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Cell Communication and Signaling : CCS Jun 2024Multidrug resistance (MDR) limits successful cancer chemotherapy. P-glycoprotein (P-gp), BCRP and MRP1 are the key triggers of MDR. Unfortunately, no MDR modulator was...
BACKGROUND
Multidrug resistance (MDR) limits successful cancer chemotherapy. P-glycoprotein (P-gp), BCRP and MRP1 are the key triggers of MDR. Unfortunately, no MDR modulator was approved by FDA to date. Here, we will investigate the effect of BI-2865, a pan-KRAS inhibitor, on reversing MDR induced by P-gp, BCRP and MRP1 in vitro and in vivo, and its reversal mechanisms will be explored.
METHODS
The cytotoxicity of BI-2865 and its MDR removal effect in vitro were tested by MTT assays, and the corresponding reversal function in vivo was assessed through the P-gp mediated KBv200 xenografts in mice. BI-2865 induced alterations of drug discharge and reservation in cells were estimated by experiments of Flow cytometry with fluorescent doxorubicin, and the chemo-drug accumulation in xenografts' tumor were analyzed through LC-MS. Mechanisms of BI-2865 inhibiting P-gp substrate's efflux were analyzed through the vanadate-sensitive ATPase assay, [I]-IAAP-photolabeling assay and computer molecular docking. The effects of BI-2865 on P-gp expression and KRAS-downstream signaling were detected via Western blotting, Flow cytometry and/or qRT-PCR. Subcellular localization of P-gp was visualized by Immunofluorescence.
RESULTS
We found BI-2865 notably fortified response of P-gp-driven MDR cancer cells to the administration of chemo-drugs including paclitaxel, vincristine and doxorubicin, while such an effect was not observed in their parental sensitive cells and BCRP or MRP1-driven MDR cells. Importantly, the mice vivo combination study has verified that BI-2865 effectively improved the anti-tumor action of paclitaxel without toxic injury. In mechanism, BI-2865 prompted doxorubicin accumulating in carcinoma cells by directly blocking the efflux function of P-gp, which more specifically, was achieved by BI-2865 competitively binding to the drug-binding sites of P-gp. What's more, at the effective MDR reversal concentrations, BI-2865 neither varied the expression and location of P-gp nor reduced its downstream AKT or ERK1/2 signaling activity.
CONCLUSIONS
This study uncovered a new application of BI-2865 as a MDR modulator, which might be used to effectively, safely and specifically improve chemotherapeutic efficacy in the clinical P-gp mediated MDR refractory cancers.
Topics: Humans; Animals; Drug Resistance, Neoplasm; Drug Resistance, Multiple; Mice; Cell Line, Tumor; ATP Binding Cassette Transporter, Subfamily B, Member 1; Xenograft Model Antitumor Assays; Mice, Nude; Doxorubicin; Mice, Inbred BALB C; Female
PubMed: 38872211
DOI: 10.1186/s12964-024-01698-4 -
Synthetic and Systems Biotechnology Dec 2024Taxanes are kinds of diterpenoids with important bioactivities, such as paclitaxel (taxol®) is an excellent natural broad-spectrum anticancer drug. Attempts to...
Taxanes are kinds of diterpenoids with important bioactivities, such as paclitaxel (taxol®) is an excellent natural broad-spectrum anticancer drug. Attempts to biosynthesize taxanes have made with limited success, mainly due to the bottleneck of the low efficiency catalytic elements. In this study, we developed an artificial synthetic system to produce taxanes from mevalonate (MVA) by coupling biological and chemical methods, which comprises multi-enzyme catalytic module, chemical catalytic module and yeast cell catalytic module. Through optimizing multienzyme catalytic system, the yield of taxadiene was increased to 946.7 mg/L from MVA within 8 h and the productivity was 14.2-fold higher than microbial fermentation. By incorporating palladium catalysis, the conversion rate of Taxa-4(20),11(12)-dien-5α-yl acetate (T5α-AC) reached 48 %, effectively addressing the product promiscuity and the low yield rate of T5αOH. Finally, we optimized the expression of T10βOH in yeast resulting in the biosynthesis of Taxa-4(20),11(12)-dien-5α-acetoxy-10β-ol(T5α-AC-10β-ol) at a production of 15.8 mg/L, which displayed more than 2000-fold higher than that produced by co-culture fermentation strategy. These technologies offered a promising new approach for efficient synthesis of taxanes.
PubMed: 38868609
DOI: 10.1016/j.synbio.2024.05.002 -
Heliyon Jun 2024An mRNA expression-based stemness index (mRNAsi) has been developed to characterize cancer stemness. However, the predictive value of mRNAsi-based signature in...
OBJECTIVE
An mRNA expression-based stemness index (mRNAsi) has been developed to characterize cancer stemness. However, the predictive value of mRNAsi-based signature in therapeutic resistance and immunotherapy in thyroid cancer (THCA) remains unclarified. This study evaluated and validated the role of mRNAsi in drug sensitivity, its relationship between mRNAsi and THCA clinical features and immunity based on bioinformatics.
METHODS
Based on transcriptome data of THCA patients from the Tumor Genome Atlas Project (TCGA) database, and expression data of multifunctional stem cell samples from the Progenitor Cell Biology Consortium (PCBC) databases, mRNAsi was calculated by the " one class logistic regression (OCLR)" method, Molecular subtypes of TCGA-THCA samples were identified with mRNAsi-related genes using ConsensusClusterPlus method. The gene mutation, clinical characteristics, immune characteristics, TIDE and drug sensitivity were compared among molecular subtypes. A prognostic model was designed with Lasso cox method. Modulation of malignant phenotype of THCA cell lines by model characterization genes is validated by CCK-8, flow cytometry. DNA methylation disorder in promoter region was analyzed between risk groups. The model was validated for survival in the internal Test dataset, while TCGA pan-cancer and immunotherapy datasets were further employed to validate the performance of this model.
RESULTS
We obtained a total of 78 stem cell samples, each containing the expression profile of 8087 mRNA genes. Based on mRNAsi, THCA was divided into 3 subtypes. Subtype C2 had the poorest prognosis and highest immune score, while subtype C3 had the best prognosis, lowest mRANsi and highest TIDE score. Patients in subtype C2 showed higher sensitivity to Cisplatin, Erlotinib, Paclitaxel, and Lapatinib. The prognostic signature was generated using 5 mRNAsi-related genes, which could predict prognosis for THCA. qRT-PCR results showed that the expression of 5 genes were various in Hth7 and KTC-1 cells, and inhibition CELSR3 expression increased percentage of apoptosis in Hth7 and KTC-1 cells. mRNAsi related DNA methylation sites were mainly enriched in tumor related pathways. Good performance of this model was validated in Test dataset, pan-cancer and immunotherapy datasets.
CONCLUSION
This study identified three subtypes for classification and developed a prognostic model with mRNAsi-related genes, which provided great potential for prognosis and immunotherapy prediction.
PubMed: 38868069
DOI: 10.1016/j.heliyon.2024.e31970 -
Communications Chemistry Jun 2024The discovery of selective Nav1.7 inhibitors is a promising approach for developing anti-nociceptive drugs. In this study, we present a novel oxindole-based readily...
The discovery of selective Nav1.7 inhibitors is a promising approach for developing anti-nociceptive drugs. In this study, we present a novel oxindole-based readily accessible library (OREAL), which is characterized by readily accessibility, unique chemical space, ideal drug-like properties, and structural diversity. We used a scaffold-based approach to screen the OREAL and discovered compound C4 as a potent Nav1.7 inhibitor. The bioactivity characterization of C4 reveals that it is a selective Nav1.7 inhibitor and effectively reverses Paclitaxel-induced neuropathic pain (PINP) in rodent models. Preliminary toxicology study shows C4 is negative to hERG. The consistent results of molecular docking and molecular simulations further support the reasonability of the in-silico screening and show the insight of the binding mode of C4. Our discovery of C4 paves the way for pushing the Nav1.7-based anti-nociceptive drugs forward to the clinic.
PubMed: 38866907
DOI: 10.1038/s42004-024-01213-3 -
Annals of Oncology : Official Journal... Jun 2024Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary...
BACKGROUND
Part 1 of the RUBY trial (NCT03981796) evaluated dostarlimab plus carboplatin-paclitaxel compared with placebo plus carboplatin-paclitaxel in patients with primary advanced or recurrent endometrial cancer. At the first interim analysis, the trial met one of its dual-primary endpoints with statistically significant progression-free survival benefits in the mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) and overall populations. Overall survival (OS) results are reported from the second interim analysis.
PATIENTS AND METHODS
RUBY is a phase 3, global, double-blind, randomized, placebo-controlled trial. Part 1 of RUBY enrolled eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer who were randomly assigned (1:1) to receive either dostarlimab (500 mg) or placebo, plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. OS was a dual-primary endpoint.
RESULTS
A total of 494 patients were randomized (245 in dostarlimab arm; 249 in placebo arm). In the overall population, with 51% maturity, RUBY met the dual-primary endpoint for OS at this second interim analysis, with a statistically significant reduction in the risk of death (HR = 0.69; 95% CI, 0.54-0.89; P = 0.0020) in patients treated with dostarlimab plus carboplatin-paclitaxel versus carboplatin-paclitaxel alone. The risk of death was lower in the dMMR/MSI-H population (HR = 0.32; 95% CI, 0.17-0.63; nominal P = 0.0002) and a trend in favor of dostarlimab was seen in the mismatch repair proficient/microsatellite stable (MMRp/MSS) population (HR = 0.79; 95% CI, 0.60-1.04; nominal P = 0.0493). The safety profile for dostarlimab plus carboplatin-paclitaxel was consistent with the first interim analysis.
CONCLUSIONS
Dostarlimab in combination with carboplatin-paclitaxel demonstrated a statistically significant and clinically meaningful overall survival benefit in the overall population of patients with primary advanced or recurrent endometrial cancer while demonstrating an acceptable safety profile.
PubMed: 38866180
DOI: 10.1016/j.annonc.2024.05.546 -
Journal of Cellular and Molecular... Jun 2024Chemotherapy resistance remains a significant challenge in treating ovarian cancer effectively. This study addresses this issue by utilizing a dual drug-loaded...
Chemotherapy resistance remains a significant challenge in treating ovarian cancer effectively. This study addresses this issue by utilizing a dual drug-loaded nanomicelle system comprising albendazole (ABZ) and paclitaxel (PTX), encapsulated in a novel carrier matrix of D-tocopheryl polyethylene glycol 1000 succinate vitamin E (TPGS), soluplus and folic acid. Our objective was to develop and optimize this nanoparticulate delivery system using solvent evaporation techniques to enhance the therapeutic efficacy against ovarian cancer. The formulation process involved pre-formulation, formulation, optimization, and comprehensive characterization of the micelles. Optimization was conducted through a 32 factorial design, focusing on the effects of polymer ratios on particle size, zeta potential, polydispersity index (PDI) and entrapment efficiency (%EE). The optimal formulation demonstrated improved dilution stability, as indicated by a critical micelle concentration (CMC) of 0.0015 mg/mL for the TPGS-folic acid conjugate (TPGS-FOL). Extensive characterization included differential scanning calorimetry (DSC), nuclear magnetic resonance (NMR), and Fourier-transform infrared spectroscopy (FTIR). The release profile exhibited an initial burst followed by sustained release over 90 h. The cytotoxic potential of the formulated micelles was superior to that of the drugs alone, as assessed by MTT assays on SKOV3 ovarian cell lines. Additionally, in vivo studies confirmed the presence of both drugs in plasma and tumour tissues, suggesting effective targeting and penetration. In conclusion, the developed TPGS-Fol-based nanomicelles for co-delivering ABZ and PTX show promising results in overcoming drug resistance, enhancing solubility, sustaining drug release, and improving therapeutic outcomes in ovarian cancer treatment.
Topics: Female; Paclitaxel; Micelles; Albendazole; Ovarian Neoplasms; Humans; Animals; Cell Line, Tumor; Drug Carriers; Polyethylene Glycols; Vitamin E; Folic Acid; Mice; Drug Liberation; Particle Size; Polyvinyls; Polymers; Xenograft Model Antitumor Assays
PubMed: 38864691
DOI: 10.1111/jcmm.18389 -
Aging Jun 2024Lung adenocarcinoma (LUAD) is a prevalent malignant tumor worldwide, with high incidence and mortality rates. However, there is still a lack of specific and sensitive...
PURPOSE
Lung adenocarcinoma (LUAD) is a prevalent malignant tumor worldwide, with high incidence and mortality rates. However, there is still a lack of specific and sensitive biomarkers for its early diagnosis and targeted treatment. Disulfidptosis is a newly identified mode of cell death that is characteristic of disulfide stress. Therefore, exploring the correlation between disulfidptosis-related long non-coding RNAs (DRGs-lncRNAs) and patient prognosis can provide new molecular targets for LUAD patients.
METHODS
The study analysed the transcriptome data and clinical data of LUAD patients in The Cancer Genome Atlas (TCGA) database, gene co-expression, and univariate Cox regression methods were used to screen for DRGs-lncRNAs related to prognosis. The risk score model of lncRNA was established by univariate and multivariate Cox regression models. TIMER, CIBERSORT, CIBERSORT-ABS, and other methods were used to analyze immune infiltration and further evaluate immune function analysis, immune checkpoints, and drug sensitivity. Real-time polymerase chain reaction (RT-PCR) was performed to detect the expression of DRGs-lncRNAs in LUAD cell lines.
RESULTS
A total of 108 lncRNAs significantly associated with disulfidptosis were identified. A prognostic model was constructed by screening 10 lncRNAs with independent prognostic significance through single-factor Cox regression analysis, LASSO regression analysis, and multiple-factor Cox regression analysis. Survival analysis of patients through the prognostic model showed that there were obvious survival differences between the high- and low-risk groups. The risk score of the prognostic model can be used as an independent prognostic factor independent of other clinical traits, and the risk score increases with stage. Further analysis showed that the prognostic model was also different from tumor immune cell infiltration, immune function, and immune checkpoint genes in the high- and low-risk groups. Chemotherapy drug susceptibility analysis showed that high-risk patients were more sensitive to Paclitaxel, 5-Fluorouracil, Gefitinib, Docetaxel, Cytarabine, and Cisplatin. Additionally, RT-PCR analysis demonstrated differential expression of DRGs-lncRNAs between LUAD cell lines and the human bronchial epithelial cell line.
CONCLUSIONS
The prognostic model of DRGs-lncRNAs constructed in this study has certain accuracy and reliability in predicting the survival prognosis of LUAD patients, and provides clues for the interaction between disulfidptosis and LUAD immunotherapy.
Topics: Humans; RNA, Long Noncoding; Adenocarcinoma of Lung; Lung Neoplasms; Prognosis; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Immunotherapy; Male; Female; Cell Line, Tumor; Transcriptome; Middle Aged
PubMed: 38862217
DOI: 10.18632/aging.205911 -
PLoS Computational Biology Jun 2024Cell sedimentation in 3D hydrogel cultures refers to the vertical migration of cells towards the bottom of the space. Understanding this poorly examined phenomenon may...
Cell sedimentation in 3D hydrogel cultures refers to the vertical migration of cells towards the bottom of the space. Understanding this poorly examined phenomenon may allow us to design better protocols to prevent it, as well as provide insights into the mechanobiology of cancer development. We conducted a multiscale experimental and mathematical examination of 3D cancer growth in triple negative breast cancer cells. Migration was examined in the presence and absence of Paclitaxel, in high and low adhesion environments and in the presence of fibroblasts. The observed behaviour was modeled by hypothesizing active migration due to self-generated chemotactic gradients. Our results did not reject this hypothesis, whereby migration was likely to be regulated by the MAPK and TGF-β pathways. The mathematical model enabled us to describe the experimental data in absence (normalized error<40%) and presence of Paclitaxel (normalized error<10%), suggesting inhibition of random motion and advection in the latter case. Inhibition of sedimentation in low adhesion and co-culture experiments further supported the conclusion that cells actively migrated downwards due to the presence of signals produced by cells already attached to the adhesive glass surface.
Topics: Humans; Cell Adhesion; Cell Movement; Paclitaxel; Cell Line, Tumor; Models, Biological; Cell Culture Techniques, Three Dimensional; Triple Negative Breast Neoplasms; Computational Biology; Fibroblasts; Chemotaxis
PubMed: 38861575
DOI: 10.1371/journal.pcbi.1012112 -
RSC Advances Jun 2024Among sulfur-including heterocycles, the benzothiophene skeleton is one of the worthy structure fragments that exhibit structural similarities with active substrates to...
β-Enaminonitrile in the synthesis of tetrahydrobenzo[]thiophene candidates with DFT simulation, antiproliferative assessment, molecular docking, and modeling pharmacokinetics.
Among sulfur-including heterocycles, the benzothiophene skeleton is one of the worthy structure fragments that exhibit structural similarities with active substrates to develop various potent lead molecules in drug design. Thus, some tetrahydrobenzo[]thiophene candidates were prepared from the β-enaminonitrile scaffold reactions with diverse carbon-centered electrophilic reagents and supported with DFT studies. The antiproliferative effect was screened against MCF7 and HePG2 cancer cell lines, and the results displayed the highest potency of imide 5, Schiff base 11, and phthalimido 12 candidates. A molecular docking study was operated to explore the probable binding modes of interaction, and the results revealed the good binding affinity of compounds 5, 11, and 12 toward the tubulin protein (PDB ID 5NM5) with respect to paclitaxel (a tubulin inhibitor) and co-crystallized ligand (GTP). Besides, modeling pharmacokinetics analyses displayed their desirable drug-likeness and bioavailability properties.
PubMed: 38860247
DOI: 10.1039/d4ra03363a -
Cureus May 2024Bloom syndrome (BS) is a rare autosomal recessive genetic disorder characterized by photosensitivity, rashes on the nose and cheeks, short stature, and a predisposition...
Bloom syndrome (BS) is a rare autosomal recessive genetic disorder characterized by photosensitivity, rashes on the nose and cheeks, short stature, and a predisposition to develop cancers. In this report, we discuss the diagnosis and management of a 34-year-old Canadian male BS patient, originally from Honduras, who developed B-cell lymphoma and a subsequent non-small cell lung carcinoma (NSCLC). Given the radiosensitivity of the patient due to his BS diagnosis and the early stage of the low-grade B-cell lymphoma, we relied on surveillance as the clinical approach to his management. The treatment for NSCLC was initiated in stage III of the disease and was palliative in intent. Chemotherapy (12 rounds of paclitaxel, with the dosage gradually increasing from 48 mg to 58 mg and finally to 72 mg) was employed to shrink the left upper lobe (LUL) lung mass. Subsequently, radiotherapy (3000 cGY in 20 fractions) was administered to improve symptoms further. The radiotherapy dose schedule was modified given the patient's BS diagnosis to avoid excessive toxicity. The palliative treatment course was well tolerated by the patient and resulted in symptom relief. However, his cancer progressed over the course of the treatment, ultimately resulting in his death 18 months after the initial diagnosis of NSCLC; no autopsy was performed. We believe this report will spur clinicians to engage in fruitful discussions about tailoring chemotherapy and radiation therapy regimens for treating cancer in BS patients.
PubMed: 38860091
DOI: 10.7759/cureus.60107