BCRP drug resistance pump and its specific shRNA in MCF-7 cancer cells.

Genetically modified Pichia pastoris, a powerful resistant factory for gold and palladium bioleaching and nanostructure heavy metal biosynthesis.

A metal-resistant engineered Pichia pastoris was developed here to fulfil the metal bioleaching in aqueous conditions. Parent and recombinant yeasts were grown in YPD medium containing different concentrations of ion metals. XRD, electron microscopy and particle size analyser were used for the characterisation and the nanoparticle analyses. The nanoparticle production kinetics were studied by ICP-OES. The cytotoxicity of nanoparticles was assayed against human cell lines. Media colours changed to a range from purplish-brown to grey during early fermentation stages. The maximum biosorption capacities were recorded 81.23 and 493.35 mg/g for gold and palladium in batch conditions, respectively. Various physical investigations proved monodispersed spherical nanoparticles around 100 nm in size. Pure palladium nanoparticles and PdCl2 represented the least cytotoxic potency towards T47D and EPG85.257 cells. The results demonstrated that the genetically modified yeast is a cost-effective, high-throughput, robust, and facile system for metal biosorption.

Enhancing the Therapeutic Efficacy of Daunorubicin and Mitoxantrone with Bavachinin, Candidone, and Tephrosin.

The capability of flavonoids in sensitizing cancer cells was demonstrated in numerous works to chemotherapy and converse multidrug resistance by modulating efflux pumps and apoptosis mechanisms. Three flavonoids, namely, bavachinin, tephrosin, and candidone, have been recently introduced to cancer treatment research presenting various activities, such as antibacterial, immunomodulatory, cell death, and anticancer. Less information exists regarding the therapeutic significance of these flavonoids in cancer treatment, especially in overcoming multidrug resistance (MDR). Here, we tempted to investigate the potency of these agents in reversing MDR by analyzing their effects as chemosensitizers on cell cytotoxicity, P-gp and ABCG2 protein expression levels, and their function on two multidrug-resistant cell lines, P-gp-overexpressing human gastric adenocarcinoma cell line (EPG85.257RDB) and ABCG2-overexpressing human epithelial breast cancer cell line (MCF7/MX). The inhibitory concentration of 10% (IC10) of bavachinin, tephrosin, and candidone in EPG85.257RDB cells was 1588.7 ± 202.2, 264.8 ± 86.15, and 1338.6 ± 114.11 nM, respectively. Moreover, these values in MCF7/MX cell were 2406.4 ± 257.63, 38.8 ± 4.28, and 27.9 ± 5.59 nM, respectively. Expression levels of ABCG2 and P-gp were not significantly downregulated by these flavonoids. Maximum levels of daunorubicin and mitoxantrone accumulations and minimum rates of drug efflux in both cell lines were detected 48 hrs posttreatment with tephrosin and bavachinin, respectively. Chemosensitization to mitoxantrone and daunorubicin treatments was, respectively, achieved in MCF7/MX and EPG85.257RDB cells in response to IC10 of bavachinin and tephrosin, independently. These effects did not follow time-dependent manner, and each flavonoid had its cell-dependent patterns. Overall, bavachinin, tephrosin, and candidone showed potency to sensitize MDR cells to daunorubicin and mitoxantrone and could be considered as attractive MDR modulators for cancer treatment. However, their action was time and cell specific.

Inflammatory pathway interactions and cancer multidrug resistance regulation.

Multidrug resistances against chemotherapeutics are among the major challenges related to cancer treatment. Recent studies have demonstrated that different conditions may tune the expression and activity of MDR transporters. For instance, inflammation occurs through a complex cytological process and chemical reactions in the most tumor microenvironment; it can play a critical role in cancer development and is capable of altering the expression and function of MDR transporters. Cytokines, interleukins, and prostaglandins are potent inflammatory mediators that can modulate the expression of MDRs at transcriptional and post-transcriptional levels in the most human cancer cells and tissues and potentially contribute to balance bioavailability of chemotherapeutic agents. Since cancer cases are usually accompanied by inflammatory responses, glucocorticoids and NSAIDs are the primary useful combination chemotherapies in a variety of cancer treatment protocols. In addition to the anti-inflammatory activities of these agents, they exert diverse modulatory effects on MDR-mediated drug resistance via specific mechanisms. Several factors, including cell and MDR-protein types, pharmacokinetics, and pharmacogenetics, mainly influence the regulatory mechanisms. Uncovering the networks between inflammation and multidrug resistance will be clinically helpful in the treatment of malignant cancers and decreasing the cancer mortality rates.

Intelligent TAT-coupled anti-HER2 immunoliposomes knock downed MDR1 to produce chemosensitize phenotype of multidrug resistant carcinoma.

Gene therapy using biocompatible cationic liposomes is amongst promising approaches that decreases death from cancers. Here an invasive multidrug resistant cell model has been developed by lentiviral transfection. In parallel phospholipids have been covalently conjugated to TAT, MMP2, and Herceptin. The functional lipids have been mixed to generate intelligent liposome harboring small interfering RNA (siRNA) with high efficiency. The final liposomal complex was uniformly monodisperse and particle dimension and zeta-potential were respectively around 200 nm and -42.21 mV. Minimal cytotoxic effects have been reported for nanocarriers due to good biocompatibility of the selected phospholipids. Flourescence-activated cell sorter (FACS) analyses have been represented that surface trastuzumab and TAT specifically promote cellular uptake of liposomes in the malignant tumor cells. Assessment of MDR1 transcript and protein expression has been exhibited maximum significant downregulation around of 128-fold and 50-fold, respectively after 48 hr of liposome exposure. As it has been concluded, targeted liposomes may become a potential tool in gene delivery for improving chemotherapeutic efficiency in cancer treatment.

Unlike Butylcycloheptylprodigiosin, Isolated Undecylprodigiosin from Streptomyces parvulus Is Not a MDR1 and BCRP Substrate in Multidrug-Resistant Cancers.

The search for new chemotherapeutics unaffected by efflux pumps would significantly increase life expectancy in patients with malignant cancers. In this study, butylcycloheptylprodigiosin and undecylprodigiosin were HPLC-purified and verified, using nuclear magnetic resonance spectroscopy. Cell cytotoxicity and transportation kinetics on multiple-drug resistance (MDR) cells were evaluated. Daunorubicin and butylcycloheptylprodigiosin were less toxic in the MDR1 overexpressing line, but undecylprodigiosin revealed potent toxicity toward MDR1 and BCRP expressing malignant cells. There was no noticeable change in MDR1 and BCRP transcripts during 3 days of treatment with prodiginines. While daunorubicin and mitoxantrone uptake from the cell environment significantly decreased with increasing multidrug resistance up to 46% and 62%, respectively, the accumulation of undecylprodigiosin and to a lesser extent butylcycloheptylprodigiosin in the resistance cells occurred cell- and dose-dependently via a passive diffusion process and were almost equally sensitive to the parent lines. The efflux of xenobiotics commenced immediately with different kinetics in various cells. A greater amount of daunorubicin and mitoxantrone were rapidly thrown out of their corresponding MDR cells in the absence of the specific inhibitor (3.01 and 1.81 dF/min, respectively) and represented functional efflux pumps. MDR pumps did not apparently influence undecylprodigiosin efflux patterns; but butylcycloheptylprodigiosin was partially removed from EPG85.257RDB cells at the rate of 2.66 and 1.41 dF/min in the absence and presence of verapamil, respectively.

Broad blocking of MDR efflux pumps by acetylshikonin and acetoxyisovalerylshikonin to generate hypersensitive phenotype of malignant carcinoma cells.

Cytotoxic activities of acetylshikonin and acetoxyisovalerylshikonin alone and in combination with chemotherapeutic agents against parental and drug resistant cell lines were determined using the MTT assay. Effects of Shikonin derivatives on BCRP, MDR1 and MRP transcript and protein levels were relatively measured. Finally, accumulation and efflux kinetics were conducted. The results revealed cell- and concentration-dependency of the cell cytotoxicity. Acetylshikonin and acetoxyisovalerylshikonin transiently made the mRNA ocean turbulent, but FACS analyses using fluorescent-labeled antibodies showed no significant change in the MDR-protein levels. Functional kinetics revealed significant block of MDR1, BCRP and MRP transporter in the presence of shikonin derivatives. Maximum accumulation fold changes was quantified to be 4.4 and consequently, acetoxyisovalerylshikonin pretreated EPG85.257RDB cells was chemosensitized to daunorubicin tension 3.1-fold. Although, the MDR blockage was reported to follow time- and cell-dependent patterns, MDR1, BCRP and MRP2 responses to the shikonins are concentration-independent. These data suggest uncompetitive transporter blockage behavior of these agents. The results indicated that shikonin derivatives stimulate uptake and reduce efflux of chemotherapeutic agents in the malignant cancer cells, suggesting that chemotherapy in combination with shikonin compounds may be beneficial to cancer cells that overexpress multidrug resistance transporters.