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Cells Jul 2023Triple-negative breast cancer (TNBC) is among the most aggressive breast cancer subtypes. Despite being initially responsive to chemotherapy, patients develop...
Triple-negative breast cancer (TNBC) is among the most aggressive breast cancer subtypes. Despite being initially responsive to chemotherapy, patients develop drug-resistant and metastatic tumors. Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a secreted protein with a tumor suppressor function due to its anti-proteolytic activity. Nevertheless, evidence indicates that TIMP-1 binds to the CD63 receptor and activates noncanonical oncogenic signaling in several cancers, but its role in mediating TNBC chemoresistance is still largely unexplored. Here, we show that mesenchymal-like TNBC cells express TIMP-1, whose levels are further increased in cells generated to be resistant to cisplatin (Cis-Pt-R) and doxorubicin (Dox-R). Moreover, public dataset analyses indicate that high TIMP-1 levels are associated with a worse prognosis in TNBC subjected to chemotherapy. Knock-down of TIMP-1 in both Cis-Pt-R and Dox-R cells reverses their resistance by inhibiting AKT activation. Consistently, TNBC cells exposed to recombinant TIMP-1 or TIMP-1-enriched media from chemoresistant cells, acquire resistance to both cisplatin and doxorubicin. Importantly, released TIMP-1 reassociates with plasma membrane by binding to CD63 and, in the absence of CD63 expression, TIMP-1-mediated chemoresistance is blocked. Thus, our results identify TIMP-1 as a new biomarker of TNBC chemoresistance and lay the groundwork for evaluating whether blockade of TIMP-1 signal is a viable treatment strategy.
Topics: Humans; Triple Negative Breast Neoplasms; Tissue Inhibitor of Metalloproteinase-1; Cisplatin; Drug Resistance, Neoplasm; Doxorubicin
PubMed: 37443843
DOI: 10.3390/cells12131809 -
Angewandte Chemie (International Ed. in... Apr 2019Nanoparticles show great potential for drug delivery. However, suitable nanostructures capable of loading a range of drugs together with the co-delivery of siRNAs, which...
Nanoparticles show great potential for drug delivery. However, suitable nanostructures capable of loading a range of drugs together with the co-delivery of siRNAs, which avoid the problem of cation-associated cytotoxicity, are lacking. Herein, we report an small interfering RNA (siRNA)-based vesicle (siRNAsome), which consists of a hydrophilic siRNA shell, a thermal- and intracellular-reduction-sensitive hydrophobic median layer, and an empty aqueous interior that meets this need. The siRNAsome can serve as a versatile nanostructure to load drug agents with divergent chemical properties, therapeutic proteins as well as co-delivering immobilized siRNAs without transfection agents. Importantly, the inherent thermal/reduction-responsiveness enables controlled drug loading and release. When siRNAsomes are loaded with the hydrophilic drug doxorubicin hydrochloride and anti-P-glycoprotein siRNA, synergistic therapeutic activity is achieved in multidrug resistant cancer cells and a tumor model.
Topics: Antibiotics, Antineoplastic; Breast Neoplasms; Cell Proliferation; Cell Survival; Doxorubicin; Drug Delivery Systems; Drug Resistance, Multiple; Drug Screening Assays, Antitumor; Humans; Hydrophobic and Hydrophilic Interactions; MCF-7 Cells; Nanostructures; RNA, Small Interfering
PubMed: 30737876
DOI: 10.1002/anie.201814289 -
International Journal of Sports Medicine Dec 2022Doxorubicin is an anti-neoplasmic drug that prevents DNA replication but induces senescence and cellular toxicity. Intensive research has focused on strategies to... (Review)
Review
Doxorubicin is an anti-neoplasmic drug that prevents DNA replication but induces senescence and cellular toxicity. Intensive research has focused on strategies to alleviate the doxorubicin-induced skeletal myotoxicity. The aim of the present review is to critically discuss the relevant scientific evidence about the role of exercise and growth factor administration and offer novel insights about newly developed-tools to combat the adverse drug reactions of doxorubicin treatment on skeletal muscle. In the first part, we discuss current data and mechanistic details on the impact of doxorubicin on skeletal myotoxicity. We next review key aspects about the role of regular exercise and the impact of growth factors, administered either pharmacologically or via genetic interventions. Future strategies such as combination of exercise and growth factor administration remain to be established to combat the pharmacologically-induced myotoxicity.
Topics: Humans; Myotoxicity; Doxorubicin; Muscle, Skeletal; Exercise; Cellular Senescence; Intercellular Signaling Peptides and Proteins
PubMed: 35288882
DOI: 10.1055/a-1797-7622 -
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 -
Scientific Reports Jul 2021The aim of the present study was to investigate combined effects of cold atmospheric plasma (CAP) and the chemotherapeutic drug doxorubicin (DOX) on murine and human...
The aim of the present study was to investigate combined effects of cold atmospheric plasma (CAP) and the chemotherapeutic drug doxorubicin (DOX) on murine and human melanoma cells, and normal cells. In addition to free drug, the combination of CAP with a liposomal drug (DOX-LIP) was also studied for the first time. Thiazolyl blue tetrazolium bromide (MTT) and Trypan Blue exclusion assays were used to evaluate cell viability; the mechanism of cell death was evaluated by flow cytometry. Combined treatment effects on the clonogenic capability of melanoma cells, was also tested with soft agar colony formation assay. Furthermore the effect of CAP on the cellular uptake of DOX or DOX-LIP was examined. Results showed a strong synergistic effect of CAP and DOX or DOX-LIP on selectively decreasing cell viability of melanoma cells. CAP accelerated the apoptotic effect of DOX (or DOX-LIP) and dramatically reduced the aggressiveness of melanoma cells, as the combination treatment significantly decreased their anchorage independent growth. Moreover, CAP did not result in increased cellular uptake of DOX under the present experimental conditions. In conclusion, CAP facilitates DOX cytotoxic effects on melanoma cells, and affects their metastatic potential by reducing their clonogenicity, as shown for the first time.
Topics: Animals; Cell Line, Tumor; Cell Proliferation; Cell Survival; Doxorubicin; Drug Synergism; Humans; Melanoma; Mice; Plasma Gases; Polyethylene Glycols
PubMed: 34285268
DOI: 10.1038/s41598-021-94130-7 -
Advanced Science (Weinheim,... Apr 2022Current pharmacotherapy is challenged by side effects and drug resistance issues due to the lack of drug selectivity. Mechanochemistry-based strategies provide new...
Current pharmacotherapy is challenged by side effects and drug resistance issues due to the lack of drug selectivity. Mechanochemistry-based strategies provide new avenues to overcome the related problems by improving drug selectivity. It is recently shown that sonomechanical bond scission enables the remote-controlled drug release from their inactive parent macromolecules using ultrasound (US). To further expand the scope of the US-controlled drug activation strategy, herein a mechano-responsive nanoswitch for the selective activation of doxorubicin (DOX) to inhibit cancer cell proliferation is constructed. As a proof-of-concept, the synthesis, characterization, and US-responsive drug activation evaluation of the mechano-nanoswitch, which provides a blueprint for tailoring nanosystems for force-induced pharmacotherapy is presented.
Topics: Activation, Metabolic; Doxorubicin; Drug Liberation; Humans; Macromolecular Substances; Neoplasms
PubMed: 35195372
DOI: 10.1002/advs.202104696 -
Revista Da Associacao Medica Brasileira... Apr 2022We aimed to examine the potential anticancer effects of ozone applied after chemotherapeutic treatment with different concentrations of doxorubicin in Luminal-A subtype...
OBJECTIVE
We aimed to examine the potential anticancer effects of ozone applied after chemotherapeutic treatment with different concentrations of doxorubicin in Luminal-A subtype of human breast cancer cell line (MCF-7) and compare the results with effects on L929 fibroblast cell line.
METHODS
Both cell lines were incubated with increasing doses of doxorubicin (1-50 μM) for 24 h at 37°C. Then, half of groups were incubated with 30 μg/mL ozone for 25 min as combination groups. Cell viability was analyzed by MTT assay, apoptosis by flow cytometry, and levels of tumor necrosis factor alpha, transforming growth factor beta, and matrix metalloproteinase-2 and MMP-9 by immunocytochemistry.
RESULTS
Doxorubicin + ozone treatment enhanced viability of L929 (p<0.01) but reduced viability of MCF-7 compared to only doxorubicin-applied cells without ozone treatment (p<0.001). This combined treatment also enhanced apoptotic effect of doxorubicin on MCF-cells (p<0.001), but not on L929. It significantly increased all protein levels of L929 compared with those of other groups (p<0.05 for tumor necrosis factor alpha and MMP-2; p<0.01 for transforming growth factor beta and MMP-9). This treatment reversed the effect of doxorubicin on tumor necrosis factor alpha levels and considerably reduced MMP-2 and MMP-9 levels of MCF-7 compared with those of control group (p<0.01 and p<0.001, respectively).
CONCLUSION
Ozone treatment potentiated the apoptotic and anticancer activities of doxorubicin in MCF-7 cells and showed repairing and healing effect on healthy fibroblast cells, which were damaged from cytotoxic effects of chemotherapeutic agent. MCF-7 cells may acquire sensitivity against the doxorubicin combined with ozone treatment through activating tumor necrosis factor alpha, MMP-2, and MMP-9 expressions.
Topics: Antineoplastic Agents; Breast Neoplasms; Cell Line, Tumor; Doxorubicin; Female; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Ozone; Transforming Growth Factor beta; Tumor Necrosis Factor-alpha
PubMed: 35649075
DOI: 10.1590/1806-9282.20211193 -
International Journal of Nanomedicine 2017Multidrug resistance (MDR) due to overexpression of P-glycoprotein (P-gp) is a major obstacle that hinders the treatment of hepatocellular carcinoma (HCC). It has been...
Multidrug resistance (MDR) due to overexpression of P-glycoprotein (P-gp) is a major obstacle that hinders the treatment of hepatocellular carcinoma (HCC). It has been shown that miR-375 inhibits P-gp expression via inhibition of astrocyte elevated gene-1 (AEG-1) expression in HCC, and induces apoptosis in HCC cells by targeting AEG-1 and YAP1. In this study, we prepared lipid-coated hollow mesoporous silica nanoparticles (LH) containing doxorubicin hydrochloride (DOX) and miR-375 (LHD/miR-375) to deliver the two agents into MDR HCC cells in vitro and in vivo. We found that LHD/miR-375 overcame drug efflux and delivered miR-375 and DOX into MDR HepG2/ADR cells or HCC tissues. MiR-375 delivered by LHD/miR-375 was taken up through phagocytosis and clathrin- and caveolae-mediated endocytosis. Following release from late endosomes, it repressed the expression of P-gp in HepG2/ADR cells. The synergistic effects of miR-375 and hollow mesoporous silica nanoparticles (HMSN) resulted in a profound increase in the uptake of DOX by the HCC cells and prevented HCC cell growth. Enhanced antitumor effects of LHD/miR-375 were also validated in HCC xenografts and primary tumors; however, no significant toxicity was observed. Mechanistic studies also revealed that miR-375 and DOX exerted a synergistic antitumor effect by promoting apoptosis. Our study illustrates that delivery of miR-375 using HMSN is a feasible approach to circumvent MDR in the management of HCC. It, therefore, merits further development for potential clinical application.
Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Animals; Antibiotics, Antineoplastic; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Doxorubicin; Drug Delivery Systems; Drug Resistance, Neoplasm; Humans; Lipids; Liver Neoplasms; Mice, Inbred BALB C; MicroRNAs; Nanoparticles; Silicon Dioxide; Tissue Distribution; Xenograft Model Antitumor Assays
PubMed: 28769563
DOI: 10.2147/IJN.S135306 -
Advanced Drug Delivery Reviews Nov 2021We review the drug development of lyso-thermosensitive liposomal doxorubicin (LTLD) which is the first heat-activated formulation of a liposomal drug carrier to be... (Review)
Review
We review the drug development of lyso-thermosensitive liposomal doxorubicin (LTLD) which is the first heat-activated formulation of a liposomal drug carrier to be utilized in human clinical trials. This class of compounds is designed to carry a payload of a cytotoxic agent and adequately circulate in order to accumulate at a tumor that is being heated. At the target the carrier is activated by heat and releases its contents at high concentrations. We summarize the preclinical and clinical experience of LTLD including its successes and challenges in the development process.
Topics: Animals; Antibiotics, Antineoplastic; Doxorubicin; Drug Delivery Systems; Drug Development; Drug Liberation; Humans; Hyperthermia; Hyperthermia, Induced; Polyethylene Glycols
PubMed: 34555486
DOI: 10.1016/j.addr.2021.113985 -
ACS Biomaterials Science & Engineering Oct 2022This work reports the development of a biomimetic membrane-wrapped nanoparticle (MWNP) platform for targeted chemotherapy of acute myeloid leukemia (AML). Doxorubicin...
This work reports the development of a biomimetic membrane-wrapped nanoparticle (MWNP) platform for targeted chemotherapy of acute myeloid leukemia (AML). Doxorubicin (DOX), a chemotherapeutic used to treat leukemias, lymphomas, and other cancers, was encapsulated in polymeric NPs that were coated with cytoplasmic membranes derived from human AML cells. The release rate of DOX from the MWNPs was characterized under both storage and physiological conditions, with faster release observed at pH 5.5 than pH 7.4. The system was then introduced to AML cell cultures to test the functionality of the released DOX cargo as compared to DOX delivered freely or NPs coated with poly(ethylene glycol) (PEG). The MWNPs delivered DOX in an efficient and targeted manner, inducing up to 80% apoptosis in treated cells at a dose of 5 μM, compared to 15% for free DOX and 17% for DOX-loaded PEG-coated NPs at the same drug concentration. The mechanism of cell death was confirmed as DNA double-strand breaks through a γH2A.X assay, indicating that the released DOX retained its expected mechanism of action. These findings designate MWNPs as a robust drug delivery system with great potential for future development in treatments of AML and other blood cancers.
Topics: DNA; Doxorubicin; Drug Delivery Systems; Humans; Leukemia, Myeloid, Acute; Nanoparticles; Polyethylene Glycols
PubMed: 36103274
DOI: 10.1021/acsbiomaterials.2c00832