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Antiviral Research Feb 2012Mitoxantrone, an FDA-approved therapeutic for the treatment of cancer and multiple sclerosis, was previously reported to exhibit antiviral activity against vaccinia...
Mitoxantrone, an FDA-approved therapeutic for the treatment of cancer and multiple sclerosis, was previously reported to exhibit antiviral activity against vaccinia virus. To determine whether this activity extends to other orthopoxviruses, mitoxantrone was tested against cowpox and monkeypox. Mitoxantrone demonstrated an EC(50) of 0.25 μM against cowpox and 0.8 μM against monkeypox. Intraperitoneal treatment of cowpox virus-challenged C57Bl/6 mice with 0.5 mg/kg mitoxantrone resulted in 25% survival and a significant increase in survival time. In an effort to improve its efficacy, mitoxantrone was tested for synergistic activity with cidofovir. In vitro tests demonstrated significant synergy between the two drugs against cowpox; however, no synergistic effect on animal survival or median time-to-death was seen in intranasally-infected BALB/c mice. Significantly fewer animals survived when treated with a combination of 0.5 mg/kg mitoxantrone and 100 mg/kg cidofovir than with 100 mg/kg cidofovir alone. This is, to our knowledge, the first report of limited anti-orthopoxvirus activity by mitoxantrone in an animal model.
Topics: Animals; Antiviral Agents; Cowpox; Cowpox virus; Female; Humans; Mice; Mice, Inbred C57BL; Mitoxantrone; Mpox (monkeypox); Monkeypox virus
PubMed: 22182595
DOI: 10.1016/j.antiviral.2011.12.001 -
The AAPS Journal Jun 2012We conducted a pharmacokinetic (PK) study of mitoxantrone (Novantrone®), a clinically well-established anticancer agent, in mice and developed a mechanism-based PBPK...
We conducted a pharmacokinetic (PK) study of mitoxantrone (Novantrone®), a clinically well-established anticancer agent, in mice and developed a mechanism-based PBPK (physiologically based pharmacokinetic) model to describe its disposition. Mitoxantrone concentrations in plasma and six organs (lung, heart, liver, kidney, spleen, and brain) were determined after a 5 mg/kg i.v. dose. We evaluated three different PBPK models in order to characterize our experimental data: model 1 containing Kp values, model 2 incorporating a deep binding compartment, and model 3 incorporating binding of mitoxantrone to DNA and protein. Among the three models, only model 3 with DNA and protein binding captured all the experimental data well. The estimated binding affinity for DNA (K (DNA)) and protein (K (macro)) were 0.0013 and 1.44 μM, respectively. Predicted plasma and tissue AUC values differed from observed values by <19 %, except for heart (60 %). Model 3 was further used to simulate plasma mitoxantrone concentrations in humans for a 12-mg/m(2) dose, using human physiological parameters. The simulated results generally agreed with the observed time course of mitoxantrone plasma concentrations in patients after a standard dose of 12 mg/m(2). In summary, we reported for the first time a mechanism-based PBPK model of mitoxantrone incorporating macromolecule binding which may have clinical applicability in optimizing clinical therapy. Since mitoxantrone is a substrate of the efflux transporters ABCG2 and ABCB1, the incorporation of efflux transporters may also be necessary to characterize the data obtained in low-dose studies.
Topics: Animals; DNA; Humans; Male; Mice; Mitoxantrone; Models, Biological; Protein Binding; Tissue Distribution
PubMed: 22451016
DOI: 10.1208/s12248-012-9344-7 -
Anti-cancer Agents in Medicinal... May 2013Focal Adhesion Kinase (FAK) is a non-receptor kinase that is overexpressed in many types of tumors and plays a key role in cell adhesion, spreading, motility,...
Focal Adhesion Kinase (FAK) is a non-receptor kinase that is overexpressed in many types of tumors and plays a key role in cell adhesion, spreading, motility, proliferation, invasion, angiogenesis, and survival. Recently, FAK has been proposed as a target for cancer therapy, and we performed computer modeling and screening of the National Cancer Institute (NCI) small molecule compounds database to target the ATP-binding site of FAK, K454. More than 140,000 small molecule compounds were docked into the crystal structure of the kinase domain of FAK in 100 different orientations using DOCK5.1 that identified small molecule compounds, targeting the K454 site, called A-compounds. To find the therapeutic efficacy of these compounds, we examined the effect of twenty small molecule compounds on cell viability by MTT assays in different cancer cell lines. One compound, A18 (1,4-bis(diethylamino)-5,8- dihydroxy anthraquinon) was a mitoxantrone derivative and significantly decreased viability in most of the cells comparable to the to the level of FAK kinase inhibitors TAE-226 (Novartis, Inc) and PF-573,228 (Pfizer). The A18 compound specifically blocked autophosphorylation of FAK like TAE-226 and PF-228. ForteBio Octet Binding assay demonstrated that mitoxantrone (1,4-dihydroxy- 5,8-bis[2-(2-hydroxyethylamino) ethylamino] anthracene-9,10-dione directly binds the FAK-kinase domain. In addition, mitoxantrone significantly decreased the viability of breast cancer cells in a dose-dependent manner and inhibited the kinase activity of FAK and Y56/577 FAK phosphorylation at 10-20 μM. Mitoxantrone did not affect phosphorylation of EGFR, but decreased Pyk-2, c-Src, and IGF-1R kinase activities. The data demonstrate that mitoxantrone decreases cancer viability, binds FAK-Kinase domain, inhibits its kinase activity, and also inhibits in vitro kinase activities of Pyk-2 and IGF-1R. Thus, this novel function of the mitoxantrone drug can be critical for future development of anti-cancer agents and FAK-targeted therapy research.
Topics: Adenosine Triphosphate; Antineoplastic Combined Chemotherapy Protocols; Binding Sites; Cell Survival; Drug Screening Assays, Antitumor; Enzyme Activation; Humans; Mitoxantrone; Models, Molecular; Molecular Structure; Molecular Weight; Neoplasms; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Structure-Activity Relationship; Tumor Cells, Cultured
PubMed: 22292772
DOI: 10.2174/1871520611313040003 -
miR-130-3p Promotes MTX-Induced Immune Killing of Hepatocellular Carcinoma Cells by Targeting EPHB4.Journal of Healthcare Engineering 2021The vast majority of primary hepatocellular cancer is hepatocellular carcinomas (HCCs). Currently, HCC is one of the more common cancers in humans, and it has a high...
The vast majority of primary hepatocellular cancer is hepatocellular carcinomas (HCCs). Currently, HCC is one of the more common cancers in humans, and it has a high mortality and disability rate. Mitoxantrone (MTX) is an antitumor drug that can block type II topoisomerase. It has been reported that immunogenic cell death evoked by MTX can induce the discharge of damage associated with molecular patterns (DAMPs) and subsequently influence immune cell infiltration in the tumor microenvironment. High mobilities aggregation box 1 (HMGB1) is the prototypical extracellular DAMP. Many cellular processes have been reported to involve EPHB4 receptor tyrosine kinases, but the relation of DAMP and EPHB4 is uncertain. In this research, we assessed the impact of miR-130-3p by Edu incorporation test on cell proliferation, and we have proven its impact on HCC cell migration through Transwell and wound healing tests. Flow cytometry was applied to study its influence on apoptosis. Luciferase report test was integrated in detecting the miR-130-3p target gene. The influence of miR-130-3p on the manifestation of classical DAMPs was studied, such as HMGB1, ATP, and Calreticulin. A coculture experiment was carried out to further confirm its effects on immune cell infiltration. The result displayed that miR-130-3p overexpression considerably facilitates apoptosis and suppresses the migration or proliferation of HCC cells. EPHB4 was confirmed as the target gene of miR-130-3p. Overexpression of this target gene promotes emission of Calreticulin, ATP, and HMGB1 and subsequently promotes DCs maturation and proliferation of CD4+ T cells. In summary, our results demonstrated that miR-130-3p inhibits HCC cell proliferation and migration by targeting EPHB4 and promotes drug-induced immunogenic cell death.
Topics: Carcinoma, Hepatocellular; Cell Line, Tumor; Humans; Liver Neoplasms; MicroRNAs; Mitoxantrone; Receptor, EphB4; Tumor Microenvironment
PubMed: 34336153
DOI: 10.1155/2021/4650794 -
American Journal of Veterinary Research Sep 2001To establish 2 vaccine-associated feline sarcoma (VAFS) cell lines and to determine their in vitro sensitivity to the chemotherapeutic agents doxorubicin and...
OBJECTIVE
To establish 2 vaccine-associated feline sarcoma (VAFS) cell lines and to determine their in vitro sensitivity to the chemotherapeutic agents doxorubicin and mitoxantrone.
SAMPLE POPULATION
Tumor specimens collected from 2 cats undergoing surgery for removal of vaccine-associated sarcomas.
PROCEDURES
Tumor specimens were minced and treated with trypsin under aseptic conditions to obtain single-cell suspensions, which were then cultured in vitro in medium supplemented with 5% heat-inactivated fetal bovine serum. Growth rates and sensitivity after 24 hours of exposure to various concentrations (0.1 to 100 microg/ml) of doxorubicin and mitoxantrone were assessed for each cell line. Survival of cells was estimated 3 days after exposure to the 2 agents, and the concentration of each drug that resulted in a 50% reduction in the number of viable cells (IC50) was calculated.
RESULTS
Two tumor-derived cell lines (FSA and FSB) were successfully established and determined to be sensitive to doxorubicin and mitoxantrone. Under the conditions tested, the IC50 of doxorubicin were 0.6 and 1.5 microg/ml for cell lines FSB and FSA, respectively. The IC50 of mitoxantrone was 0.4 microg/ml for both cell lines.
CONCLUSIONS AND CLINICAL RELEVANCE
The establishment of VAFS cell lines provides a tool for the in vitro screening of antitumor drugs. Doxorubicin and mitoxantrone were effective in decreasing the number of viable cells in the 2 cell lines tested. Both of these anthracycline antibiotics have been used to treat various neoplasias in cats, and their efficacy for adjuvant treatment of vaccine-associated sarcomas should be further evaluated.
Topics: Animals; Antineoplastic Agents; Cat Diseases; Cats; Cell Culture Techniques; Doxorubicin; Female; Inhibitory Concentration 50; Male; Mitoxantrone; Sarcoma; Tumor Cells, Cultured; Vaccination
PubMed: 11560259
DOI: 10.2460/ajvr.2001.62.1354 -
Molekuliarnaia Biologiia 2021Neutrophils fight with invading pathogens through various mechanisms including degranulation, phagocytosis, and the release of neutrophil extracellular traps (NETs)....
Neutrophils fight with invading pathogens through various mechanisms including degranulation, phagocytosis, and the release of neutrophil extracellular traps (NETs). This study aimed to determine the impact of a synthetic formyl-peptide (FMLP) on human neutrophils in vitro, and to determine the role of mitoxantrone (MTX), a pharmacological blocker of mitochondrial Ca^(2+) Uniporter (MCU), on FMLP-induced alterations. Isolated neutrophils and a whole-blood preparation of neutrophils were pre-treated with MTX and then stimulated with FMLP. Field's-stained smears and brightfield microscopy were employed for morphological characterization and quantification of neutrophils. The release of cell-free DNA (cfDNA) was also measured for determining neutrophil damage. Our data demonstrated degenerative changes in neutrophils and a greater cfDNA release upon stimulation with FMLP which was negatively associated with the presence of resting platelets in whole blood preparation. Interestingly, MTX pre-treatment significantly reduced FMLP-triggered neutrophil damage and cfDNA release. Metformin, a known inhibitor of NETs formation, also decreased the FMLP-induced changes in neutrophils. In addition to confirming the degenerative potential of FMLP, this study reveals a novel contribution of MCU in regulating FMLP-induced morphological alterations in human neutrophils.
Topics: Blood Platelets; Humans; Mitoxantrone; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Peptides
PubMed: 34671008
DOI: 10.31857/S0026898421050025 -
ACS Nano Apr 2018The design of nanoparticulate systems which can perform multiple synergistic functions in cells with high specificity and selectivity is of great importance in...
The design of nanoparticulate systems which can perform multiple synergistic functions in cells with high specificity and selectivity is of great importance in applications. Here we combine recent advances in DNA-gold nanoparticle self-assembly and sensing to develop gold nanoparticle dimers that are able to perform multiplexed synergistic functions within a cellular environment. These dimers can sense two mRNA targets and simultaneously or independently deliver one or two DNA-intercalating anticancer drugs (doxorubicin and mitoxantrone) in live cells. Our study focuses on the design of sophisticated nanoparticle assemblies with multiple and synergistic functions that have the potential to advance sensing and drug delivery in cells.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Cell Survival; Dimerization; Doxorubicin; Drug Delivery Systems; Drug Screening Assays, Antitumor; Gold; Humans; Metal Nanoparticles; Mitoxantrone; RNA, Messenger
PubMed: 29557641
DOI: 10.1021/acsnano.7b08620 -
Molecular Pharmaceutics Feb 2016Liposomes incorporating porphyrin-phospholipid (PoP) can be formulated to release entrapped contents in response to near-infrared (NIR) laser irradiation. Here, we...
Liposomes incorporating porphyrin-phospholipid (PoP) can be formulated to release entrapped contents in response to near-infrared (NIR) laser irradiation. Here, we examine effects of chelating copper or zinc into the PoP. Cu(II) and Zn(II) PoP liposomes, containing 10 molar % HPPH-lipid, exhibited unique photophysical properties and released entrapped cargo in response to NIR light. Cu-PoP liposomes exhibited minimal fluorescence and reduced production of reactive oxygen species upon irradiation. Zn-PoP liposomes retained fluorescence and singlet oxygen generation properties; however, they rapidly self-bleached under laser irradiation. Compared to the free base form, both Cu- and Zn-PoP liposomes exhibited reduced phototoxicity in mice. When loaded with mitoxantrone and administered intravenously at 5 mg/kg to mice bearing human pancreatic cancer xenografts, synergistic effects between the drug and the light treatment (for this particular dose and formulation) were realized with metallo-PoP liposomes. The drug-light-interval affected chemophototherapy efficacy and safety.
Topics: Animals; Copper; Humans; Infrared Rays; Lasers; Liposomes; Male; Mice; Mice, Nude; Mitoxantrone; Pancreatic Neoplasms; Phospholipids; Phototherapy; Porphyrins; Singlet Oxygen; Tumor Cells, Cultured; Xenograft Model Antitumor Assays; Zinc
PubMed: 26691879
DOI: 10.1021/acs.molpharmaceut.5b00653 -
Acta Biochimica Polonica 2016Numerous adverse effects limit the applicability of mitoxantrone for the treatment of drug-resistant tumors, including carcinosarcoma. Here, we estimated the additive...
Numerous adverse effects limit the applicability of mitoxantrone for the treatment of drug-resistant tumors, including carcinosarcoma. Here, we estimated the additive effects of mitoxantrone and curcumin, a plant-derived biomolecule isolated from Curcuma longa, on the neoplastic and invasive potential of carcinosarcoma cells in vitro. Curcumin augmented the cytostatic, cytotoxic and anti-invasive effects of mitoxantrone on the Walker-256 cells. It also strengthened the inhibitory effects of mitoxantrone on the motility of drug-resistant Walker-256 cells that had retained viability after a long-term mitoxantrone/curcumin treatment. Thus, curcumin reduces the effective doses of mitoxantrone and augments its interference with the invasive potential of drug-resistant carcinosarcoma cells.
Topics: Animals; Antineoplastic Agents, Phytogenic; Carcinosarcoma; Cell Line, Tumor; Cell Movement; Cell Proliferation; Curcuma; Curcumin; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Synergism; Mitoxantrone; Plant Extracts; Rats
PubMed: 27390785
DOI: 10.18388/abp.2016_1314 -
Journal of the American Veterinary... Jan 2019OBJECTIVE To evaluate effects of substituting mitoxantrone for doxorubicin in a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapeutic...
Substitution of mitoxantrone for doxorubicin in a multidrug chemotherapeutic protocol for first-line treatment of dogs with multicentric intermediate- to large-cell lymphoma.
OBJECTIVE To evaluate effects of substituting mitoxantrone for doxorubicin in a cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapeutic protocol for first-line treatment of dogs with multicentric intermediate- to large-cell lymphoma. DESIGN Retrospective cohort study. ANIMALS 44 dogs treated with cyclophosphamide, mitoxantrone, vincristine, and prednisone (CMOP) and 51 dogs treated with CHOP at 12 referral institutions. PROCEDURES Medical records were reviewed to determine response to treatment, progression-free survival time, and overall survival time. For dogs treated with CMOP, adverse events were also recorded. RESULTS All 44 (100%) dogs treated with CMOP and 37 of 38 (97.4%) dogs treated with CHOP had a complete or partial response. Median progression-free survival time for dogs treated with CMOP was 165 days (95% confidence interval [CI], 143 to 187 days), and median overall survival time was 234 days (95% CI, 165 to 303 days). For dogs treated with CHOP, median progression-free survival time was 208 days (95% CI, 122 to 294 days), and median overall survival time was 348 days (95% CI, 287 to 409 days). Progression-free and overall survival times were not significantly different between groups. Overall, 9 of the 44 (20%) dogs treated with CMOP had adverse events likely or probably related to mitoxantrone, but all of these adverse events were mild. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that mitoxantrone may be a reasonable substitution in a CHOP protocol for treatment of dogs with multicentric intermediate- to large-cell lymphoma when doxorubicin is contraindicated.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Dog Diseases; Dogs; Doxorubicin; Female; Lymphoma, Non-Hodgkin; Male; Mitoxantrone; Prednisone; Retrospective Studies; Vincristine
PubMed: 30605381
DOI: 10.2460/javma.254.2.236