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International Journal of Molecular... Apr 2024Glioblastoma (GBM) is the most lethal and common malignant primary brain tumor in adults. An important feature that supports GBM aggressiveness is the unique composition...
Glioblastoma (GBM) is the most lethal and common malignant primary brain tumor in adults. An important feature that supports GBM aggressiveness is the unique composition of its extracellular matrix (ECM). Particularly, fibronectin plays an important role in cancer cell adhesion, differentiation, proliferation, and chemoresistance. Thus, herein, a hydrogel with mechanical properties compatible with the brain and the ability to disrupt the dynamic and reciprocal interaction between fibronectin and tumor cells was produced. High-molecular-weight hyaluronic acid (HMW-HA) functionalized with the inhibitory fibronectin peptide Arg-Gly-Asp-Ser (RGDS) was used to produce the polymeric matrix. Liposomes encapsulating doxorubicin (DOX) were also included in the hydrogel to kill GBM cells. The resulting hydrogel containing liposomes with therapeutic DOX concentrations presented rheological properties like a healthy brain. In vitro assays demonstrated that unmodified HMW-HA hydrogels only caused GBM cell killing after DOX incorporation. Conversely, RGDS-functionalized hydrogels displayed per se cytotoxicity. As GBM cells produce several proteolytic enzymes capable of disrupting the peptide-HA bond, we selected MMP-2 to illustrate this phenomenon. Therefore, RGDS internalization can induce GBM cell apoptosis. Importantly, RGDS-functionalized hydrogel incorporating DOX efficiently damaged GBM cells without affecting astrocyte viability, proving its safety. Overall, the results demonstrate the potential of the RGDS-functionalized hydrogel to develop safe and effective GBM treatments.
Topics: Glioblastoma; Humans; Doxorubicin; Oligopeptides; Fibronectins; Hydrogels; Cell Line, Tumor; Hyaluronic Acid; Brain Neoplasms; Liposomes; Apoptosis; Matrix Metalloproteinase 2
PubMed: 38732135
DOI: 10.3390/ijms25094910 -
International Journal of Molecular... Apr 2024Cancer treatment is greatly challenged by drug resistance, highlighting the need for novel drug discoveries. Here, we investigated novel organoarsenic compounds...
(2,6-Dimethylphenyl)arsonic Acid Induces Apoptosis through the Mitochondrial Pathway, Downregulates XIAP, and Overcomes Multidrug Resistance to Cytostatic Drugs in Leukemia and Lymphoma Cells In Vitro.
Cancer treatment is greatly challenged by drug resistance, highlighting the need for novel drug discoveries. Here, we investigated novel organoarsenic compounds regarding their resistance-breaking and apoptosis-inducing properties in leukemia and lymphoma. Notably, the compound (2,6-dimethylphenyl)arsonic acid (As2) demonstrated significant inhibition of cell proliferation and induction of apoptosis in leukemia and lymphoma cells while sparing healthy leukocytes. As2 reached half of its maximum activity (AC50) against leukemia cells at around 6.3 µM. Further experiments showed that As2 overcomes multidrug resistance and sensitizes drug-resistant leukemia and lymphoma cell lines to treatments with the common cytostatic drugs vincristine, daunorubicin, and cytarabine at low micromolar concentrations. Mechanistic investigations of As2-mediated apoptosis involving FADD (FAS-associated death domain)-deficient or Smac (second mitochondria-derived activator of caspases)/DIABLO (direct IAP binding protein with low pI)-overexpressing cell lines, western blot analysis of caspase-9 cleavage, and measurements of mitochondrial membrane integrity identified the mitochondrial apoptosis pathway as the main mode of action. Downregulation of XIAP (x-linked inhibitor of apoptosis protein) and apoptosis induction independent of (B-cell lymphoma 2) and caspase-3 expression levels suggest the activation of additional apoptosis-promoting mechanisms. Due to the selective apoptosis induction, the synergistic effects with common anti-cancer drugs, and the ability to overcome multidrug resistance in vitro, As2 represents a promising candidate for further preclinical investigations with respect to refractory malignancies.
Topics: X-Linked Inhibitor of Apoptosis Protein; Humans; Apoptosis; Drug Resistance, Neoplasm; Lymphoma; Leukemia; Drug Resistance, Multiple; Mitochondria; Cell Line, Tumor; Down-Regulation; Cell Proliferation; Cytostatic Agents; Antineoplastic Agents
PubMed: 38731935
DOI: 10.3390/ijms25094713 -
Scientific Reports May 2024While some clinics have adopted abbreviated neoadjuvant treatment for HER2-positive breast cancer, there remains a shortage of comprehensive clinical data to support... (Comparative Study)
Comparative Study
While some clinics have adopted abbreviated neoadjuvant treatment for HER2-positive breast cancer, there remains a shortage of comprehensive clinical data to support this practice. This is a retrospective, multicenter study. A total of 142 patients were included in the study who are HER2-positive breast cancer, aged ≤ 65 years, with left ventricular ejection fraction ≥ 50%, received neoadjuvant chemotherapy and underwent surgery at 10 different oncology centers in Türkiye between October 2016 and December 2022. The treatment arms were divided into 4-6 cycles of docetaxel/trastuzumab/pertuzumab for arm A, 4 cycles of adriamycin/cyclophosphamide followed by 4 cycles of taxane/TP for arm B. There were 50 patients (35.2%) in arm A and 92 patients (64.8%) in arm B. The median follow-up of all of the patients was 19.9 months (95% CI 17.5-22.3). The 3-year DFS rates for treatment arms A and B were 90.0% and 83.8%, respectively, and the survival outcomes between the groups were similar (p = 0.34). Furthermore, the pathologic complete response rates were similar in both treatment arms, at 50.0% and 51.1%, respectively (p = 0.90). This study supports shortened neoadjuvant treatment of HER2-positive breast cancer, a common practice in some clinics.
Topics: Humans; Breast Neoplasms; Female; Middle Aged; Neoadjuvant Therapy; Receptor, ErbB-2; Anthracyclines; Adult; Antineoplastic Combined Chemotherapy Protocols; Retrospective Studies; Trastuzumab; Cyclophosphamide; Docetaxel; Taxoids; Doxorubicin; Bridged-Ring Compounds; Treatment Outcome; Aged; Antibodies, Monoclonal, Humanized
PubMed: 38724585
DOI: 10.1038/s41598-024-61562-w -
Scientific Reports May 2024Individual theranostic agents with dual-mode MRI responses and therapeutic efficacy have attracted extensive interest due to the real-time monitor and high effective...
Individual theranostic agents with dual-mode MRI responses and therapeutic efficacy have attracted extensive interest due to the real-time monitor and high effective treatment, which endow the providential treatment and avoid the repeated medication with side effects. However, it is difficult to achieve the integrated strategy of MRI and therapeutic drug due to complicated synthesis route, low efficiency and potential biosafety issues. In this study, novel self-assembled ultrasmall FeO nanoclusters were developed for tumor-targeted dual-mode T/T-weighted magnetic resonance imaging (MRI) guided synergetic chemodynamic therapy (CDT) and chemotherapy. The self-assembled ultrasmall FeO nanoclusters synthesized by facilely modifying ultrasmall FeO nanoparticles with 2,3-dimercaptosuccinic acid (DMSA) molecule possess long-term stability and mass production ability. The proposed ultrasmall FeO nanoclusters shows excellent dual-mode T and T MRI capacities as well as favorable CDT ability due to the appropriate size effect and the abundant Fe ion on the surface of ultrasmall FeO nanoclusters. After conjugation with the tumor targeting ligand Arg-Gly-Asp (RGD) and chemotherapy drug doxorubicin (Dox), the functionalized FeO nanoclusters achieve enhanced tumor accumulation and retention effects and synergetic CDT and chemotherapy function, which serve as a powerful integrated theranostic platform for cancer treatment.
Topics: Magnetic Resonance Imaging; Theranostic Nanomedicine; Animals; Mice; Humans; Doxorubicin; Cell Line, Tumor; Neoplasms; Magnetite Nanoparticles; Succimer; Antineoplastic Agents
PubMed: 38724530
DOI: 10.1038/s41598-024-59525-2 -
Journal of Translational Medicine May 2024Doxorubicin (DOX) is a broad-spectrum and highly efficient anticancer agent, but its clinical implication is limited by lethal cardiotoxicity. Growing evidences have... (Review)
Review
Doxorubicin (DOX) is a broad-spectrum and highly efficient anticancer agent, but its clinical implication is limited by lethal cardiotoxicity. Growing evidences have shown that alterations in intestinal microbial composition and function, namely dysbiosis, are closely linked to the progression of DOX-induced cardiotoxicity (DIC) through regulating the gut-microbiota-heart (GMH) axis. The role of gut microbiota and its metabolites in DIC, however, is largely unelucidated. Our review will focus on the potential mechanism between gut microbiota dysbiosis and DIC, so as to provide novel insights into the pathophysiology of DIC. Furthermore, we summarize the underlying interventions of microbial-targeted therapeutics in DIC, encompassing dietary interventions, fecal microbiota transplantation (FMT), probiotics, antibiotics, and natural phytochemicals. Given the emergence of microbial investigation in DIC, finally we aim to point out a novel direction for future research and clinical intervention of DIC, which may be helpful for the DIC patients.
Topics: Gastrointestinal Microbiome; Humans; Doxorubicin; Cardiotoxicity; Animals; Dysbiosis; Fecal Microbiota Transplantation
PubMed: 38720361
DOI: 10.1186/s12967-024-05232-5 -
ACS Nano May 2024Mesoporous silica nanoparticles (MSNs) represent a promising avenue for targeted brain tumor therapy. However, the blood-brain barrier (BBB) often presents a formidable...
Mesoporous silica nanoparticles (MSNs) represent a promising avenue for targeted brain tumor therapy. However, the blood-brain barrier (BBB) often presents a formidable obstacle to efficient drug delivery. This study introduces a ligand-free PEGylated MSN variant (RMSN-PEG-TA) with a 25 nm size and a slight positive charge, which exhibits superior BBB penetration. Utilizing two-photon imaging, RMSN-PEG-TA particles remained in circulation for over 24 h, indicating significant traversal beyond the cerebrovascular realm. Importantly, DOX@RMSN-PEG-TA, our MSN loaded with doxorubicin (DOX), harnessed the enhanced permeability and retention (EPR) effect to achieve a 6-fold increase in brain accumulation compared to free DOX. In vivo evaluations confirmed the potent inhibition of orthotopic glioma growth by DOX@RMSN-PEG-TA, extending survival rates in spontaneous brain tumor models by over 28% and offering an improved biosafety profile. Advanced LC-MS/MS investigations unveiled a distinctive protein corona surrounding RMSN-PEG-TA, suggesting proteins such as apolipoprotein E and albumin could play pivotal roles in enabling its BBB penetration. Our results underscore the potential of ligand-free MSNs in treating brain tumors, which supports the development of future drug-nanoparticle design paradigms.
Topics: Blood-Brain Barrier; Silicon Dioxide; Doxorubicin; Nanoparticles; Animals; Porosity; Mice; Drug Delivery Systems; Humans; Polyethylene Glycols; Drug Carriers; Brain Neoplasms; Particle Size; Cell Line, Tumor; Glioma; Ligands; Antibiotics, Antineoplastic
PubMed: 38718220
DOI: 10.1021/acsnano.3c08993 -
PloS One 2024Tracking small extracellular vesicles (sEVs), such as exosomes, requires staining them with dyes that penetrate their lipid bilayer, a process that leaves excess dye...
Tracking small extracellular vesicles (sEVs), such as exosomes, requires staining them with dyes that penetrate their lipid bilayer, a process that leaves excess dye that needs to be mopped up to achieve high specificity. Current methods to remove superfluous dye have limitations, among them that they are time-intensive, carry the risk of losing sample and can require specialized equipment and materials. Here we present a fast, easy-to-use, and cost-free protocol for cleaning excess dye from stained sEV samples by adding their parental cells to the mixture to absorb the extra dye much like sponges do. Since sEVs are considered a next-generation drug delivery system, we further show the success of our approach at removing excess chemotherapeutic drug, daunorubicin, from the sEV solution.
Topics: Extracellular Vesicles; Humans; Daunorubicin; Coloring Agents; Staining and Labeling
PubMed: 38718025
DOI: 10.1371/journal.pone.0301761 -
Revista Da Associacao Medica Brasileira... 2024Anticipatory nausea and vomiting are unpleasant symptoms observed before undergoing chemotherapy sessions. Less is known about the occurrence of symptoms since the...
OBJECTIVE
Anticipatory nausea and vomiting are unpleasant symptoms observed before undergoing chemotherapy sessions. Less is known about the occurrence of symptoms since the advent of the new neurokinin-1 antagonist.
METHODS
This prospective cohort study was performed at a single Brazilian Institution. This study included breast cancer patients who received doxorubicin and cyclophosphamide chemotherapy and an appropriate antiemetic regimen (dexamethasone 10 mg, palonosetron 0.56 mg, and netupitant 300 mg in the D1 followed by dexamethasone 10 mg 12/12 h in D2 and D4). Patients used a diary to record nausea, vomiting, and use of rescue medication in the first two cycles of treatment. The prevalence of anticipatory nausea and vomiting was assessed before chemotherapy on day 1 of C2.
RESULTS
From August 4, 2020, to August 12, 2021, 60 patients were screened, and 52 patients were enrolled. The mean age was 50.8 (28-69) years, most had stage III (53.8%), and most received chemotherapy with curative intent (94%). During the first cycle, the frequency of overall nausea and vomiting was 67.31%, and that of severe nausea and vomiting (defined as grade>4 on a 10-point visual scale or use of rescue medication) was 55.77%. Ten patients had anticipatory nausea and vomiting (19.23%). The occurrence of nausea and vomiting during C1 was the only statistically significant predictor of anticipatory nausea and vomiting (OR=16, 95%CI 2.4-670.9, p=0.0003).
CONCLUSION
The prevalence of anticipatory nausea is still high in the era of neurokinin-1 antagonists, and failure of antiemetic control in C1 remains the main risk factor. All efforts should be made to control chemotherapy-induced nausea or nausea and vomiting on C1 to avoid anticipatory nausea.
Topics: Humans; Female; Breast Neoplasms; Middle Aged; Prospective Studies; Adult; Antiemetics; Aged; Nausea; Prevalence; Brazil; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Doxorubicin; Vomiting, Anticipatory; Vomiting; Dexamethasone; Palonosetron
PubMed: 38716933
DOI: 10.1590/1806-9282.20230937 -
Journal of Diabetes Investigation Jun 2024The aim of this study was to better understand how the chemotherapy drug doxorubicin contributes to the development of β-cell dysfunction and to explore its...
AIMS
The aim of this study was to better understand how the chemotherapy drug doxorubicin contributes to the development of β-cell dysfunction and to explore its relationship with mitochondrial aldehyde dehydrogenase-2 (ALDH2).
MATERIALS AND METHODS
In order to investigate this hypothesis, doxorubicin was administered to INS-1 cells, a rat insulinoma cell line, either with or without several target protein activators and inhibitors. ALDH2 activity was detected with a commercial kit and protein levels were determined with western blot. Mitochondrial ROS, membrane potential, and lipid ROS were determined by commercial fluorescent probes. The cell viability was measured by CCK-assay.
RESULTS
Exposure of INS-1 cells to doxorubicin decreased active insulin signaling resulting in elevated ALDH2 degradation, compared with control cells by the induction of acid sphingomyelinase mediated ceramide induction. Further, ceramide induction potentiated doxorubicin induced mitochondrial dysfunction. Treatment with the ALDH2 agonist, ALDA1, blocked doxorubicin-induced acid sphingomyelinase activation which significantly blocked ceramide induction and mitochondrial dysfunction mediated cell death. Treatment with the ALDH2 agonist, ALDA1, stimulated casein kinase-2 (CK2) mediated insulin signaling activation. CK2 silencing neutralized the function of ALDH2 in the doxorubicin treated INS-1 cells.
CONCLUSIONS
Mitochondrial ALDH2 activation could inhibit the progression of doxorubicin induced pancreatic β-cell dysfunction by inhibiting the acid sphingomyelinase induction of ceramide, by regulating the activation of CK2 signaling. Our research lays the foundation of ALDH2 activation as a therapeutic target for the precise treatment of chemotherapy drug induced β-cell dysfunction.
Topics: Doxorubicin; Rats; Animals; Insulin-Secreting Cells; Apoptosis; Aldehyde Dehydrogenase, Mitochondrial; Signal Transduction; Mitochondria; Cell Survival; Casein Kinase II; Cell Line, Tumor; Ceramides; Reactive Oxygen Species; Antibiotics, Antineoplastic
PubMed: 38713732
DOI: 10.1111/jdi.14230 -
International Journal of Nanomedicine 2024Current treatment approaches for Prostate cancer (PCa) often come with debilitating side effects and limited therapeutic outcomes. There is urgent need for an...
PURPOSE
Current treatment approaches for Prostate cancer (PCa) often come with debilitating side effects and limited therapeutic outcomes. There is urgent need for an alternative effective and safe treatment for PCa.
METHODS
We developed a nanoplatform to target prostate cancer cells based on graphdiyne (GDY) and a copper-based metal-organic framework (GDY-CuMOF), that carries the chemotherapy drug doxorubicin (DOX) for cancer treatment. Moreover, to provide GDY-CuMOF@DOX with homotypic targeting capability, we coated the PCa cell membrane (DU145 cell membrane, DCM) onto the surface of GDY-CuMOF@DOX, thus obtaining a biomimetic nanoplatform (DCM@GDY-CuMOF@DOX). The nanoplatform was characterized by using transmission electron microscope, atomic force microscope, X-ray diffraction, etc. Drug release behavior, antitumor effects in vivo and in vitro, and biosafety of the nanoplatform were evaluated.
RESULTS
We found that GDY-CuMOF exhibited a remarkable capability to load DOX mainly through π-conjugation and pore adsorption, and it responsively released DOX and generated Cu in the presence of glutathione (GSH). In vivo experiments demonstrated that this nanoplatform exhibits remarkable cell-killing efficiency by generating lethal reactive oxygen species (ROS) and mediating cuproptosis. In addition, DCM@GDY-CuMOF@DOX effectively suppresses tumor growth in vivo without causing any apparent side effects.
CONCLUSION
The constructed DCM@GDY-CuMOF@DOX nanoplatform integrates tumor targeting, drug-responsive release and combination with cuproptosis and chemodynamic therapy, offering insights for further biomedical research on efficient PCa treatment.
Topics: Male; Prostatic Neoplasms; Doxorubicin; Animals; Humans; Cell Line, Tumor; Copper; Graphite; Metal-Organic Frameworks; Mice; Drug Liberation; Reactive Oxygen Species; Biomimetic Materials; Mice, Nude; Nanoparticles; Antineoplastic Agents; Drug Carriers; Xenograft Model Antitumor Assays
PubMed: 38711614
DOI: 10.2147/IJN.S455355