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Oncology Reports Mar 2021Leukemia stem cells (LSCs), which evade standard chemotherapy, may lead to chemoresistance and disease relapse. The overexpression of ATP‑binding cassette subfamily G...
Leukemia stem cells (LSCs), which evade standard chemotherapy, may lead to chemoresistance and disease relapse. The overexpression of ATP‑binding cassette subfamily G member 2 (ABCG2) is an important determinant of drug resistance in LSCs and it can serve as a marker for LSCs. Targeting ABCG2 is a potential strategy to selectively treat and eradicate LSCs, and, hence, improve leukemia therapy. Tucatinib (Irbinitinib) is a novel tyrosine kinase inhibitor, targeting ErbB family member HER2, and was approved by the Food and Drug Administration in April 2020, and in Switzerland in May 2020 for the treatment of HER2‑positive breast cancer. In the present study, the results demonstrated that tucatinib significantly improved the efficacy of conventional chemotherapeutic agents in ABCG2‑overexpressing leukemia cells and primary leukemia blast cells, derived from patients with leukemia. In addition, tucatinib markedly decreased the proportion of leukemia stem cell‑like side population (SP) cells. In SP cells, isolated from leukemia cells, the intracellular accumulation of Hoechst 33342, which is an ABCG2 substrate, was significantly elevated by tucatinib. Furthermore, tucatinib notably inhibited the efflux of [3H]‑mitoxantrone and, hence, there was a higher level of [3H]‑mitoxantrone in the HL60/ABCG2 cell line. The result from the ATPase assay revealed that tucatinib may interact with the drug substrate‑binding site and stimulated ATPase activity of ABCG2. However, the protein expression level and cellular location of ABCG2 were not affected by tucatinib treatment. Taken together, these data suggested that tucatinib could sensitize conventional chemotherapeutic agents, in ABCG2‑overexpressing leukemia cells and LSCs, by blocking the pump function of the ABCG2 protein. The present study revealed that combined treatment with tucatinib and conventional cytotoxic agents could be a potential therapeutic strategy in ABCG2‑positive leukemia.
Topics: ATP Binding Cassette Transporter, Subfamily G, Member 2; Adenosine Triphosphatases; Adult; Antineoplastic Agents; Benzimidazoles; Cell Survival; Drug Resistance, Neoplasm; Female; Humans; Leukemia; Male; Mitoxantrone; Neoplasm Proteins; Neoplastic Stem Cells; Oxazoles; Pyridines; Quinazolines; Side-Population Cells; Tumor Cells, Cultured
PubMed: 33650639
DOI: 10.3892/or.2020.7915 -
Turkish Journal of Medical Sciences Aug 2019High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has become the standard approach for patients with relapsed/refractory Hodgkin’s...
BACKGROUND/AIM
High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) has become the standard approach for patients with relapsed/refractory Hodgkin’s lymphoma (HL) or non-Hodgkin’s lymphoma (NHL). In this study, we report the outcome of the mitoxantrone-melphalan conditioning regimen for lymphoma.
MATERIALS AND METHODS
The study group included 53 patients who were relapsed/refractory HL (n = 14) and NHL (n = 39) and received mitoxantrone and melphalan followed by ASCT. The transplant regimen consisted of mitoxantrone (60 mg/m2) and melphalan (180 mg/m2) followed by peripheral blood stem cell infusion (PBSC).
RESULTS
Prior to high-dose chemotherapy, 37.7% of the patients were in complete remission (CR) and 45.3% were in partial remission (PR), and 17% had stable or progressive disease. After high-dose chemotherapy and PBSC, 44 out of 51 patients achieved CR (86.2%). CR was achieved in 24 out of 33 patients (72.7%) who were transplanted in a marginally active phase of the disease. At a median followup of 25.4 months (1.8–131.3 months) after ASCT, 13 patients relapsed/ progressed and 8 patients died. The estimated 2-year overall survival (OS) was 81.9%, and event-free survival (EFS) was 59.3%.
CONCLUSION
High-dose chemotherapy followed by ASCT is an effective conditioning regimen in relapsed/refractory lymphoma patients who are undergoing ASCT.
Topics: Adolescent; Adult; Aged; Antineoplastic Agents; Female; Hematopoietic Stem Cell Transplantation; Humans; Lymphoma; Male; Melphalan; Middle Aged; Mitoxantrone; Recurrence; Retrospective Studies; Young Adult
PubMed: 31293116
DOI: 10.3906/sag-1809-36 -
BMC Neuroscience Mar 2022Mitoxantrone has proved efficacy in treatment of multiple sclerosis (MS). The fact that physical exercise could slow down the progression of disease and improve...
BACKGROUND
Mitoxantrone has proved efficacy in treatment of multiple sclerosis (MS). The fact that physical exercise could slow down the progression of disease and improve performance is still a debatable issue, hence; we aimed at studying whether combining mitoxantrone with exercise is of value in the management of MS.
METHODS
Thirty-six male rats were divided into sedentary and exercised groups. During a 14-day habituation period rats were subjected to exercise training on a rotarod (30 min/day) before Experimental Autoimmune Encephalomyelitis (EAE) induction and thereafter for 17 consecutive days. On day 13 after induction, EAE groups (exercised &sedentary) were divided into untreated and mitoxantrone treated ones. Disease development was evaluated by motor performance and EAE score. Cerebrospinal fluid (CSF) was used for biochemical analysis. Brain stem and cerebellum were examined histopathological and immunohistochemically.
RESULTS
Exercise training alone did not add a significant value to the studied parameters, except for reducing Foxp3 immunoreactivity in EAE group and caspase-3 in the mitoxantrone treated group. Unexpectedly, exercise worsened the mitoxantrone effect on EAE score, Bcl2 and Bax. Mitoxantrone alone decreased EAE/demyelination/inflammation scores, Foxp3 immunoreactivity, and interleukin-6, while increased the re-myelination marker BDNF without any change in tumor necrosis factor-α. It clearly interrupted the apoptotic pathway in brain stem, but worsened EAE mediated changes of the anti-apoptotic Bcl2 and pro-apoptotic marker Bax in the CSF.
CONCLUSIONS
The neuroprotective effect of mitoxantrone was related with remyelination, immunosuppressive and anti-inflammatory potentials. Exercise training did not show added value to mitoxantrone, in contrast, it disrupts the apoptotic pathway.
Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Forkhead Transcription Factors; Male; Mice; Mice, Inbred C57BL; Mitoxantrone; Multiple Sclerosis; Proto-Oncogene Proteins c-bcl-2; Rats; bcl-2-Associated X Protein
PubMed: 35247984
DOI: 10.1186/s12868-022-00692-1 -
PloS One 2021Synthetic lethality is a successful strategy employed to develop selective chemotherapeutics against cancer cells. Inactivation of RAD52 is synthetically lethal to...
Synthetic lethality is a successful strategy employed to develop selective chemotherapeutics against cancer cells. Inactivation of RAD52 is synthetically lethal to homologous recombination (HR) deficient cancer cell lines. Replication protein A (RPA) recruits RAD52 to repair sites, and the formation of this protein-protein complex is critical for RAD52 activity. To discover small molecules that inhibit the RPA:RAD52 protein-protein interaction (PPI), we screened chemical libraries with our newly developed Fluorescence-based protein-protein Interaction Assay (FluorIA). Eleven compounds were identified, including FDA-approved drugs (quinacrine, mitoxantrone, and doxorubicin). The FluorIA was used to rank the compounds by their ability to inhibit the RPA:RAD52 PPI and showed mitoxantrone and doxorubicin to be the most effective. Initial studies using the three FDA-approved drugs showed selective killing of BRCA1-mutated breast cancer cells (HCC1937), BRCA2-mutated ovarian cancer cells (PE01), and BRCA1-mutated ovarian cancer cells (UWB1.289). It was noteworthy that selective killing was seen in cells known to be resistant to PARP inhibitors (HCC1937 and UWB1 SYr13). A cell-based double-strand break (DSB) repair assay indicated that mitoxantrone significantly suppressed RAD52-dependent single-strand annealing (SSA) and mitoxantrone treatment disrupted the RPA:RAD52 PPI in cells. Furthermore, mitoxantrone reduced radiation-induced foci-formation of RAD52 with no significant activity against RAD51 foci formation. The results indicate that the RPA:RAD52 PPI could be a therapeutic target for HR-deficient cancers. These data also suggest that RAD52 is one of the targets of mitoxantrone and related compounds.
Topics: Apoptosis; BRCA1 Protein; Cell Death; Cell Line, Tumor; Cell Survival; DNA Damage; DNA Repair; Doxorubicin; Fluorescence; High-Throughput Screening Assays; Homologous Recombination; Humans; Mitoxantrone; Neoplasms; Protein Binding; Quinacrine; Rad52 DNA Repair and Recombination Protein; Replication Protein A; Small Molecule Libraries
PubMed: 33784323
DOI: 10.1371/journal.pone.0248941 -
The Canadian Veterinary Journal = La... Nov 1994The purpose of this study was to examine the feasibility of a combination chemotherapy protocol ("CYCLONE") in cats, utilizing mitoxantrone and cyclophosphamide. Three...
The purpose of this study was to examine the feasibility of a combination chemotherapy protocol ("CYCLONE") in cats, utilizing mitoxantrone and cyclophosphamide. Three normal adult cats were administered mitoxantrone (6.5 mg/m2 intravenously) and cyclophosphamide (100 mg/m2 intravenously) every 21 days for a total of three doses. Individual white blood cell count nadirs (range, 2.0-9.5 x 10(9)/L) and neutrophil count nadirs (range, 0.3 to 5.0 x 10(9)/L) occurred between days 2 and 10 after each dose of chemotherapy. Mean white blood cell count nadirs (range of mean, 5.5 to 8.4 x 10(9)/L) occurred between days 6 and 8, as did the mean neutrophil count nadir (range of mean, 1.7-4.0 x 10(9)/L). Side effects were limited to transient appetite suppression in one cat and loose stools in two cats. Myelosuppression and gastrointestinal side effects were comparable to those observed with single-agent mitoxantrone protocols. Further investigation of this protocol is warranted.
Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Blood Cell Count; Cats; Cyclophosphamide; Feasibility Studies; Female; Injections, Intravenous; Male; Mitoxantrone
PubMed: 7866961
DOI: No ID Found -
Anthracycline antibiotics derivate mitoxantrone-Destructive sorption and photocatalytic degradation.PloS One 2018Nanostructured titanium(IV) oxide was used for the destructive adsorption and photocatalytic degradation of mitoxantrone (MTX), a cytostatic drug from the group of...
Nanostructured titanium(IV) oxide was used for the destructive adsorption and photocatalytic degradation of mitoxantrone (MTX), a cytostatic drug from the group of anthracycline antibiotics. During adsorption on a titania dioxide surface, four degradation products of MTX, mitoxantrone dicarboxylic acid, 1,4-dihydroxy-5-((2-((2-hydroxyethyl)amino)ethyl)amino)-8-((2-(methylamino)ethyl)amino)anthracene-9,10-dione, 1,4-dihydroxy-5,8-diiminoanthracene-9,10(5H,8H)-dione and 1,4-dihydroxy-5-imino-8-(methyleneamino)anthracene-9,10(5H,8H)-dione, were identified. In the case of photocatalytic degradation, only one degradation product after 15 min at m/z 472 was identified. This degradation product corresponded to mitoxantrone dicarboxylic acid, and complete mineralization was attained in one hour. Destructive adsorbent manganese(IV) oxide, MnO2, was used only for the destructive adsorption of MTX. Destructive adsorption occurred only for one degradation product, mitoxantrone dicarboxylic acid, against anatase TiO2.
Topics: Adsorption; Anthracyclines; Catalysis; Manganese Compounds; Mitoxantrone; Nanoparticles; Oxides; Titanium
PubMed: 29534071
DOI: 10.1371/journal.pone.0193116 -
European Journal of Medical Research Jun 2024Multiple Sclerosis (MS) is a complex autoimmune disorder that significantly impacts the central nervous system, leading to a range of complications. While intracranial... (Review)
Review
Multiple Sclerosis (MS) is a complex autoimmune disorder that significantly impacts the central nervous system, leading to a range of complications. While intracranial haemorrhage (ICH) is a rare but highly morbid complication, more common CNS complications include progressive multifocal leukoencephalopathy (PML) and other CNS infections. This severe form of stroke, known for its high morbidity and mortality rates, presents a critical challenge in the management of MS. The use of disease-modifying drugs (DMDs) in treating MS introduces a nuanced aspect to patient care, with certain medications like Dimethyl Fumarate and Fingolimod showing potential in reducing the risk of ICH, while others such as Alemtuzumab and Mitoxantrone are associated with an increased risk. Understanding the intricate relationship between these DMDs, the pathophysiological mechanisms of ICH, and the individualised aspects of each patient's condition is paramount. Factors such as genetic predispositions, existing comorbidities, and lifestyle choices play a crucial role in tailoring treatment approaches, emphasising the importance of a personalised, vigilant therapeutic strategy. The necessity for ongoing and detailed research cannot be overstated. It is crucial to explore the long-term effects of DMDs on ICH occurrence and prognosis in MS patients, aiming to refine clinical practices and promote patient-centric, informed therapeutic decisions. This approach ensures that the management of MS is not only comprehensive but also adaptable to the evolving understanding of the disease and its treatments.
Topics: Humans; Multiple Sclerosis; Cerebral Hemorrhage; Immunosuppressive Agents; Mitoxantrone; Fingolimod Hydrochloride; Dimethyl Fumarate
PubMed: 38918831
DOI: 10.1186/s40001-024-01945-x -
IARC Monographs on the Evaluation of... 2000
Review
Topics: Amsacrine; Antineoplastic Agents; Carcinogens; Disease Models, Animal; Etoposide; Evidence-Based Medicine; Humans; Intestinal Absorption; Mitoxantrone; Neoplasms; Nucleic Acid Synthesis Inhibitors; Research Design; Risk Factors; Teniposide; Tissue Distribution; Topoisomerase II Inhibitors
PubMed: 11000976
DOI: No ID Found -
Molecular Pharmacology Jan 2017Myeloperoxidase is expressed exclusively in granulocytes and immature myeloid cells and transforms the topoisomerase II (TOP2) poisons etoposide and mitoxantrone to...
Myeloperoxidase is expressed exclusively in granulocytes and immature myeloid cells and transforms the topoisomerase II (TOP2) poisons etoposide and mitoxantrone to chemical forms that have altered DNA damaging properties. TOP2 poisons are valuable and widely used anticancer drugs, but they are associated with the occurrence of secondary acute myeloid leukemias. These factors have led to the hypothesis that myeloperoxidase inhibition could protect hematopoietic cells from TOP2 poison-mediated genotoxic damage and, therefore, reduce the rate of therapy-related leukemia. We show here that myeloperoxidase activity leads to elevated accumulation of etoposide- and mitoxantrone-induced TOP2A and TOP2B-DNA covalent complexes in cells, which are converted to DNA double-strand breaks. For both drugs, the effect of myeloperoxidase activity was greater for TOP2B than for TOP2A. This is a significant finding because TOP2B has been linked to genetic damage associated with leukemic transformation, including etoposide-induced chromosomal breaks at the MLL and RUNX1 loci. Glutathione depletion, mimicking in vivo conditions experienced during chemotherapy treatment, elicited further MPO-dependent increase in TOP2A and especially TOP2B-DNA complexes and DNA double-strand break formation. Together these results support targeting myeloperoxidase activity to reduce genetic damage leading to therapy-related leukemia, a possibility that is enhanced by the recent development of novel specific myeloperoxidase inhibitors for use in inflammatory diseases involving neutrophil infiltration.
Topics: Antigens, Neoplasm; Antineoplastic Agents; Cell Line, Tumor; Cytoprotection; DNA; DNA Damage; DNA Topoisomerases, Type II; DNA-Binding Proteins; Enzyme Inhibitors; Etoposide; Glutathione; Histones; Humans; Mitoxantrone; Myeloid Cells; Neoplasms; Peroxidase; Phosphorylation; Poly-ADP-Ribose Binding Proteins; Small Molecule Libraries
PubMed: 27974636
DOI: 10.1124/mol.116.106054 -
APMIS : Acta Pathologica,... Feb 2012Metronomic chemotherapy with cytotoxic agents has been shown to inhibit angiogenesis and, consequently, tumor growth by targeting vascular endothelial cells (ECs). In...
Metronomic chemotherapy with cytotoxic agents has been shown to inhibit angiogenesis and, consequently, tumor growth by targeting vascular endothelial cells (ECs). In these regimens, anti-tumor activities additional to anti-angiogenesis may operate. Moreover, chemotherapy typically generates reactive oxygen species in targeted ECs, which can affect angiogenesis. The aim of the present study was to assess the systemic effect of low-dosage metronomic treatment with either irinotecan or mitoxantrone on angiogenesis induced by VEGF-A. Angiogenesis was induced in normal adult rat mesentery by intraperitoneal injection of a low dosage of VEGF-A. Thereafter, irinotecan and mitoxantrone were infused separately continuously at minimally toxic dosages for 14 consecutive days via a subcutaneous osmotic minipump. Angiogenesis was assessed in terms of objective and quantitative variables using morphologic and computerized image analyses. Irinotecan or mitoxantrone significantly stimulated angiogenesis, with ironotecan increasing angiogenesis by 104%, when compared with the vehicle-treated animals. Low-dosage metronomic chemotherapy with irinotecan or mitoxantrone stimulates angiogenesis in the normal mesentery of rats, probably by inducing low-level oxidative stress in the targeted ECs. Whether or not this pertains to tumor angiogenesis may be difficult to confirm, as several anti-tumor modes may operate during low-dosage metronomic chemotherapy.
Topics: Animals; Body Weight; Camptothecin; Endothelial Cells; Irinotecan; Male; Mesentery; Mitoxantrone; Neovascularization, Pathologic; Neovascularization, Physiologic; Rats; Rats, Sprague-Dawley; Statistics, Nonparametric; Topoisomerase Inhibitors; Vascular Endothelial Growth Factor A
PubMed: 22229270
DOI: 10.1111/j.1600-0463.2011.02830.x