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Anticancer Research Nov 2023Previously, selenocompounds (Se-compounds) and in particular selenoesters have shown promising anticancer activities. Since molecular symmetry can enhance the anticancer...
BACKGROUND/AIM
Previously, selenocompounds (Se-compounds) and in particular selenoesters have shown promising anticancer activities. Since molecular symmetry can enhance the anticancer activity, nine symmetrical selenoesters (Se-esters) have been designed as novel, potentially active anticancer agents against doxorubicin resistant breast cancer cells.
MATERIALS AND METHODS
To assess the biological effects of the symmetrical Se-esters, the antiproliferative activity was determined on sensitive MCF-7 and doxorubicin resistant KCR breast cancer cell lines. The interaction of the derivatives with doxorubicin was evaluated by checkerboard combination assay on KCR cells. Furthermore, apoptosis induction and ATPase activity in the presence of Se-esters were also determined on KCR cells.
RESULTS
The symmetrical derivatives showed a noteworthy antiproliferative activity, with two of them showing IC values in submicromolar concentration on MCF-7 cells. In addition, some derivatives showed selectivity towards the resistant KCR cells. The combination of most of them with doxorubicin resulted in synergistic interaction, and all Se-esters could induce early and late apoptosis in KCR cells. Finally, the compounds affected the ATPase activity of ABCB1 (P-gp).
CONCLUSION
The symmetrical Se-esters showed potent anticancer activity, according to in vitro tests. Further research needs to be performed to obtain similar derivatives with a better activity and selectivity, and to ascertain the potential application of these Se-containing compounds using in vivo systems.
Topics: Humans; Female; Breast Neoplasms; Doxorubicin; Apoptosis; Biological Assay; Esters; Adenosine Triphosphatases
PubMed: 37909996
DOI: 10.21873/anticanres.16683 -
Colloids and Surfaces. B, Biointerfaces Aug 2023Due to the inability of nano-carriers to passively cross the cell membrane, cell penetration enhancers are used to accelerate cytoplasmic delivery of antineoplastic...
HYPOTHESIS
Due to the inability of nano-carriers to passively cross the cell membrane, cell penetration enhancers are used to accelerate cytoplasmic delivery of antineoplastic drugs. In this regard, snake venom phospholipase A2 peptides are known for their ability to destabilize natural and artificial membranes. In this context, functionalized liposomes with peptide pEM-2 should favor the incorporation of doxorubicin and increase its cytotoxicity in HeLa cells compared to free doxorubicin, and doxorubicin encapsulated in non-functionalized liposomes.
EXPERIMENTS
Several characteristics were monitored, including doxorubicin loading capacity of the liposomes, as well as the release and uptake before and after functionalization. Cell viability and half-maximal inhibition concentrations were determined in HeLa cells.
FINDINGS
In vitro studies showed that functionalization of doxorubicin-loaded PC-NG liposomes with pEM-2 not only improved the amount of doxorubicin delivered compared to free doxorubicin or other doxorubicin-containing formulations, but also showed enhanced cytotoxicity against HeLa cells. The PC-NG liposomes loaded with doxorubicin improved treatment efficacy by reducing the IC value and incubation time. This increase in cell toxicity was directly related to the concentration of pEM-2 peptide bound to the liposomes. We conclude that the cytotoxicity observed in HeLa cells due to the action of doxorubicin was strongly favored when encapsulated in synthetic liposomes and functionalized with the pEM-2 peptide.
Topics: Humans; Liposomes; HeLa Cells; Doxorubicin; Peptides; Drug Delivery Systems; Cell Line, Tumor
PubMed: 37379702
DOI: 10.1016/j.colsurfb.2023.113420 -
Advanced Healthcare Materials Jun 2024The emergence of nanomotor provides an innovative concept for tumor treatment strategies. Conventional chemotherapeutic agents for tumors exit various therapeutic...
The emergence of nanomotor provides an innovative concept for tumor treatment strategies. Conventional chemotherapeutic agents for tumors exit various therapeutic constraints due to the unique microenvironment of the tumor itself. Calcium overload, the aberrant accumulation of free calcium ions in the cytoplasm, is a well-recognized contributor to damage and even cell death in numerous cell types. Such undesired destructive processes can be a novel means applicable to cancer ion interference therapy. Herein, the chemotherapeutic drug doxorubicin (DOX) and calcium peroxide as the driving force into nanomotors through a facile and understandable experimental scheme are successfully assembled. The modification of nucleic acid aptamer and NIR-II fluorescent molecules on its surface simultaneously strengthens both the active targeting and imaging capability of tumor loci. Therefore, by a comprehensive assessment of nanomotors both in vitro and in vivo experiments, CaO/DOX@HPS-IR-1061-AS1411 demonstrates superior killing effects on tumor cells, and the intracellular reactive oxygen species produced by nanomotors is verified by molecular biology experiments to induce apoptosis of tumor cells and further achieve tumor therapeutic effects.
Topics: Doxorubicin; Humans; Animals; Cell Line, Tumor; Mice; Neoplasms; Reactive Oxygen Species; Peroxides; Apoptosis; Aptamers, Nucleotide; Nanoparticles; Antineoplastic Agents; Mice, Nude; Mice, Inbred BALB C
PubMed: 38259234
DOI: 10.1002/adhm.202304212 -
Clinical and Experimental Pharmacology... Nov 2023Preventing or treating heart failure (HF) by blocking cardiomyocyte apoptosis is an effective strategy that improves survival and reduces ventricular remodelling and...
Preventing or treating heart failure (HF) by blocking cardiomyocyte apoptosis is an effective strategy that improves survival and reduces ventricular remodelling and dysfunction in the chronic stage. Autophagy is a mechanism that degrades intracellular components and compensates for energy deficiency, which is commonly observed in cardiomyocytes of failed hearts. Cardiomyocytes activated by doxorubicin (DOX) exhibit strong autophagy. This study aims to investigate the potential protective effect of ligustrazine and its derivative liguzinediol on regulating DOX-induced cardiomyocyte apoptosis and explore the use of the embryonic rat heart-derived myoblast cell line H9C2 for identifying novel treatments for HF. The results indicated that it has been demonstrated to reverse myocardial infarction remodelling in failed hearts by promoting autophagy in salvaged cardiomyocytes and anti-apoptosis of cardiomyocytes in granulation tissue. Our study suggests that ligustrazine and liguzinediol can be a promising agents and autophagy is potential pathway in the management of HF.
Topics: Rats; Animals; Myocytes, Cardiac; Doxorubicin; Heart Failure; Apoptosis; Autophagy
PubMed: 37574718
DOI: 10.1111/1440-1681.13811 -
Cardiovascular and Interventional... May 2024Antiangiogenic agents have been used for many years as a first-line systemic treatment for advanced HCC. Embolization with cytostatic drugs on the other hand is the...
Combination of Doxorubicin and Antiangiogenic Agents in Drug-Eluting Beads: In Vitro Loading and Release Dynamics in View of a Novel Therapeutic Approach for Hepatocellular Carcinoma.
PURPOSE
Antiangiogenic agents have been used for many years as a first-line systemic treatment for advanced HCC. Embolization with cytostatic drugs on the other hand is the first-line treatment for intermediate HCC. The two types of drugs have not been combined for intraarterial delivery yet. The loading and release dynamics and the in vitro effect of their combination are tested in this experimental study.
MATERIALS AND METHODS
Drug-eluting beads were loaded with doxorubicin, sunitinib and sunitinib analogue piperazine (SAP) alone and with their combinations. Diameter change, loading, release, and effect in cellular proliferation were assessed.
RESULTS
The average microsphere diameter after loading was 473.7 µm (μm) for Doxorubicin, 388.4 μm for Sunitinib, 515.5 μm for SAP, 414.8 μm for the combination Doxorubicin/Sunitinib and 468.8 μm for the combination Doxorubicin /SAP. Drug release in 0.9% NaCl was 10% for Doxorubicin, 49% for Sunitinib, 25% for SAP, 20%/18% for the combination Doxorubicin/Sunitinib, and 18%/23% for the combination Doxorubicin/SAP whereas in human plasma it was 56%, 27%, 13%, 76%/63% and 62%/15%, respectively. The mean concentration of Doxorubicin that led to inhibition of 50% of cellular proliferation in an HCC Huh7 cell line was 163.1 nM (nM), for Sunitinib 10.3 micromolar (μΜ), for SAP 16.7 μΜ, for Doxorubicin/Sunitinib 222.4 nM and for Doxorubicin/SAP 275 nM.
CONCLUSIONS
Doxorubicin may be combined with antiangiogenic drugs with satisfactory in vitro loading and release outcomes and effect on cellular lines.
Topics: Doxorubicin; Carcinoma, Hepatocellular; Sunitinib; Liver Neoplasms; Angiogenesis Inhibitors; Humans; Indoles; Microspheres; Cell Proliferation; Pyrroles; Piperazines; Cell Line, Tumor; Chemoembolization, Therapeutic; In Vitro Techniques; Drug Liberation
PubMed: 38609583
DOI: 10.1007/s00270-024-03714-z -
Pakistan Journal of Biological Sciences... Mar 2024<b>Background and Objective:</b> Doxorubicin is an anticancer therapy belonging to the anthracycline class, which has clinical activity in breast cancer....
<b>Background and Objective:</b> Doxorubicin is an anticancer therapy belonging to the anthracycline class, which has clinical activity in breast cancer. Doxorubicin can cause cardiotoxic effects due to the formation of doxorubicinol as its main metabolite. The purpose of this study was to obtain the optimum sample preparation conditions for the analysis of doxorubicin in VAMS and as a form of therapeutic drug monitoring (TDM) in patients with cancer breasts. <b>Materials and Methods:</b> Analyze doxorubicin and doxorubicinol levels with Volumetric Absorptive Microsampling (VAMS) in patients' cancer breasts receiving doxorubicin in their therapeutic regimen. The sample was analyzed using Ultra Performance Liquid Chromatography tandem Mass Spectrometry (LC-MS/MS). The method uses deep linear range concentrations of 8-200 ng/mL for doxorubicin and 3-100 ng/mL for doxorubicinol. <b>Results:</b> Multiple reaction monitoring (MRM) value set at m/z 544.22>396.9 for doxorubicin; m/z 546.22>398.9 for doxorubicinol and m/z 528.5>362.95 for daunorubicin. The LLOQ value obtained was 8 ng/mL for doxorubicin and 3 ng/mL for doxorubicinol with linearity of 0.9904 for doxorubicin and 0.9902 for doxorubicinol. Analysis results show doxorubicin levels were in the range of 9.47 ng/mL to 87.84 ng/mL and doxorubicinol range between 4.24 and 54.02 ng/mL. <b>Conclusion:</b> Dosage cumulative doxorubicin ranges between 47.93 and 346.09 mg/m<sup>2</sup>; with this, the risk of cardiomyopathy in the patients surveyed is under 4%, according to the literature.
Topics: Doxorubicin; Humans; Breast Neoplasms; Tandem Mass Spectrometry; Female; Cardiotoxicity; Drug Monitoring; Antibiotics, Antineoplastic; Chromatography, Liquid; Chromatography, High Pressure Liquid; Liquid Chromatography-Mass Spectrometry
PubMed: 38686734
DOI: 10.3923/pjbs.2024.125.131 -
Ultrasonics Aug 2023Phase-changing nanodroplets are nanometric sized constructs that can be vaporized via external stimuli, such as focused ultrasound, to generate gaseous bubbles that are...
Phase-changing nanodroplets are nanometric sized constructs that can be vaporized via external stimuli, such as focused ultrasound, to generate gaseous bubbles that are visible in ultrasound. Their activation can also be leveraged to release their payload, creating a method for ultrasound-modulated localized drug delivery. Here, we develop a perfluoropentane core nanodroplet that can simultaneously load paclitaxel and doxorubicin, and release them in response to an acoustic trigger. A double emulsion method is used to incorporate the two drugs with different physio-chemical properties, which allows for a combinatorial chemotherapy regimen to be used. Their loading, release, and biological effects on a triple negative breast cancer mouse model are investigated. We show that activation enhances the drug-delivery effect and delays the tumor growth rate in vivo. Overall, the phase-changing nanodroplets are a useful platform to allow on-demand delivery of combinations of drugs.
Topics: Animals; Mice; Pharmaceutical Preparations; Nanoparticles; Drug Delivery Systems; Doxorubicin; Drug Therapy, Combination; Fluorocarbons
PubMed: 37269682
DOI: 10.1016/j.ultras.2023.107056 -
Cellular Signalling Oct 2023Resistance to chemo-drug is a major cause of bad outcome in diffuse large B-cell lymphoma (DLBCL). It was reported that TCFL5 may be related to chemoresistance in...
BACKGROUND
Resistance to chemo-drug is a major cause of bad outcome in diffuse large B-cell lymphoma (DLBCL). It was reported that TCFL5 may be related to chemoresistance in childhood acute lymphoblastic leukemia. However, it is still unclear whether TCFL5 is involved in DLBCL drug-resistance.
METHODS
To explore the underlying mechanism of doxorubicin resistance, recombinant lentivirus was applied to control expression of TCFL5 in DLBCL cells. CCK-8 assay was perfomed to investigate the influence of doxorubicin on proliferation of TCFL5-overexpressed or sh-TCFL5 DLBCL cells. Correlation between TCFL5 and GPX4 was analyzed with bioinformatic methods, which was further confirmed by qPCR and western blot. TCFL5 overexpression conferred doxorubicin resistance via regulating GPX4 and was verified by TUNEL assay and western blot in vitro and mice model in vivo.
RESULTS
TCFL5 was enriched in DLBCL cells and conferred doxorubicin resistance through binding to GPX4. Inhibition of TCFL5 enhanced the sensitivity of DLBCL cells to doxorubicin. GPX4 knockdown reversed doxorubicin resistance in TCFL5-overexpressed DLBCL cells.
CONCLUSION
DLBCL cells overexpress TCFL5 that promotes chemoresistance by regulating GPX4. Targeting TCFL5 may provide a prospective therapeutic strategy for doxorubicin-resistant DLBCL.
Topics: Animals; Mice; Cell Line, Tumor; Cyclophosphamide; Doxorubicin; Drug Resistance, Neoplasm; Lymphoma, Large B-Cell, Diffuse; Vincristine; Humans; Phospholipid Hydroperoxide Glutathione Peroxidase; Basic Helix-Loop-Helix Transcription Factors
PubMed: 37516394
DOI: 10.1016/j.cellsig.2023.110831 -
International Journal of Molecular... Jul 2023Treatment of highly malignant soft tissue sarcomas (STSs) requires multicomponent therapy including surgery, radiotherapy, and chemotherapy. Despite the advancements in...
Treatment of highly malignant soft tissue sarcomas (STSs) requires multicomponent therapy including surgery, radiotherapy, and chemotherapy. Despite the advancements in targeted cancer therapies, cytostatic drug combinations remain the gold standard for STS chemotherapy. The lack of algorithms for personalized selection of STS chemotherapy leads to unhelpful treatment of chemoresistant tumors, causing severe side effects in patients. The goal of our study is to assess the applicability of in vitro chemosensitivity/resistance assays (CSRAs) in predicting STS chemoresistance. Primary cell cultures were obtained from 148 surgery samples using enzymatic and mechanical disaggregation. CSRA was performed using resazurin-based metabolic activity measurement in cells cultured with doxorubicin, ifosfamide, their combination and docetaxel, gemcitabine, and also their combination for 7 days. Both the clinical data of patients and the CSRA results demonstrated a higher resistance of some cancer histotypes to specific drugs and their combinations. The correlation between the CSRA results for doxorubicin and ifosfamide and clinical responses to the combination chemotherapy with these drugs was demonstrated via Spearman rank order correlation. Statistically significant differences in recurrence-free survival were also shown for the groups of patients formed, according to the CSRA results. Thus, CSRAs may help both practicing physicians to avoid harmful and useless treatment, and researchers to study new resistance markers and to develop new STS drugs.
Topics: Humans; Ifosfamide; Antineoplastic Combined Chemotherapy Protocols; Sarcoma; Soft Tissue Neoplasms; Doxorubicin
PubMed: 37569668
DOI: 10.3390/ijms241512292 -
Advanced Healthcare Materials Dec 2023Blockage of blood supply while administering chemotherapy to tumors, using trans-arterial chemoembolization (TACE), is the most common treatment for intermediate and...
Blockage of blood supply while administering chemotherapy to tumors, using trans-arterial chemoembolization (TACE), is the most common treatment for intermediate and advanced-stage unresectable Hepatocellular carcinoma (HCC). However, HCC is characterized by a poor prognosis and high recurrence rates (≈30%), partly due to a hypoxic pro-angiogenic and pro-cancerous microenvironment. This study investigates how modifying tissue stress while improving drug exposure in target organs may maximize the therapeutic outcomes. Porous degradable polymeric microspheres (MS) are designed to obtain a gradual occlusion of the hepatic artery that nourishes the liver, while enabling efficient drug perfusion to the tumor site. The fabricated porous MS are introduced intrahepatically and designed to release a combination therapy of Doxorubicin (DOX) and Tirapazamine (TPZ), which is a hypoxia-activated prodrug. Liver cancer cell lines that are treated with the combination therapy under hypoxia reveal a synergic anti-proliferation effect. An orthotopic liver cancer model, based on N1-S1 hepatoma in rats, is used for the efficacy, biodistribution, and safety studies. Porous DOX-TPZ MS are very effective in suppressing tumor growth in rats, and induction tissue necrosis is associated with high intratumor drug concentrations. Porous particles without drugs show some advantages over nonporous particles, suggesting that morphology may affect the treatment outcomes.
Topics: Rats; Animals; Liver Neoplasms; Carcinoma, Hepatocellular; Microspheres; Tissue Distribution; Porosity; Chemoembolization, Therapeutic; Doxorubicin; Tirapazamine; Hypoxia; Tumor Microenvironment
PubMed: 37315950
DOI: 10.1002/adhm.202301548