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Journal of Cellular and Molecular... Nov 2020Oncolytic adenovirus (OA) has attracted increasing attention due to their specific proliferation in tumour cells and resulting in lysis of tumour cells. To further...
Oncolytic adenovirus (OA) has attracted increasing attention due to their specific proliferation in tumour cells and resulting in lysis of tumour cells. To further improve the antitumour effect of OA, in this study, we combined CD55-TRAIL-IETD-MnSOD (CD55-TMn), a CEA-controlled OA constructed previously, and chemotherapy to investigate their synergistic effect and possible mechanisms. MTT assay was performed to detect antitumour effects. Hoechst 33 342 and flow cytometric analysis were used to examine cell apoptosis. Western blotting was performed to examine cell pyroptosis and apoptosis mechanism. Animal experiment was used to detect antitumour effect of doxorubicin hydrochloride (Dox) combined with CD55-TMn in vivo. We firstly found that Dox promotes gene expression mediated by CEA-regulated OA and virus progeny replication by activating phosphorylation of Smad3, and Dox can enhance antitumour effect of CEA-regulated CD55-TMn by promoting cell apotopsis and cell pyroptosis. Thus, our results provide an experimental and theoretical basis on tumour therapy by combination treatment of the oncolytic virotherapy and chemotherapy and it is expected to become a novel strategy for liver cancer therapy.
Topics: Adenoviridae; Animals; Antibiotics, Antineoplastic; Apoptosis; Biomarkers; Carcinoembryonic Antigen; Caspase 3; Cell Line, Tumor; Cell Survival; Combined Modality Therapy; Disease Models, Animal; Doxorubicin; Female; Genetic Therapy; Genetic Vectors; Humans; Immunohistochemistry; Liver Neoplasms; Mice; Oncolytic Virotherapy; Oncolytic Viruses; Phosphorylation; Smad3 Protein; Xenograft Model Antitumor Assays
PubMed: 33251723
DOI: 10.1111/jcmm.15966 -
Journal of the American Veterinary... Sep 2022To evaluate the efficacy of doxorubicin for treatment of histiocytic sarcoma (HS) in dogs, whether administered as the sole treatment or as an adjunct to surgery or...
OBJECTIVE
To evaluate the efficacy of doxorubicin for treatment of histiocytic sarcoma (HS) in dogs, whether administered as the sole treatment or as an adjunct to surgery or radiation therapy.
ANIMALS
31 client-owned dogs with localized or disseminated HS examined between 2003 and 2017.
PROCEDURES
Medical records were reviewed retrospectively, and data were collected. The Kaplan-Meier method was used to estimate time-to-progression from the date of first doxorubicin administration and survival time from initial diagnosis. Factors that could be associated with poorer outcomes with doxorubicin treatment were analyzed with log-rank tests.
RESULTS
The objective response rate (ORR) was 26%. When stratified by disease status, dogs with localized and disseminated forms experienced 43% and 21% ORRs, respectively. Median time to progression after initiating doxorubicin treatment (n = 30 dogs) was 42 days. Median survival time from initial diagnosis to death (n = 29 dogs) was 169 days. Complete responses were obtained in only 2 dogs that had localized disease and received multimodality therapy.
CLINICAL RELEVANCE
Benefits of doxorubicin administration in canine HS are modest, with a limited ORR and delay in tumor progression, and are comparable to effects attained with other single-agent regimens.
Topics: Dogs; Animals; Histiocytic Sarcoma; Retrospective Studies; Dog Diseases; Doxorubicin; Treatment Outcome
PubMed: 36054007
DOI: 10.2460/javma.21.11.0498 -
ACS Applied Materials & Interfaces Apr 2023Despite the enormous advancements in nanomedicine research, a limited number of nanoformulations are available on the market, and few have been translated to clinics. An...
Despite the enormous advancements in nanomedicine research, a limited number of nanoformulations are available on the market, and few have been translated to clinics. An easily scalable, sustainable, and cost-effective manufacturing strategy and long-term stability for storage are crucial for successful translation. Here, we report a system and method to instantly formulate NF achieved with a nanoscale polyelectrolyte coacervate-like system, consisting of anionic pseudopeptide poly(l-lysine isophthalamide) derivatives, polyethylenimine, and doxorubicin (Dox) via simple "mix-and-go" addition of precursor solutions in seconds. The coacervate-like nanosystem shows enhanced intracellular delivery of Dox to patient-derived multidrug-resistant (MDR) cells in 3D tumor spheroids. The results demonstrate the feasibility of an instant drug formulation using a coacervate-like nanosystem. We envisage that this technique can be widely utilized in the nanomedicine field to bypass the special requirement of large-scale production and elongated shelf life of nanomaterials.
Topics: Humans; Feasibility Studies; Doxorubicin; Neoplasms; Nanostructures; Drug Carriers; Nanoparticles; Cell Line, Tumor; Drug Delivery Systems
PubMed: 36976817
DOI: 10.1021/acsami.2c21586 -
Integrative Cancer Therapies 2021Doxorubicin (Dox) induces senescence in numerous cancer cell types, but these senescent cancer cells relapse again if they are not eliminated. On this principle, we...
Doxorubicin (Dox) induces senescence in numerous cancer cell types, but these senescent cancer cells relapse again if they are not eliminated. On this principle, we investigated the apoptotic effect of thymoquinone (TQ), the active ingredient of seeds and costunolide (COS), the active ingredient of , on the senescent colon (Sen-HCT116) and senescent breast (Sen-MCF7) cancer cell lines in reference to their corresponding proliferative cells to rapidly eliminate the senescent cancer cells. The senescence markers of Sen-HCT116 and Sen-MCF7 were determined by a significant decrease in bromodeoxyuridine (BrdU) incorporation and significant increases in SA-β-gal, p53, and p21 levels. Then proliferative, Sen-HCT116, and Sen-MCF7 cells were subjected to either TQ (50 µM) or COS (30 µM), the Bcl2-associated X protein (Bax), B-cell lymphoma 2 (Bcl2), caspase 3 mRNA expression and its activity were established. Results revealed that TQ significantly increased the Bax/Bcl2 ratio in HCT116 + Dox5 + TQ, MCF7 + TQ, and MCF7 + Dox5 + TQ compared with their corresponding controls. COS significantly increased the Bax/Bcl2 ratio in HCT116 + Dox5 + TQ and MCF7 + Dox5 + TQ compared with their related controls. Also, TQ and COS were significantly increased caspase 3 activity and cell proliferation of Sen-HCT116 and Sen-MCF7. The data revealed a higher sensitivity of senescent cells to TQ or COS than their corresponding proliferative cells.
Topics: Apoptosis; Benzoquinones; Colon; Doxorubicin; Humans; Neoplasm Recurrence, Local; Sesquiterpenes
PubMed: 34490824
DOI: 10.1177/15347354211035450 -
European Journal of Pharmaceutical... Sep 2022To evaluate the bioequivalence of a hybrid pegylated liposomal doxorubicin (PLD) hydrochloride injection with reference product Caelyx®. (Randomized Controlled Trial)
Randomized Controlled Trial
Bioequivalence of a hybrid pegylated liposomal doxorubicin hydrochloride injection and Caelyx®: A single-dose, randomized, multicenter, open-label, two-period crossover study in patients with advanced ovarian cancer.
OBJECTIVE
To evaluate the bioequivalence of a hybrid pegylated liposomal doxorubicin (PLD) hydrochloride injection with reference product Caelyx®.
METHODS
This multicenter, open-label, balanced, randomized, two-treatment, two-period, two-sequence, single-dose, crossover, bioequivalence study was conducted in female patients aged ≥18 years and ≤75 years with ovarian cancer, whose disease progressed or recurred after platinum-based chemotherapy, and who were scheduled to start PLD therapy. Patients were intravenously infused drugs over 1 h at 50 mg/m dose two hours after breakfast on the first day of the chemotherapy cycle in period-I and crossed over to the other arm in period-II (day 29). Pharmacokinetic (PK) analyses were performed using two separate, validated liquid chromatography-mass spectrometry methods for encapsulated and unencapsulated doxorubicin.
RESULTS
Both the test and reference formulations were well-tolerated and safe. The pharmacokinetic analysis for both encapsulated and unencapsulated doxorubicin was conducted in 50 patients and PK parameters were found to be comparable between test and reference products. The geometric mean ratios (90% confidence interval) of hybrid PLD/Caelyx® were; maximum measured plasma concentration (C): 91.94-97.28%, area under the plasma concentration versus time from time 0 to t (AUC): 95.19-103.67% AUC from time 0 to ∞ (AUC): 95.13-103.66% for encapsulated doxorubicin and for unencapsulated doxorubicin C: 92.08-116.46% AUC: 91.91-108.28% AUC: 93.45-110.05%.
CONCLUSION
The PLD formulation was found to be bioequivalent to Caelyx®.
Topics: Adolescent; Adult; Area Under Curve; Cross-Over Studies; Doxorubicin; Female; Humans; Ovarian Neoplasms; Polyethylene Glycols; Tablets; Therapeutic Equivalency
PubMed: 35777616
DOI: 10.1016/j.ejps.2022.106248 -
International Journal of Nanomedicine 2020Synergistic treatment integrating photothermal therapy (PTT) and chemotherapy is a promising strategy for hepatocellular carcinoma (HCC). However, the most commonly used...
INTRODUCTION
Synergistic treatment integrating photothermal therapy (PTT) and chemotherapy is a promising strategy for hepatocellular carcinoma (HCC). However, the most commonly used photothermal agent, IR820, and chemotherapeutic drug, doxorubicin hydrochloride (DOX), are both hydrophilic molecules that suffer from the drawbacks of a short circulation time, rapid elimination and off-target effects.
METHODS AND RESULTS
Herein, a novel nanodrug that combined HCC-targeted IR820 and DOX was developed based on excipient-free co-assembly. First, lactosylated IR820 (LA-IR820) was designed to target HCC. Then, the LA-IR820/DOX nanodrug (LA-IR820/DOX ND) was purely self-assembled without excipient assistance. The physicochemical properties and the chemo-photothermal antitumour activity of the excipient-free LA-IR820/DOX ND were evaluated. More importantly, the obtained LA-IR820/DOX ND exhibited 100% drug loading, remarkable HCC targeting and excellent antitumour efficacy.
CONCLUSION
This excipient-free LA-IR820/DOX ND may be a promising candidate for the synchronous delivery and synergistic targeting of IR820 and DOX as a combined chemo-photothermal therapy.
Topics: Animals; Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line, Tumor; Doxorubicin; Drug Delivery Systems; Drug Liberation; Drug Synergism; Humans; Indocyanine Green; Lactose; Liver Neoplasms; Mice; Nanoparticles
PubMed: 32606687
DOI: 10.2147/IJN.S247617 -
International Journal of Medical... 2022Omega-3 fatty acids from fish oil (FO) and selenium (Se) potentiate some conventional therapies and have anticancer immune potential. This study aims to determine...
Fish Oil and Selenium with Doxorubicin Modulates Expression of Fatty Acid Receptors and Selenoproteins, and Targets Multiple Anti-Cancer Signaling in Triple-negative Breast Cancer Tumors.
Omega-3 fatty acids from fish oil (FO) and selenium (Se) potentiate some conventional therapies and have anticancer immune potential. This study aims to determine whether FO/Se modulates G-protein-coupled polyunsaturated fatty acid receptors (GPR-40 and GPR-120) and selenoproteins (Sel-H, Sel-W, and GPx4), and increases the therapeutic effect of doxorubicin in a dose-dependent manner on triple-negative breast cancer (TNBC) mouse. Mice were randomized into 5 groups (n = 7/group) and treated with physiological saline (control), low-dose doxorubicin, and doxorubicin in combination with low, medium, or high doses of FO/Se. The expression of signaling molecules in tumors was determined by measuring either mRNA or protein expression. Compared with doxorubicin alone, combination treatment resulted in lower tumor sizes and fewer overall metastasis, lower GPR-40 mRNA levels, and higher expression of all selenoproteins. Doxorubicin-FO/Se combination treatment decreased expression of membrane EGFR and FGFR, down-regulated downstream PI3K/AKT/mTOR, MAPK/ERK, and JAK2/c-Src/STAT3 signaling, increased tumor suppressor PTEN/TSC1/TSC2 expression and P53 activation, and suppressed oncogenic transcription factor expression. Dose-dependent inhibition of proliferation index Ki-67, cell cycle, and stem-cell-related markers were observed. Decreased immune check-points PD-L1/CTLA-4/Foxp3/CD86 and increased PD-1/CD28/IL-2 expression was also found. These observations suggest that the nutritional supplements FO/Se increase the chemotherapeutic efficacy of doxorubicin against TNBC by modulating GPR-40 and selenoprotein and targeting multiple signaling pathways in tumor tissues.
Topics: Mice; Animals; Humans; Selenium; Triple Negative Breast Neoplasms; Fish Oils; Fatty Acids; Phosphatidylinositol 3-Kinases; Doxorubicin; RNA, Messenger
PubMed: 36483592
DOI: 10.7150/ijms.75848 -
Molecules (Basel, Switzerland) Jul 2020Recently, nanogels have been identified as innovative formulations for enlarging the application of hydrogels (HGs) in the area of drug delivery or in diagnostic...
Recently, nanogels have been identified as innovative formulations for enlarging the application of hydrogels (HGs) in the area of drug delivery or in diagnostic imaging. Nanogels are HGs-based aggregates with sizes in the range of nanometers and formulated in order to obtain injectable preparations. Regardless of the advantages offered by peptides in a hydrogel preparation, until now, only a few examples of peptide-based nanogels (PBNs) have been developed. Here, we describe the preparation of stable PBNs based on Fmoc-Phe-Phe-OH using three different methods, namely water/oil emulsion (W/O), top-down, and nanogelling in water. The effect of the hydrophilic-lipophilic balance (HLB) in the formulation was also evaluated in terms of size and stability. The resulting nanogels were found to encapsulate the anticancer drug doxorubicin, chosen as the model drug, with a drug loading comparable with those of the liposomes.
Topics: Doxorubicin; Drug Carriers; Drug Liberation; Emulsions; Hydrophobic and Hydrophilic Interactions; Molecular Structure; Nanogels; Peptides; Theranostic Nanomedicine
PubMed: 32751321
DOI: 10.3390/molecules25153455 -
International Journal of Molecular... Feb 2022In this study, actively-targeted (CD44-receptors) and dual stimuli (pH/redox)-responsive lipid-polymer nanoparticles were proposed as a delivery vehicle of doxorubicin...
In this study, actively-targeted (CD44-receptors) and dual stimuli (pH/redox)-responsive lipid-polymer nanoparticles were proposed as a delivery vehicle of doxorubicin hydrochloride in triple negative breast cancer cell lines. A phosphatidylcholine lipid film was hydrated with a solution of oxidized hyaluronic acid and doxorubicin, chosen as model drug, followed by a crosslinking reaction with cystamine hydrochloride. The obtained spherical nanoparticles (mean diameter of 30 nm) were found to be efficiently internalized in cancer cells by a receptor-mediated endocytosis process, and to modulate the drug release depending on the pH and redox potential of the surrounding medium. In vitro cytotoxicity assays demonstrated the safety and efficacy of the nanoparticles in enhancing the cytotoxic effect of the free anticancer drug, with the IC values being reduced by two and three times in MDA-MB-468 and MDA-MB-231, respectively. The combination of self-assembled phospholipid molecules with a polysaccharide counterpart acting as receptor ligand, and stimuli-responsive chemical moieties, was carried out on smart multifunctional nanoparticles able to actively target breast cancer cells and improve the in vitro anticancer activity of doxorubicin.
Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Doxorubicin; Drug Delivery Systems; Drug Liberation; Endocytosis; Female; Humans; Hyaluronan Receptors; Hyaluronic Acid; Hydrogen-Ion Concentration; Lipids; Liposomes; Nanoparticles; Particle Size; Polysaccharides
PubMed: 35216501
DOI: 10.3390/ijms23042386 -
Biomedicine & Pharmacotherapy =... Apr 2023Melanoma is a highly aggressive neoplasm with a high degree of malignancy and rapid acquisition of resistance by cancer cells.
BACKGROUND
Melanoma is a highly aggressive neoplasm with a high degree of malignancy and rapid acquisition of resistance by cancer cells.
METHODS
Biological studies of a series of isoxazole compounds with immunomodulatory properties were preceded by in silico analysis. The assay evaluated the viability of NHDF and A375 cell cultures after the administration of isoxazole compounds after a 24-hour incubation period in the MTT test. Analyzes of ROS and NO scavenging, P-glycoprotein activity, and properties were performed. The levels of Caspase 3 and Caspase 9 were measured using ELISA to assess which pathways induced apoptosis by the tested compounds. On the chip, the synergistic effect of doxorubicin and the most active compound from the MM9 series on cells of the A375 melanoma line was determined.
RESULTS
All tested N'-substituted derivatives of 5-amino-N,3-dimethyl-1,2-oxazole-4-carbohydrazide with immunomodulatory activity show multidirectional antitumor activity on A375 melanoma lines with an affinity for P-glycoprotein, induction of free radical formation and generation of DNA damage leading to the death of cancer cells, as well as formation of complexes with DNA Topoisomerase II. Most of the tested compounds show pro-apoptotic activity. The most active compound in the series induces apoptosis in three distinct pathways and acts synergistically with doxorubicin.
CONCLUSIONS
The most active compound with immunomodulatory properties showed multidirectional antitumor activity against cells of the A375 melanoma line and also had a synergistic pro-apoptotic effect with doxorubicin, which may result in a reduction of this cytostatic dose with increased effectiveness.
Topics: Humans; Immunomodulating Agents; Melanoma; Apoptosis; Doxorubicin; Isoxazoles; Cell Line, Tumor; Antineoplastic Agents; Cell Proliferation
PubMed: 36774726
DOI: 10.1016/j.biopha.2023.114374