Target For Drug Resistance Research Articles

Biofilm formation in cardiovascular infection and bioengineering approaches for treatment and prevention

AbstractAt present, cardiovascular infection such as infective endocarditis (IE) has become a major disease with a high mortality rate. The essence of IE is actually the infection associated with biofilm formation, which can occur not only on native heart valves, but also on prosthetic heart valves and cardiovascular implants such as left heart assist devices, vascular grafts, and pacemakers. Biofilms are bacterial aggregates that are composed of a self‐produced extracellular polymeric substance (EPS), which is difficult and challenging for the treatment of cardiovascular infections. Therefore, it is important to explore and develop effective anti‐biofilm methods for the treatment of biofilm‐associated cardiovascular infection. This review provides comprehension of strategies for degrading EPS in biofilm, the application of nanodrug delivery systems for biofilm‐related infections, the strategy for targeting drug resistance genes through gene editing technology and strategy for targeting quorum sensing in biofilm. Furthermore, this review also provides some strategies to optimize the antibacterial properties of cardiovascular implants to prevent biofilm formation. The applications of these strategies will provide novel preventive and therapeutic ways for biofilm‐associated cardiovascular infections.

Precision Therapy for Prostate Cancer: Advancements in Polymeric Nanocarrier Systems.

Prostate cancer is a major worldwide health concern, and existing treatments often face challenges such as drug resistance, systemic toxicity, and insufficient targeting. Polymeric nanocarriers are currently employed as sophisticated tools in the field of oncology, offering the possibility to augment the administration and efficacy of anticancer therapies. In order to effectively eradicate prostate cancer, this review delves into the function of polymeric nanocarriers. Databases such as PubMed, ScienceDirect, and Google Scholar were utilized to do a comprehensive literature assessment. For this search, we used terms like "polymeric nanocarriers," "prostate cancer," "drug delivery," and "nanotechnology." Studies have shown that polymeric nanocarriers greatly improve the delivery and effectiveness of treatments for prostate cancer. Nanocarriers enhance the solubility, stability, and bioavailability of drugs, resulting in improved therapeutic effects. Functionalization using targeting ligands, such as folic acid and prostate-specific membrane antigen (PSMA) antibodies, has demonstrated the ability to enhance targeted specificity, resulting in a decrease in off-target effects and systemic toxicity. Polymeric nanocarriers facilitate precise and prolonged drug delivery, leading to elevated drug levels in tumor tissues. Polymeric nanocarriers are a notable breakthrough in the management of prostate cancer, providing precise medication administration, decreased toxicity, and improved therapy effectiveness. However, additional study is necessary to enhance the design of nanocarriers, evaluate their long-term safety, and enable their use in clinical applications. Continued interdisciplinary research and collaboration are essential for addressing current obstacles and maximizing the promise of polymeric nanocarriers in the treatment of prostate cancer.

Niosomal Encapsulation of Anti-Cancer Peptides: A Revolutionary Strategy in Cancer Therapy.

Cancer treatment has evolved significantly over the years, incorporating a range of modalities including surgery, radiation, chemotherapy, and immunotherapy. However, challenges such as drug resistance, systemic toxicity, and poor targeting necessitate innovative approaches. Peptides have gained attention in cancer therapy due to their specificity, potency, and ability to modulate various biological pathways. Peptide-based drugs can act as hormones, enzyme inhibitors, or targeting ligands, contributing to their versatile role in cancer treatment. However, peptides face several challenges, including instability, rapid degradation, and poor bioavailability. One promising strategy is the use of niosomal delivery systems for peptidebased therapies. Niosomes, which resemble liposomes in structure, are vesicles based on nonionic surfactants. They are composed of a bilayer created through the self-assembly of non-ionic surfactants in water, enabling them to encapsulate hydrophilic, lipophilic, and amphiphilic drugs. Their unique properties, such as biocompatibility, biodegradability, and ability to encapsulate diverse therapeutic agents, make them suitable for drug delivery applications. This review aims to explore how the niosomal preparation of peptides can revolutionize oncology drugs by overcoming critical challenges like drug resistance, systemic toxicity, poor targeting, instability, rapid degradation, and low bioavailability. This review aims to explore how niosomes can specifically address key limitations in cancer therapy, including targeting, bioavailability, and stability of peptide-based drugs. By consolidating recent advancements, the review sheds light on how niosomal encapsulation can overcome barriers in cancer treatment and improve therapeutic outcomes for patients.

MiRNAs: main players of cancer drug resistance target ABC transporters.

Chemotherapy remains the cornerstone of cancer treatment; however, its efficacy is frequently compromised by the development of chemoresistance. Multidrug resistance (MDR), characterized by the refractoriness of cancer cells to a wide array of chemotherapeutic agents, presents a significant barrier to achieving successful and sustained cancer remission. One critical factor contributing to this chemoresistance is the overexpression of ATP-binding cassette (ABC) transporters. Furthermore, additional mechanisms, such as the malfunctioning of apoptosis, alterations in DNA repair systems, and resistance mechanisms inherent to cancer stem cells, exacerbate the issue. Intriguingly, microRNAs (miRNAs) have demonstrated potential in modulating chemoresistance by specifically targeting ABC transporters, thereby offering promising new avenues for overcoming drug resistance. This narrative review aims to elucidate the molecular underpinnings of drug resistance, with a particular focus on the roles of ABC transporters and the regulatory influence of miRNAs on these transporters.

Innovative nanocarrier systems for enhanced delivery of phyto-active compounds in cancer therapy.

Millions of people worldwide suffer from cancer, facing challenges such as treatments affecting healthy cells, suboptimal responses, adverse effects, recurrence risk, drug resistance, and nonspecific targeting. Chemoresistance leads to fatalities, but phytoactives show promise in cancer management despite limitations such as high metabolism, poor absorption, and high dosage requirements. Challenges in the large-scale isolation of phytoactive compounds, solubility, bioavailability, and targeting limit their development. Recent developments, including carbohydrate, lipid, and protein-based nanoparticles, have enhanced cancer treatment by improving the bioavailability and targeted delivery of phytoactives such as polyphenols, alkaloids, sulfur-containing compounds, flavonoids, and terpenes. Despite advancements, clinical application faces hurdles such as poor bioavailability and inconsistent immune responses. This article discusses the promise of phytoactive-loaded nanoformulations in cancer management, highlighting targeted drug delivery, unmet needs, and challenges. Further research is needed to overcome these challenges and fully understand the potential of phytoactives in cancer management.

LOC730101 improves ovarian cancer drug sensitivity by inhibiting autophagy-mediated DNA damage repair via BECN1

Drug resistance and recurrence are still the bottlenecks in the clinical treatment of ovarian cancer (OC), seriously affecting patients’ prognosis. Therefore, it is an urgent challenge for OC to be overcome towards precision therapy by studying the mechanism of OC drug resistance, finding new drug resistance targets and developing new effective treatment strategies. In this study, we found that lncRNA LOC730101 played an essential role in attenuating drug resistance in OC. LOC730101 was significantly down-regulated in platinum-resistant ovarian cancer tissues, and ectopic overexpression of LOC730101 substantially increased chemotherapy-induced apoptosis. Mechanistically, LOC730101 specifically binds to BECN1 and inhibits the formation of autophagosome BECN1/VPS34 by reducing phosphorylation of BECN1, thereby inhibiting autophagy and promoting drug sensitivity in ovarian cancer cells following treatment with cisplatin and PARP inhibitors. Moreover, LOC730101 inhibits the expression and activity of RNF168 via p62, which in turn affects H2A ubiquitination-mediated DNA damage repair and promotes drug sensitivity in ovarian cancer cells. Our findings demonstrated that LOC730101 played an important role in regulating the formation of the autophagic complex and that inhibition of autophagy significantly enhances the drug sensitivity of OC. And LOC730101 may be used as a prognostic marker to predict the sensitivity of OC to platinum and PARP inhibitors.

Loop-mediated isothermal amplification assays for the detection of antimicrobial resistance elements in Vibrio cholera

BackgroundThe bacterium Vibrio cholerae causes diarrheal illness and can acquire genetic material leading to multiple drug resistance (MDR). Rapid detection of resistance-conferring mobile genetic elements helps avoid the prescription of ineffective antibiotics for specific strains. Colorimetric loop-mediated isothermal amplification (LAMP) assays provide a rapid and cost-effective means for detection at point-of-care since they do not require specialized equipment, require limited expertise to perform, and can take less than 30 min to perform in resource limited regions. LAMP output is a color change that can be viewed by eye, but it can be difficult to design primer sets, determine target specificity, and interpret subjective color changes.MethodsWe developed an algorithm for the in silico design and evaluation of LAMP assays within the open-source PCR Signature Erosion Tool (PSET) and a computer vision application for the quantitative analysis of colorimetric outputs. First, Primer3 calculates LAMP primer sequence candidates with settings based on GC-content optimization. Next, PSET aligns the primer sequences of each assay against large sequence databases to calculate sufficient sequence similarity, coverage, and primer arrangement to the intended taxa, ultimately generating a confusion matrix. Finally, we tested assay candidates in the laboratory against synthetic constructs.ResultsAs an example, we generated new LAMP assays targeting drug resistance in V. cholerae and evaluated existing ones from the literature based on in silico target specificity and in vitro testing. Improvements in the design and testing of LAMP assays, with heightened target specificity and a simple analysis platform, increase utility for in-field applications. Overall, 9 of the 16 tested LAMP assays had positive signal through visual and computer vision-based detection methods developed here. Here we show LAMP assays tested on synthetic AMR gene targets for aph(6), varG, floR, qnrVC5, and almG, which allow for resistance to aminoglycosides, penicillins, carbapenems, phenicols, fluoroquinolones, and polymyxins respectively.

A Pioneer Review on Lactoferrin-Conjugated Extracellular Nanovesicles for Targeting Cellular Melanoma: Recent Advancements and Future Prospects.

Melanoma, a highly aggressive form of skin cancer, presents a formidable challenge in terms of treatment due to its propensity for metastasis and resistance to conventional therapies. The development of innovative nanocarriers for targeted drug delivery has opened new avenues in cancer therapy. Lactoferrin-conjugated extracellular nanovesicles (LF-EVs) have emerged as a promising vehicle in the targeted treatment of cellular melanoma, owing to their natural biocompatibility, enhanced bioavailability, and ability to traverse biological barriers effectively. This review synthesizes recent advancements in the use of LF-EVs as a novel drug delivery system for melanoma, emphasizing their unique capacity to enhance cellular uptake through LF's receptor-mediated endocytosis pathways. Key studies demonstrate that LF conjugation significantly increases the specificity of extracellular nanovesicles for melanoma cells, minimizes off-target effects, and promotes efficient intracellular drug release. Furthermore, we explore how LF-EVs interact with the tumor microenvironment, potentially inhibiting melanoma progression and metastasis while supporting antitumor immune responses. Future prospects in this field include optimizing LF conjugation techniques, improving the scalability of LF-EV production, and integrating multifunctional payloads to target drug resistance mechanisms. This review highlights the potential of LF-EVs to transform melanoma treatment strategies, bridging current gaps in therapeutic delivery and paving the way for personalized and less invasive melanoma therapies.

Genetic surveillance shows spread of ACT resistance during period of malaria decline in Vietnam (2018-2020).

Vietnam's goal to eliminate malaria by 2030 is challenged by the further spread of drug-resistant Plasmodium falciparum malaria to key antimalarials, particularly dihydroartemisinin-piperaquine (DHA-PPQ). The custom targeted NGS amplicon sequencing assay, AmpliSeq Pf Vietnam v2, targeting drug resistance, population genetic- and other markers, was applied to detect genetic diversity and resistance profiles in samples from 8 provinces in Vietnam (n = 354), in a period of steep decline of incidence (2018-2020). Variants in 14 putative resistance genes, including P. falciparum Kelch 13 (PfK13) and P. falciparum chloroquine resistance transporter (Pfcrt), were analyzed and within-country parasite diversity was evaluated. Other targets included KEL1-lineage markers and diagnostic markers of Pfhrp2/3. A concerning level of DHA-PPQ resistance was detected. The C580Y mutation in PfK13 was found in nearly 80% of recent samples, a significant rise from previous data. Vietnam has experienced a significant challenge with the spread of DHA-PPQ resistant malaria parasites, particularly in the provinces of Binh Phuoc and Gia Lai. Resistance spread to high levels in Binh Thuan prior to the country-wide treatment policy change from DHA-PPQ to pyronadine-artesunate (PA). A complex picture of PPQ-resistance dynamics was observed, with an increase of PPQ-resistance associated Pfcrt mutations, indicating an evolutionary response to antimalarial pressure. Additionally, the compensatory mutation C258W in Pfcrt, which increases chloroquine (CQ) resistance while reversing PPQ resistance, is emerging in Gia Lai following the adoption of PA as the first-line treatment. This study found high levels of multidrug resistance, with over 70% of parasites in 6 out of 8 provinces showing significant sulfadoxine-pyrimethamine (SP) resistance and widespread chloroquine-resistant Pfcrt haplotypes. We also report an absence of P. falciparum histidine rich protein 2 and 3 (Pfhrp2/3) gene deletions, ensuring the continued reliability of HRP2/3-based rapid diagnostic tests. P. falciparum populations in Vietnam are becoming more isolated, with clonal populations showing high geographical clustering by province. The central highlands, particularly Gia Lai province, have the highest residual malaria burden but exhibit low diversity and clonal populations, likely due to the pressures from the antimalarial drugs and targeted national malaria control program (NMCP) efforts. In conclusion, examining a broad panel of full-length resistance genes and SNPs provided high-resolution insights into genetic diversity and resistance evolution in Vietnam, offering valuable information to inform local treatment and intervention strategies.

Magnetic Field/Ultrasound-Responsive Fe3O4 Microbubbles for Targeted Mechanical/Catalytic Removal of Bacterial Biofilms.

Conventional antibiotics are limited by drug resistance, poor penetration, and inadequate targeting in the treatment of bacterial biofilm-associated infections. Microbubble-based ultrasound (US)-responsive drug delivery systems can disrupt biofilm structures and enhance antibiotic penetration through cavitation effects. However, currently developed US-responsive microbubbles still depend on antibiotics and lack targeting capability. In this work, magnetic field/ultrasound (MF/US)-responsive Fe3O4 microbubbles (FMB) were constructed based on Fe3O4 nanoparticles (NPs) with superparamagnetic and peroxidase-like catalytic properties. In vitro experiments demonstrated that FMB can be targeted to methicillin-resistant Staphylococcus aureus (MRSA) biofilms by the direction of MF. Upon US irradiation, FMB collapse due to inertial cavitation and generate mechanical forces to disrupt the structure of MRSA biofilms and releases Fe3O4 NPs, which catalyze the generation of reactive oxygen species (ROS) from H2O2 in the biofilm microenvironment and kill the bacteria within the biofilm. In a mouse biofilm infection model, FMB efficiently destroyed MRSA biofilms grown in subcutaneous catheters with the MF and US. Magnetic-targeted mechanical/catalytic therapy based on FMB provides a promising strategy for effectively combating bacterial biofilm infection.

Advances in the Understanding of the Pathogenesis of Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by high aggressiveness, high malignancy, and poor prognosis compared to other breast cancer subtypes. This review aims to explore recent advances in understanding TNBC and to provide new insights and potential references for clinical treatment. We examined current literature on TNBC to analyze molecular subtypes, genetic mutations, signaling pathways, mechanisms of drug resistance, and emerging therapies. Findings highlight key aspects of TNBC's molecular subtypes, relevant mutations, and pathways, alongside emerging treatments that target drug resistance mechanisms. These insights into TNBC pathogenesis may help guide future therapeutic strategies and improve clinical outcomes for patients with TNBC.

Mechanism of Action and Pharmacokinetics of Approved Bispecific Antibodies.

Bispecific antibodies represent a significant advancement in therapeutic antibody engineering, offering the ability to simultaneously target two distinct antigens. This dual-targeting capability enhances therapeutic efficacy, especially in complex diseases, such as cancer and autoimmune disorders, where drug resistance and incomplete target coverage are prevalent challenges. Bispecific antibodies facilitate immune cell engagement and disrupt multiple signaling pathways, providing a more comprehensive treatment approach than traditional monoclonal antibodies. However, the intricate structure of bispecific antibodies introduces unique pharmacokinetic challenges, including issues related to their absorption, distribution, metabolism, and excretion, which can significantly affect their efficacy and safety. This review provides an in-depth analysis of the structural design, mechanisms of action, and pharmacokinetics of the currently approved bispecific antibodies. It also highlights the engineering innovations that have been implemented to overcome these challenges, such as Fc modifications and advanced dimerization techniques, which enhance the stability and half-life of bispecific antibodies. Significant progress has been made in bispecific antibody technology; however, further research is necessary to broaden their clinical applications, enhance their safety profiles, and optimize their incorporation into combination therapies. Continuous advancements in this field are expected to enable bispecific antibodies to provide more precise and effective therapeutic strategies for a range of complex diseases, ultimately improving patient outcomes and advancing precision medicine.

Rebooting the Adaptive Immune Response in Immunotherapy-Resistant Lung Adenocarcinoma Using a Supramolecular Albumin.

Despite the availability of immune checkpoint inhibitors (ICBs) significantly prolonging the life expectancy of some lung adenocarcinoma (LUAD) patients, their implementation and long-term effectiveness are hampered by the growing issue of acquired resistance. Herein, the bioinformatics analysis of immunotherapy-resistant LUAD patients and the system analysis of Anti-PD1-resistant mice models once again validate that the resistance-associated Wnt/β-catenin pathway offers a promising avenue for ICB sensitization. Consequently, a mild and convenient self-assembly between albumin and carnosic acid (CA), a Wnt inhibitor is employed, to develop a supramolecular albumin known as ABCA, serving as a reactivator for ICB. As anticipated, ABCA effectively suppress the Wnt/β-catenin cascade in vitro and leads to significant inhibition of cell proliferation while promoting apoptosis. Most notably, ABCA restores the anticancer efficacy of Anti-PD1 in immunotherapy-resistant LUAD orthotopic allografting mice models by reinvigorating the adaptive immune response mediated by T lymphocytes. Furthermore, ABCA exhibits minimal adverse effects during treatment and high-dose toxicity tests, underscoring its excellent potential for clinical translation. Collectively, the present work possesses the potential to provide innovative perspectives on the advancement of optimized immunotherapies targeting drug resistance, while also presenting a promising avenue for translating Wnt inhibitors into immunotherapeutic drugs for their clinical application.

The Global Trend of Drug Resistant Sites in Influenza A Virus Neuraminidase Protein from 2011 to 2020.

Influenza A virus (IAV) causes highly contagious respiratory disease worldwide, so prevention and control of IAV is extremely important. However, overuse of neuraminidase inhibitor (NAI) drugs leads to drug resistance. To explore the up-to-date geographical distribution and evolution of drug-resistant mutations (DRMs) in the NA protein of IAV, 81,492 near full-length NA sequences downloaded from NCBI and GISAID databases, including 34,481 H1N1 and 46,622 H3N2, were processed and analyzed. Our results showed the annual number of NA sequences from 2011 to 2019 continuously increased. Meanwhile, almost 85% of sequences were from developed countries in North America, Europe and Asia. Clustering analysis demonstrated H3N2 varied more than H1N1. Notably, H3N2 exhibited a higher frequency of DRMs than H1N1, with prevailing DRMs mainly located at non-active sites within the NA protein. Phylogenetic analyses showed NA harboring DRMs collected in the same year and from the same location clustered together, which may be related to the local economic level, clinical monitoring of DRMs and research level. Consequently, it is imperative to enhance global surveillance targeting drug resistance in IAV infections which can mitigate the transmission of drug-resistant strains. In summary, our research provides valuable insights for clinical medication while establishing a robust scientific basis for IAV prevention and treatment strategies to improve overall efficacy.

An analysis of the clinical significance of the TKI-resistant gene ZNF687 for hepatocellular carcinoma patients.

Novel treatments such as monotherapy and combined immunotherapy significantly extend overall survival (OS) for hepatocellular carcinoma (HCC) patients, but HCC is susceptible to treatment resistance during long-term therapy. The resistance mechanism to targeted drugs in HCC remains ambiguous, making research on HCC drug resistance targets crucial for the development of precision medicine. To investigate the transcriptional features, biological functions and potential clinical value of the tyrosine kinase inhibitor (TKI)-resistant gene ZNF687 in HCC. The TKI-resistant genes of HCC were identified using clustered regularly interspaced short palindromic repeats (CRISPR) in vitro screening. Then, the dependence of HCC cell lines on ZNF687 was investigated in silico. We collected global mRNA datasets of HCC tissue, integrated the mRNA expression characteristics of ZNF687 in HCC and explored the impact of ZNF687 on HCC patient prognoses using the Kaplan-Meier method (in silico). The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways analyses were then conducted, and a connectivity map and molecular docking technology were applied to find the underlying agent opposing ZNF687. In vitro, the guide RNA corresponding to ZNF687 was weakly detected in HCC cells, and ZNF687 deficiency was found to inhibit growth in HCC cell lines. ZNF687 mRNA was overexpressed and had a high discriminatory ability for HCC in 2,975 HCC samples, contrasting with 2,340 non-HCC samples. Moreover, an excessive ZNF687 transcript level was related to a worse overall survival (OS) prognosis. Histone modification, spliceosome, transcription coregulator activity, and nucleocytoplasmic transport were the most significant pathways for ZNF687 differential-related gene enrichment. Chaetocin was found to be a candidate compound and presented a strong affinity to ZNF687. ZNF687 represents a TKI-resistant and growth-dependent gene for HCC, the overexpression of which indicates poor OS for HCC patients. Additionally, ZNF687 is expected to be a druggable target for overcoming TKI resistance, and chaetocin may be a candidate therapeutic compound for ZNF687.

Overexpression of SLC2A1, ALDOC, and PFKFB4 in the glycolysis pathway drives strong drug resistance in 3D HeLa tumor cell spheroids.

The 3D multicellular tumor spheroid (MTS) model exhibits enhanced fidelity in replicating the tumor microenvironment and demonstrates exceptional resistance to clinical drugs compared to the 2D monolayer model. In this study, we used multiomics (transcriptome, proteomics, and metabolomics) tools to explore the molecular mechanisms and metabolic differences of the two culture models. Analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathways revealed that the differentially expressed genes between the two culture models were mainly enriched in cellular components and biological processes associated with extracellular matrix, extracellular structural organization, and mitochondrial function. An integrated analysis of three omics data revealed 11 possible drug resistance targets. Among these targets, seven genes, AKR1B1, ALDOC, GFPT2, GYS1, LAMB2, PFKFB4, and SLC2A1, exhibited significant upregulation. Conversely, four genes, COA7, DLD, IFNGR1, and QRSL1, were significantly downregulated. Clinical prognostic analysis using the TCGA survival database indicated that high-expression groups of SLC2A1, ALDOC, and PFKFB4 exhibited a significant negative correlation with patient survival. We further validated their involvement in chemotherapy drug resistance, indicating their potential significance in improving prognosis and chemotherapy outcomes. These results provide valuable insights into potential therapeutic targets that can potentially enhance treatment efficacy and patient outcomes.

Membrane P-glycoprotein expression in lymphocytes from adult patients with refractory glomerulonephritis.

To investigate the expression of P-glycoprotein in T-cell subpopulations of lymphocytes from adult patients with refractory glomerulonephritis (GN). Flow cytometry was used to analyze the T-cell subpopulations of lymphocytes from adult patients with refractory GN and healthy individuals. The CD243 antibody marked the membrane P-glycoprotein of immune cells. The mean ± standard deviation (SD) values of percentages of CD3+, CD3+CD4+, CD3+CD8+ cells in lymphocytes from patients with refractory GN were 63.94±26.98, 55.16±4.78, and 37.79±6.01%, respectively. These values in healthy individuals were 74.88±3.75, 56.60±9.22, and 34.20±5.21%, respectively. No significant differences were observed between the patients with refractory GN and healthy individuals. The mean ± SD values of percentages of CD3+CD4+CD243+ and CD3+CD8+CD243+ cells in the lymphocytes of patients with refractory GN were 0.14±0.11 and 0.11±0.07%, respectively. These values in healthy individuals were 0.05±0.02 and 0.04±0.02%, respectively. The difference in CD3+CD8+CD243+ percentage between patients with refractory GN and healthy individuals was significant (p=0.0216). These findings suggest that P-glycoprotein expression on CD3+CD8+ T cells is a promising marker and a suitable target of drug resistance in patients with refractory GN.

Upregulation of miRNA-450b-5p targets ACTB to affect drug resistance and prognosis of ovarian cancer via the PI3K/Akt signaling pathway.

Ovarian cancer (OC) is the most malignant gynecologic cancer, and chemoresistance is a major cause of treatment failure in patients with OC. The understanding of microRNA (miRNA) in cancer is limited, and the role of miRNA (miR)-450b-5p in cancer drug resistance is unknown. In this study, we aim to evaluate the role of miR-450b-5p in drug-resistant OC and its underlying mechanisms. MiR-450b-5p expression was assessed in drug-sensitive and resistant OC cells via quantitative real-time polymerase chain reaction. Cell viability was evaluated using the Cell Counting Kit-8 assay. Progression-free survival (PFS) and overall survival (OS) curves were generated using the Kaplan-Meier method and the log-rank test. Target genes of miR-450b-5p were identified from the Cancer MIRNome database. Co-expressed genes were obtained from The Cancer Genome Atlas and Cancer Genome cBioportal for pathway enrichment and functional clustering analysis. The miRNA-450b-5p expression was significantly increased in A2780 and SKOV3 OC-resistant cells and significantly increased by 17-fold in the A2780-CBP-Lv-miR-450b-5p cells compared to A2780-CBP and A2780-CBP-Lv-NC cells. The up-regulated expression of miR-450b-5p increased the cell viability and half maximal inhibitory concentration (IC50) of A2780 platinum-resistant cells and was associated with poor OS. We obtained 33 potential target genes of miR-450b-5p and beta-actin (ACTB) might be a potential target of miR-450b-5p. Low expression of ACTB predicted poor OS and PFS. We obtained 362 common genes co-expressed with ACTB, which involved 4 critical pathways. PI3K acted as an upstream pathway of the other three pathways, which ultimately responded to drug resistance regulation in OC. The genes enriched in four pathways were cross-analyzed and 13 overlapping genes were obtained. These 13 genes were also significantly and positively co-expressed with ACTB at both protein and mRNA levels. High expression of miRNA-450b-5p might affect drug resistance and prognosis in OC by targeting 13 co-expressed genes of ACTB directly through the PI3K/Akt signaling pathway. Thus, miR-450b-5p might provide a new therapeutic target for drug resistance in OC.

Targeting drug resistance in glioblastoma (Review).

Glioblastoma (GBM) is the most common malignancy of the central nervous system in adults. The current standard of care includes surgery, radiation therapy, temozolomide; and tumor‑treating fields leads to dismal overall survival. There are far limited treatments upon recurrence. Therapies to date are ineffective as a result of several factors, including the presence of the blood‑brain barrier, blood tumor barrier, glioma stem‑like cells and genetic heterogeneity in GBM. In the present review, the potential mechanisms that lead to treatment resistance in GBM and the measures which have been taken so far to attempt to overcome the resistance were discussed. The complex biology of GBM and lack of comprehensive understanding of the development of therapeutic resistance in GBM demands discovery of novel antigens that are targetable and provide effective therapeutic strategies.

Pitavastatin sensitizes the EGFR-TKI associated resistance in lung cancer by inhibiting YAP/AKT/BAD-BCL-2 pathway

BackgroundDespite effective strategies, resistance in EGFR mutated lung cancer remains a challenge. Metabolic reprogramming is one of the main mechanisms of tumor drug resistance. A class of drugs known as “statins” inhibit lipid cholesterol metabolism and are widely used in patients with cardiovascular diseases. Previous studies have also documented its ability to improve the therapeutic impact in lung cancer patients who receive EGFR-TKI therapy. Therefore, the effect of statins on targeted drug resistance to lung cancer remains to be investigated.MethodsProlonged exposure to gefitinib resulted in the emergence of a resistant lung cancer cell line (PC9GR) from the parental sensitive cell line (PC9), which exhibited a traditional EGFR mutation. The CCK-8 assay was employed to assess the impact of various concentrations of pitavastatin on cellular proliferation. RNA sequencing was conducted to detect differentially expressed genes and their correlated pathways. For the detection of protein expression, Western blot was performed. The antitumor activity of pitavastatin was evaluated in vivo via a xenograft mouse model.ResultsPC9 gefitinib resistant strains were induced by low-dose maintenance. Cell culture and animal-related studies validated that the application of pitavastatin inhibited the proliferation of lung cancer cells, promoted cell apoptosis, and restrained the acquired resistance to EGFR-TKIs. KEGG pathway analysis showed that the hippo/YAP signaling pathway was activated in PC9GR cells relative to PC9 cells, and the YAP expression was inhibited by pitavastatin administration. With YAP RNA interference, pAKT, pBAD and BCL-2 expression was decreased, while BAX expression as increased. Accordingly, YAP down-regulated significantly increased apoptosis and decreased the survival rate of gefitinib-resistant lung cancer cells. After pAKT was increased by SC79, apoptosis of YAP down-regulated cells induced by gefitinib was decreased, and the cell survival rate was increased. Mechanistically, these effects of pitavastatin are associated with the YAP pathway, thereby inhibiting the downstream AKT/BAD-BCL-2 signaling pathway.ConclusionOur study provides a molecular basis for the clinical application of the lipid-lowering drug pitavastatin enhances the susceptibility of lung cancer to EGFR-TKI drugs and alleviates drug resistance.