Efficacy Of Anticancer Drugs Research Articles

Machine learning model for anti-cancer drug combinations: Analysis, prediction, and validation

Drug combination therapy is a highly effective approach for enhancing the therapeutic efficacy of anti-cancer drugs and overcoming drug resistance. However, the innumerable possible drug combinations make it impractical to screen all synergistic drug pairs. Moreover, biological insights into synergistic drug pairs are still lacking. To address this challenge, we systematically analyzed drug combination datasets curated from multiple databases to identify drug pairs more likely to show synergy. We classified drug pairs based on their MoA and discovered that 110 MoA pairs were significantly enriched in synergy in at least one type of cancer. To improve the accuracy of predicting synergistic effects of drug pairs, we developed a suite of machine learning models that achieve better predictive performance. Unlike most previous methods that were rarely validated by wet-lab experiments, our models were validated using two-dimensional cell lines and three-dimensional tumor slice culture (3D-TSC) models, implying their practical utility. Our prediction and validation results indicated that the combination of the RTK inhibitors Lapatinib and Pazopanib exhibited a strong therapeutic effect in breast cancer by blocking the downstream PI3K/AKT/mTOR signaling pathway. Furthermore, we incorporated molecular features to identify potential biomarkers for synergistic drug pairs, and almost all potential biomarkers found connections between drug targets and corresponding molecular features using protein-protein interaction network. Overall, this study provides valuable insights to complement and guide rational efforts to develop drug combination treatments.

Effects of 7-ketocholesterol on tamoxifen efficacy in breast carcinoma cell line models in vitro

Oxysterols play significant roles in many physiological and pathological processes including cancer. They modulate some of the cancer hallmarks pathways, influence the efficacy of anti-cancer drugs, and associate with patient survival. In this study, we aimed to analyze the role of 7-ketocholesterol (7-KC) in breast carcinoma cells and its potential modulation of the tamoxifen effect. 7-KC effects were studied in two estrogen receptor (ER)-positive (MCF-7 and T47D) and one ER-negative (BT-20) breast cancer cell lines. First, we tested the viability of cells in the presence of 7-KC. Next, we co-incubated cells with tamoxifen and sublethal concentrations of 7-KC. We also tested changes in caspase 3/7 activity, deregulation of the cell cycle, and changes in expression of selected genes/proteins in the presence of tamoxifen, 7-KC, or their combination. Finally, we analyzed the effect of 7-KC on cellular migration and invasion. We found that the presence of 7-KC slightly decreases the efficacy of tamoxifen in MCF-7 cells, while an increased effect of tamoxifen and higher caspase 3/7 activity was observed in the BT-20 cell line. In the T47D cell line, we did not find any modulation of tamoxifen efficacy by the presence of 7-KC. Expression analysis showed the deregulation in CYP1A1 and CYP1B1 with the opposite trend in MCF-7 and BT-20 cells. Moreover, 7-KC increased cellular migration and invasion potential regardless of the ER status. This study shows that 7-KC can modulate tamoxifen efficacy as well as cellular migration and invasion, making 7-KC a promising candidate for future studies.

Synthesis, Characterization, and In Vitro Cytotoxicity Evaluation of Doxorubicin-Loaded Magnetite Nanoparticles on Triple-Negative Breast Cancer Cell Lines.

In this study, we investigated the cytotoxicity of doxorubicin (DOX)-loaded magnetic nanofluids on 4T1 mouse tumor epithelial cells and MDA-MB-468 human triple-negative breast cancer (TNBC) cells. Superparamagnetic iron oxide nanoparticles were synthesized using sonochemical coprecipitation by applying electrohydraulic discharge treatment (EHD) in an automated chemical reactor, modified with citric acid and loaded with DOX. The resulting magnetic nanofluids exhibited strong magnetic properties and maintained sedimentation stability in physiological pH conditions. The obtained samples were characterized using X-ray diffraction (XRD), transmission electron microscopy (TEM), Fourier-transform infrared spectroscopy, UV-spectrophotometry, dynamic light scattering (DLS), electrophoretic light scattering (ELS), vibrating sample magnetometry (VSM), and transmission electron microscopy (TEM). In vitro studies using the MTT method revealed a synergistic effect of the DOX-loaded citric-acid-modified magnetic nanoparticles on the inhibition of cancer cell growth and proliferation compared to treatment with pure DOX. The combination of the drug and magnetic nanosystem showed promising potential for targeted drug delivery, with the possibility of optimizing the dosage to reduce side-effects and enhance the cytotoxic effect on cancer cells. The nanoparticles' cytotoxic effects were attributed to the generation of reactive oxygen species and the enhancement of DOX-induced apoptosis. The findings suggest a novel approach for enhancing the therapeutic efficacy of anticancer drugs and reducing their associated side-effects. Overall, the results demonstrate the potential of DOX-loaded citric-acid-modified magnetic nanoparticles as a promising strategy in tumor therapy, and provide insights into their synergistic effects.

Identification of A novel anoikis-related genes-based signature for non-small cell lung cancer

The prognostic value of anoikis in NSCLC and its mechanism in tumorigenesis and progress have not been fully elucidated. This study aimed to reveal the correlation between anoikis-related genes (ARGs) and tumor prognosis, to reveal molecular and immune features, and to evaluate the anticancer drug sensitivity and the efficacy of immunotherapy of NSCLC. ARGs were selected from both the GeneCards and Harmonizome databases and then were intersected with the Cancer Genome Atlas (TCGA) database by differential expression analysis, followed by functional analysis of the target ARGs. An ARGs-based prognostic signature was constructed using LASSO (least absolute shrinkage and selection operator) Cox regression analysis; Kaplan-Meier analysis, univariant and multivariant Cox analysis were used to validate the value of this model in NSCLC prognosis. Differential analyses on molecular and immune landscapes were applied in the model. Anticancer drug sensitivity and efficacy in immune-checkpoint inhibitors (ICI) therapy were analyzed. A total of 509 ARGs and 168 differentially expressed ARGs in NSCLC were generated. Functional analysis revealed enrichment in extracolonic apoptotic signaling pathway, collagen-containing ECM, and integrin binding, and indicated an association with the PI3K-Akt signaling pathway. Subsequently, a 14-genes signature was generated. The high-risk group had a worse prognosis, with higherM0 and M2 macrophage infiltration, and fewer CD8 T-cells and T follicular helper (TFH) cells. The high-risk group had higher expression of immune checkpoint genes, HLA-I genes, and higher TIDE scores than the low-risk group, leading to less benefit of ICI therapy. Additionally, an Immunohistochemical staining comparison revealed that FADD was highly expressed in tumor tissue, compared to normal tissue, consistent with the previous results.

Hyaluronic Acid-Mediated Phenolic Compound Nanodelivery for Cancer Therapy.

Phenolic compounds are bioactive phytochemicals showing a wide range of pharmacological activities, including anti-inflammatory, antioxidant, immunomodulatory, and anticancer effects. Moreover, they are associated with fewer side effects compared to most currently used antitumor drugs. Combinations of phenolic compounds with commonly used drugs have been largely studied as an approach aimed at enhancing the efficacy of anticancer drugs and reducing their deleterious systemic effects. In addition, some of these compounds are reported to reduce tumor cell drug resistance by modulating different signaling pathways. However, often, their application is limited due to their chemical instability, low water solubility, or scarce bioavailability. Nanoformulations, including polyphenols in combination or not with anticancer drugs, represent a suitable strategy to enhance their stability and bioavailability and, thus, improve their therapeutic activity. In recent years, the development of hyaluronic acid-based systems for specific drug delivery to cancer cells has represented a pursued therapeutic strategy. This is related to the fact that this natural polysaccharide binds to the CD44 receptor that is overexpressed in most solid cancers, thus allowing its efficient internalization in tumor cells. Moreover, it is characterized by high biodegradability, biocompatibility, and low toxicity. Here, we will focus on and critically analyze the results obtained in recent studies regarding the use of hyaluronic acid for the targeted delivery of bioactive phenolic compounds to cancer cells of different origins, alone or in combination with drugs.

Development of a Novel Tool To Demystify Drug Distribution at Tissue-Blood Barriers.

Tissue endothelial cells express ABC-transporter enzymes that change the concentration of small molecules within different tissue compartments. These "blood-tissue barriers" have been shown to directly affect the efficacy and toxicity of anticancer, antimicrobial, psychiatric, and anti-epileptic drugs. Currently this phenomenon is best studied for the blood-brain barrier, but remains enigmatic for most other tissues. In addition, canonical pharmacokinetic theory specifically assumes an equal concentration of free drug within all tissue compartments. Inspired by Lipinski's "rule of 5," we here clarify current knowledge on drug-tissue distribution by: 1) curating the in-vivo literature on 73 drugs across 23 tissues and 2) developing two graphical web-based applications to visually describe and interpret data. These curated in-vivo dataset and visualization tools enabled us to achieve new insights into the logic of the barrier-tissue organization and showed remarkable correspondence to whole-body imaging of radiolabeled molecules.

Preparation and Characterization of 5‐Fluorouracil Loaded Cellulose and Exosome Nanocarriers: Sustained Release Behavior and Cytotoxicity Studies**

AbstractIn recent years, much effort has been devoted to designing nanoparticle drug delivery systems and improving the efficacy of anticancer drugs. This study focused on the preparation of a novel biocompatible nanocarrier based on bacterial cellulose (BC) in the presence of exosome (Exo) for the controlled release of 5‐fluorouracil (5‐FU), known as 5‐FU.Exo@BC. The physicochemical properties of 5‐FU.Exo@BC were thoroughly characterized using field emission scanning electron microscopy (FESEM), differential scanning calorimetry (DSC), Fourier‐transform infrared spectroscopy (FTIR), and X‐ray diffraction (XRD). These results confirmed the successful preparation of 5‐FU.Exo@BC. The release behavior of 5‐FU.Exo@BC compared with 5‐FU and 5‐FU@BC demonstrated a significant sustained release over 162 h. The release mechanism of the above three systems followed Korsmeyer‐Peppas with non‐Fickian diffusion for 5‐FU@BC and 5‐FU.Exo@BC. Furthermore, the viability of HT‐29 cells (human colon cancer cell lines) against BC, 5‐FU@BC and 5‐FU.Exo@BC indicated that 5‐FU has promising efficacy in 5‐FU.Exo@BC system. Subsequently, the prepared bio‐nanocomposite could be suggested as a potential drug delivery system with an effective controlled‐release function.

The Role of Natural Products in the Improvement of Cancer-Associated Cachexia.

The enormous library of natural products and herbal medicine prescriptions presents endless research avenues. However, the lack of research evidence and trials on cancer-induced cachexia limit the therapeutic potential of natural products. Cancer-induced cachexia is a systemic wasting syndrome characterized by continuous body weight loss with skeletal muscle and adipose tissue atrophy. Cancer cachexia is a problem in itself and reduces the quality of life by lessening the treatment efficacy of anticancer drugs. This review summarizes single natural product extracts for cancer-induced cachexia, not compounds derived from natural products and herbal medicine prescriptions. This article also discusses the effect of natural products on cachexia induced by anticancer drugs and the role of AMPK in cancer-induced cachexia. The article included the mice model used in each experiment to encourage researchers to utilize animal models for research on cancer-induced cachexia in the future.

Model-based assessment of combination therapies – ranking of radiosensitizing agents in oncology

BackgroundTo increase the chances of finding efficacious anticancer drugs, improve development times and reduce costs, it is of interest to rank test compounds based on their potential for human use as early as possible in the drug development process. In this paper, we present a method for ranking radiosensitizers using preclinical data.MethodsWe used data from three xenograft mice studies to calibrate a model that accounts for radiation treatment combined with radiosensitizers. A nonlinear mixed effects approach was utilized where between-subject variability and inter-study variability were considered. Using the calibrated model, we ranked three different Ataxia telangiectasia-mutated inhibitors in terms of anticancer activity. The ranking was based on the Tumor Static Exposure (TSE) concept and primarily illustrated through TSE-curves.ResultsThe model described data well and the predicted number of eradicated tumors was in good agreement with experimental data. The efficacy of the radiosensitizers was evaluated for the median individual and the 95% population percentile. Simulations predicted that a total dose of 220 Gy (5 radiation sessions a week for 6 weeks) was required for 95% of tumors to be eradicated when radiation was given alone. When radiation was combined with doses that achieved at least 8 mu mathrm{g}/mathrm{mL} of each radiosensitizer in mouse blood, it was predicted that the radiation dose could be decreased to 50, 65, and 100 Gy, respectively, while maintaining 95% eradication.ConclusionsA simulation-based method for calculating TSE-curves was developed, which provides more accurate predictions of tumor eradication than earlier, analytically derived, TSE-curves. The tool we present can potentially be used for radiosensitizer selection before proceeding to subsequent phases of the drug discovery and development process.

Sinapic acid and 3,3′-diindolylmethane potentiate cyclophosphamide antitumor activity through induction of apoptosis and inhibition of metastasis

New therapeutic strategies are required to enhance the anticancer efficacy of chemotherapeutic drugs and to reduce their cytotoxicity. The purpose of this study was to assess the anti-tumor, antimetastatic and anti-apoptotic activities of sinapic acid (SA) and 3,3'-diindolylmethane (DIM) in solid Ehrlich carcinoma (SEC) induced in mice and combining SA or DIM compounds with cyclophosphamide (CYP). For induction of solid tumor, the right hind limbs of mice were inoculated subcutaneously with Ehrlich carcinoma cells. After 5days of tumor inoculation, mice were treated with SA (56mg/kg), DIM (40mg/kg), CYP (10mg/kg), and their combinations (SA/CYP) and (SA/DIM) for 21days. The mRNA levels of Elabela, Serpina3, caspase-3, MMP-2 and MMP-9 were assessed by qPCR. Tumor and liver tissues were stained with hematoxylin and eosin for histological examination. Serum was investigated for ALT and AST activities. Treatment of SEC mice with SA and DIM significantly reduced solid tumor weight by 45.6% and 33.2%, respectively. They also reduced tumor size and increased life span of SEC mice. SA and DIM diminished area of metastatic nodules of tumor cells in the liver by 54.1% and 47.4%, respectively. They also reduced serum aminotransferases activities. Both SA and DIM were found to upregulate caspase 3 and downregulate MMP-2 and MMP-9. Furthermore, SA and DIM reduced gene expression of Elabela by (44.8% and 35.1%) and Serpina3 by (30.7% and 23.5%), respectively. SA and DIM were also shown to potentiate the anti-tumor activity CYP. SA and DIM showed promising antitumor effects and enhanced CYP antitumor activity mostly through upregulation of apoptotic caspase 3 and suppressing metastatic enzymes MMP-2 and MMP-9. Additionally, SA and DIM exhibited a hepatoprotective effect. Our results suggest that these natural compounds may be used to improve the efficacy and reduce the adverse effects of chemotherapeutic drugs in the treatment of solid malignancies.

The Emerging Role of Histone Deacetylase Inhibitors in Cervical Cancer Therapy.

Cervical carcinoma is one of the most common cancers among women globally. Histone deacetylase inhibitors (HDACIs) constitute anticancer drugs that, by increasing the histone acetylation level in various cell types, induce differentiation, cell cycle arrest, and apoptosis. The aim of the current review is to study the role of HDACIs in the treatment of cervical cancer. A literature review was conducted using the MEDLINE and LIVIVO databases with a view to identifying relevant studies. By employing the search terms "histone deacetylase" and "cervical cancer", we managed to identify 95 studies published between 2001 and 2023. The present work embodies the most up-to-date, comprehensive review of the literature centering on the particular role of HDACIs as treatment agents for cervical cancer. Both well-established and novel HDACIs seem to represent modern, efficacious anticancer drugs, which, alone or in combination with other treatments, may successfully inhibit cervical cancer cell growth, induce cell cycle arrest, and provoke apoptosis. In summary, histone deacetylases seem to represent promising future treatment targets in cervical cancer.

Abstract 5338: A novel in vitro assay to evaluate the roles of hepatic metabolism on anticancer drug safety and efficacy

Abstract It has been well-established that hepatic drug metabolism may have significant impact on the efficacy and off-target toxicity of anticancer drugs. We present here an in vitro assay, the metabolism-dependent cytotoxicity assay (MDCA), for the evaluation of the roles of specific pathways on the efficacy of anticancer drugs. The assay employs a novel in vitro hepatic metabolic system, the permeabilized cofactor-supplemented human hepatocytes (MetMax Human Hepatocytes, MMHH), as an exogenous metabolic activating system for the evaluation of the in vitro cytotoxicity of anticancer agents towards a designated tumor and nontumor cells. MMHH are derived from cryopreserved human hepatocytes isolated from human livers procured for but not used for transplantation provided to our laboratory from the International Institute for the Advancement of Medicine. We have previously demonstrated that MMHH retained all drug metabolizing enzyme pathways present in human hepatocytes. The advantages of MMHH include the following: 1. Drug metabolizing enzyme activities are not affected by cytotoxicity of the drug substrate, a major limitation of intact human hepatocytes; and 2. Drug metabolism pathways can be selected by cofactor specification (e.g. NADPH/NAD+ for phase 1 oxidation; Uridine 5′-diphosphoglucuronic acid (UDPGA) for glucuronidation; 3'-phosphoadenosine 5'-phosphosulfate (PAPS) for sulfation; N-acetyl coenzyme A for N-acetylation). We present here a proof-of-concept study to evaluate the role of various hepatic metabolic pathways towards the cytotoxicity of cyclophosphamide, a commonly used drug for the treatment of renal carcinoma, towards a renal cancer cell line, HEK293 cells. We observed that NADPH enhanced the cytotoxicity, consistent with the known metabolic activation of cyclophosphamide by P450 isoforms (e.g. CYP2B6; CYP3A4) to the known metabolic activation of cyclophosphamide to 4-hydroxycloophosphamide, followed by the formation of the ultimate cytotoxic metabolites phosphoramide mustard and acrolein, which are responsible for its anticancer properties. In addition, we found that the addition of L-glutathione attenuated cyclophosphamide cytotoxicity towards the HEK293 cells, an observation consistent with the roles of this cellular detoxification system in the resistance of tumor cells to chemotherapeutic agents. Minimal effects were observed for UDPGA and PAPS, consistent with the known noninvolvement of these phase 2 conjugating pathways in cyclophosphamide metabolism. MDCA represents an in vitro experimental system that can be routinely applied towards the discovery and development of novel anticancer drugs to evaluate the roles of drug metabolism in efficacy and safety, with various cancer cells (e.g. prostate carcinoma, neuroblastoma) and cells from normal tissues (e.g. cardiomyocytes, intestinal mucosal cells), respectively, as target cells. Citation Format: Albert P. Li, Hong Wei. A novel in vitro assay to evaluate the roles of hepatic metabolism on anticancer drug safety and efficacy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5338.

Abstract 4667: Establishment of patient-derived human cell lines using PDX mouse model for intrahepatic cholangiocarcinoma

Abstract Background: In recent years, patient tumor transplant models (PDX models) have attracted method that can predict the effects of anticancer drugs on patients. The PDX model is a technique in which the patient's tumor tissue is directly transplanted into immunodeficient mice. Tumors can grow three-dimensionally in a living mouse, so compared to culturing in petri dishes, the situation is like the growth of tumors in the patient's body. In addition, there are reports that the efficacy of anticancer drugs in patients and the results of administration of anticancer drugs in PDX show a high concordance rate, and it is attracting attention as a model that can predict efficacy in patients. In this time, we report on the establishment of cell lines using PDX mice for resected cases of intrahepatic cholangiocarcinoma in our hospital. Methods: Twelve patients who underwent surgical resection between September 2019 and December 2021 were included. After resected the tumor, the tumor was transplanted into up to 10 PDX mice, and cell lines were established from the formed tumor tissue. Results: Of the 12 cases, tumors formed in PDX mice after transplantation in 6 cases, and the median time to engraftment after the first transplantation was 133 days (75-188). Furthermore, among the 6 cases, 3 cases achieved the establishment of cell lines.Case1:moderately differentiated adenocarcinoma, tumor diameter 50mm, single, vascular invasion positive, no lymph node metastasis, Stage IIIA (UICC 8th)Case2:well differentiated adenocarcinoma, tumor diameter 60mm, single, vascular invasion negative, no lymph node metastasis, Stage II (UICC 8th)Case 3:moderately differentiated adenocarcinoma, tumor diameter 55mm, single, vascular invasion positive, no lymph node metastasis, Stage IIIA (UICC 8th) Conclusion: The cell line we established this time is a case of advanced cancer, and we would like to continue to increase the number of cases and continue to establish cell lines, which will lead to future research. Citation Format: Takashi Matsumoto. Establishment of patient-derived human cell lines using PDX mouse model for intrahepatic cholangiocarcinoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4667.

Replacement, Reduction, and Refinement of Animal Experiments in Anticancer Drug Development: The Contribution of 3D In Vitro Cancer Models in the Drug Efficacy Assessment.

In the last decades three-dimensional (3D) in vitro cancer models have been proposed as a bridge between bidimensional (2D) cell cultures and in vivo animal models, the gold standards in the preclinical assessment of anticancer drug efficacy. 3D in vitro cancer models can be generated through a multitude of techniques, from both immortalized cancer cell lines and primary patient-derived tumor tissue. Among them, spheroids and organoids represent the most versatile and promising models, as they faithfully recapitulate the complexity and heterogeneity of human cancers. Although their recent applications include drug screening programs and personalized medicine, 3D in vitro cancer models have not yet been established as preclinical tools for studying anticancer drug efficacy and supporting preclinical-to-clinical translation, which remains mainly based on animal experimentation. In this review, we describe the state-of-the-art of 3D in vitro cancer models for the efficacy evaluation of anticancer agents, focusing on their potential contribution to replace, reduce and refine animal experimentations, highlighting their strength and weakness, and discussing possible perspectives to overcome current challenges.

Chloroquine synergizes doxorubicin efficacy in cervical cancer cells through flux impairment and down regulation of proteins involved in the fusion of autophagosomes to lysosomes

Drug repurposing holds abundant opportunity in the development of novel anticancer drugs. Chloroquine (CQ), a FDA approved anti-malarial drug, is demonstrated to enhance anticancer efficacy of standard anticancer drugs including doxorubicin (DOX) in several types of cancer cells. Here, we aimed to exploit the chemosensitizing effects of CQ against DOX in human cervical cancer (HeLa) cells that remains to be investigated yet. We show that a combination of DOX (40 nM) and CQ (40 μM) resulted in a synergistic cytotoxicity (combination index; CI < 1) in HeLa cells compared to the DOX or CQ alone. Synergistic effect of the combination (DOX + CQ) was associated with the impaired autophagic flux and enhanced apoptosis. Following treatment with the combination (DOX + CQ), the level of p62/SQSTM and LC-3II proteins was increased, while a decrease was noted in the expression of LAMP-2, Syntaxin17, Rab 5, and Rab 7 proteins that play critical roles in the fusion of autophagosomes to lysosomes. Autophagy inhibition by combination (DOX + CQ) enhanced the apoptotic cell death synergistically by increasing the cleavage of procaspase-3 and PARP1. Further, a prior incubation of HeLa cells with Z-VAD-FMK (a pan-caspase inhibitor) for 4 h, suppressed the combination (DOX + CQ)-induced cell death. Our data suggest that a combination of DOX + CQ had a better anti-cancer efficacy in HeLa cells than either of the drugs alone. Thus, CQ, as a repurposed drug, may hold the potential to synergize anticancer effects of DOX in cervical cancer cells.

Dual roles of TRIM3 in colorectal cancer by retaining p53 in the cytoplasm to decrease its nuclear expression

Colorectal cancer is a very heterogeneous disease caused by the interaction of genetic and environmental factors. P53, as a frequent mutation gene, plays a critical role in the adenoma-carcinoma transition during the tumorous pathological process. Our team discovered TRIM3 as a tumor-associated gene in CRC by high-content screening techniques. TRIM3 demonstrated both tumor-suppressive and tumorigenic features in cell experiments dependent on the cell status of wild or mutant p53. TRIM3 could directly interact with the C terminus of p53 (residues 320 to 393), a common segment of wtp53 and mutp53. Moreover, TRIM3 could exert different neoplastic features by retaining p53 in the cytoplasm to decrease its nuclear expression in a wtp53 or mutp53-dependent pathway. Chemotherapy resistance develops in nearly all patients with advanced CRC and seriously limits the therapeutic efficacies of anticancer drugs. TRIM3 could reverse the chemotherapy resistance of oxaliplatin in mutp53 CRC cells by degradation of mutp53 in the nuclei to downregulate the multidrug resistance gene. Therefore, TRIM3 could be a potential therapeutic strategy to improve the survival of CRC patients with mutp53.

A detailed insight of the tumor targeting using nanocarrier drug delivery system

Human struggle against the deadly disease conditions is continued since ages. The contribution of science and technology in fighting against these diseases cannot be ignored exclusively due to the invention of novel procedure and products, extending their size ranges from micro to nano. Recently nanotechnology has been gaining more consideration for its ability to diagnose and treat different cancers. Different nanoparticles have been used to evade the issues related with conservative anticancer delivery systems, including their nonspecificity, adverse effects and burst release. These nanocarriers including, solid lipid nanoparticles (SLNs), liposomes, nano lipid carriers (NLCs), nano micelles, nanocomposites, polymeric and magnetic nanocarriers, have brought revolutions in antitumor drug delivery. Nanocarriers improved the therapeutic efficacy of anticancer drugs with better accumulation at the specific site with sustained release, improved bioavailability and apoptosis of the cancer cells while bypassing the normal cells. In this review, the cancer targeting techniques and surface modification on nanoparticles are discussed briefly with possible challenges and opportunities. It can be concluded that understanding the role of nanomedicine in tumor treatment is significant, and therefore, the modern progressions in this arena is essential to be considered for a prosperous today and an affluent future of tumor patients.

Short- and Long-term Repercussions of Vancomycin on Immune Surveillance and the Efficacy of Antitumor Treatments.

Although antibiotic is a major contributor to shifts in the intestinal flora that may persist for up to several months after cessation, it is now increasingly recognized that its prescription may differentially influence clinical outcome of different anticancer treatments. Intense clinical and basic research efforts aim then at gaining sufficient insights about how the cooperative action between the intestinal ecosystem and immune surveillance modulates the efficacy of anticancer treatments. In this review, we summarize multiple levels of knowledge between vancomycin exposure, the gut microbiota, and a meaningful therapeutic response. Furthermore, we discuss the mode of action of antibiotic therapy that is prescribed for prophylaxis of bacteremia and neutropenia and outline the opportunity for judiciously improving the efficacy of anticancer drugs.

Polylactic acid based biodegradable hybrid block copolymeric nanoparticle mediated co-delivery of salinomycin and doxorubicin for cancer therapy

Existence of cancer stem cells (CSCs) are primarily responsible for chemoresistance, cancer reoccurrence and treatment failure in cancer patients. Eliminating CSCs along with bulk tumor is a necessity to achieve complete cancer inhibition. Salinomycin (SAL) has potential to specifically target and kill CSCs through blocking their multiple pathways simultaneously. SAL has also been reported to improve anti-cancer efficacy of numerous chemo-based drugs when used in combination therapy. However, clinical use of SAL is restricted due to its high off targeted toxicity. Herein, we have developed a PLA based hybrid block copolymer for concomitant delivery of SAL and doxorubicin (DOX) with an aim to reduce their adverse side effects and enhance the therapeutic efficacy of the treatment. Designed PLA based nanoplatform showed high encapsulation and sustained release profile for both the drugs. Cytotoxicity evaluation on cancer cell lines confirmed the synergistic effect of SAL:DOX co-loaded NPs. Additionally, prepared SAL NPs were also found to be highly effective against chemo-resistant cancer cells and CSCs derived from cancer patient. Most importantly, encapsulation of SAL in PLA NPs improved its pharmacokinetics and biodistribution profile. Consequently, undesired toxicity with SAL NPs was significantly reduced which in-turn increased the dose tolerability in mice as compared to free SAL. Treatment of EAC tumor bearing mice with SAL:DOX co-loaded NPs resulted in excellent tumor regression and complete inhibition of cancer reoccurrence. These results conclude that concomitant delivery of SAL and DOX using PLA based block copolymeric nano-carrier have a strong potential for cancer therapy.

In Vivo Reversal of P-Glycoprotein-Mediated Drug Resistance in a Breast Cancer Xenograft and in Leukemia Models Using a Novel, Potent, and Nontoxic Epicatechin EC31.

The modulation of P-glycoprotein (P-gp, ABCB1) can reverse multidrug resistance (MDR) and potentiate the efficacy of anticancer drugs. Tea polyphenols, such as epigallocatechin gallate (EGCG), have low P-gp-modulating activity, with an EC50 over 10 μM. In this study, we optimized a series of tea polyphenol derivatives and demonstrated that epicatechin EC31 was a potent and nontoxic P-gp inhibitor. Its EC50 for reversing paclitaxel, doxorubicin, and vincristine resistance in three P-gp-overexpressing cell lines ranged from 37 to 249 nM. Mechanistic studies revealed that EC31 restored intracellular drug accumulation by inhibiting P-gp-mediated drug efflux. It did not downregulate the plasma membrane P-gp level nor inhibit P-gp ATPase. It was not a transport substrate of P-gp. A pharmacokinetic study revealed that the intraperitoneal administration of 30 mg/kg of EC31 could achieve a plasma concentration above its in vitro EC50 (94 nM) for more than 18 h. It did not affect the pharmacokinetic profile of coadministered paclitaxel. In the xenograft model of the P-gp-overexpressing LCC6MDR cell line, EC31 reversed P-gp-mediated paclitaxel resistance and inhibited tumor growth by 27.4 to 36.1% (p < 0.001). Moreover, it also increased the intratumor paclitaxel level in the LCC6MDR xenograft by 6 fold (p < 0.001). In both murine leukemia P388ADR and human leukemia K562/P-gp mice models, the cotreatment of EC31 and doxorubicin significantly prolonged the survival of the mice (p < 0.001 and p < 0.01) as compared to the doxorubicin alone group, respectively. Our results suggested that EC31 was a promising candidate for further investigation on combination therapy for treating P-gp-overexpressing cancers.