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The outlook of relapsed ALL in low- and middle-income countries (LMICs) is dismal due to high treatment-related toxicities and inadequate resources. We report our experience of using a locally adapted mitoxantrone-based protocol for non-high risk (HR) relapsed B-ALL (rALL). A retrospective cum prospective study of standard and intermediate risk (SR and IR) rALL patients treated on TMH rALL-18 protocol (adapted from COG/UKALLR3/Int-Re-ALL protocols) between November 2018 and January 2021 was analyzed. The protocol comprising of 7 blocks of multi-agent chemotherapy including mitoxantrone in induction followed by local irradiation and maintenance, underwent serial modifications based on our experience with initial patients. Eighty-two patients (SR rALL, 3; IR rALL, 79) were treated on TMH rALL-18 protocol. Of 321 grade 3/4 reported toxicities, around 43% (138 toxicities) were noted during induction. Induction chemotherapy was outpatient-based; however, 68 patients (82.9%) required supportive care admissions. Twelve out of 19 patients with gram negative bacilli sepsis (included 7 MDRO) died during reinduction. Five remission deaths were seen during block 3 after which cytarabine was dose reduced (3 g to 2 g/m2). Post-reinduction minimal residual disease was negative in 54 (80.6%) out of 67 evaluable patients. At a median follow-up of 24 months (95% CI 22–27), the estimated 2-year event-free and overall survival of the entire cohort was 58% (95% CI 48.1–69.9) and 60.3% (95% CI 50.5–72). Until the time, targeted therapies are freely accessible in LMICs, strengthening supportive care as well as local adaptation of protocols that strike a fine balance between efficacy and tolerability are mandated. [ABSTRACT FROM AUTHOR]

Background: About 50% of older patients with acute myeloid leukemia (AML) fail to attain complete remission (CR) following cytarabine plus anthracycline-based induction therapy. Salvage chemotherapy regimens are based on high-dose cytarabine (HiDAC), which is frequently combined with mitoxantrone (HAM regimen). However, CR rates remain low, with less than one-third of the patients achieving a CR. FLT3-ITD has consistently been identified as an unfavorable molecular marker in both relapsed and refractory (r/r)-AML. One-quarter of patients who received midostaurin are refractory to induction therapy and relapse rate at 2 years exceeds 40%. The oral second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib is a very selective FLT3 inhibitor, has a high capacity for sustained FLT3 inhibition, and has an acceptable toxicity profile. Methods: In this multicenter, upfront randomized phase II trial, all patients receive quizartinib combined with HAM (cytarabine 3g/m2 bidaily day one to day three, mitoxantrone 10mg/m2 days two and three) during salvage therapy. Efficacy is assessed by comparison to historical controls based on the matched threshold crossing approach with achievement of CR, complete remission with incomplete hematologic recovery (CRi), or complete remission with partial recovery of peripheral blood counts (CRh) as primary endpoint. During consolidation therapy (chemotherapy and allogeneic hematopoietic cell transplantation), patients receive either prophylactic quizartinib therapy or measurable residual disease (MRD)-triggered preemptive continuation therapy with quizartinib according to up-front randomization. The matched threshold crossing approach is a novel study-design to enhance the classic single-arm trial design by including matched historical controls from previous clinical studies. It overcomes common disadvantages of single-armed and small randomized studies, since the expected outcome of the observed study population can be adjusted based on the matched controls with a comparable distribution of known prognostic and predictive factors. Furthermore, balanced treatment groups lead to stable statistical models. However, one of the limitations of our study is the inability to adjust for unobserved or unknown confounders. Addressing the primary endpoint, CR/CRi/CRh after salvage therapy, the maximal sample size of 80 patients is assessed generating a desirable power of the used adaptive design, assuming a logistic regression is performed at a one-sided significance level α=0.05, the aspired power is 0.8, and the number of matching partners per intervention patient is at least 1. After enrolling 20 patients, the trial sample size will be recalculated in an interim analysis based on a conditional power argument. Conclusion: Currently, there is no commonly accepted standard for salvage chemotherapy treatment. The objective of the salvage therapy is to reduce leukemic burden, achieve the best possible remission, and perform a hemopoietic stem-cell transplantation. Thus, in patients with FLT3-ITD mutation, the comparison of quizartinib with intensive salvage therapy versus chemotherapy alone appears as a logical consequence in terms of efficacy and safety. Ethics and dissemination: Ethical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings. Trial registration: ClinicalTrials.gov NCT03989713; EudraCT Number: 2018-002675-17. [ABSTRACT FROM AUTHOR]

Long-term cognitive dysfunction, or "chemobrain", has been observed in cancer patients treated with chemotherapy. Mitoxantrone (MTX) is a topoisomerase II inhibitor that binds and intercalates with DNA, being used in the treatment of several cancers and multiple sclerosis. Although MTX can induce chemobrain, its neurotoxic mechanisms are poorly studied. This work aimed to identify the adverse outcome pathways (AOPs) activated in the brain upon the use of a clinically relevant cumulative dose of MTX. Three-month-old male CD-1 mice were given a biweekly intraperitoneal administration of MTX over the course of three weeks until reaching a total cumulative dose of 6 mg/kg. Controls were given sterile saline in the same schedule. Two weeks after the last administration, the mice were euthanized and their brains removed. The left brain hemisphere was used for targeted profiling of the metabolism of glutathione and the right hemisphere for an untargeted metabolomics approach. The obtained results revealed that MTX treatment reduced the availability of cysteine (Cys), cysteinylglycine (CysGly), and reduced glutathione (GSH) suggesting that MTX disrupts glutathione metabolism. The untargeted approach revealed metabolic circuits of phosphatidylethanolamine, catecholamines, unsaturated fatty acids biosynthesis, and glycerolipids as relevant players in AOPs of MTX in our in vivo model. As far as we know, our study was the first to perform such a broad profiling study on pathways that could put patients given MTX at risk of cognitive deficits. [ABSTRACT FROM AUTHOR]

A common neurodegenerative condition that still presents clinical challenges is Multiple Sclerosis (MS). Effective multiple sclerosis treatments are sorely needed in clinical settings. Experimental Autoimmune Encephalomyelitis (EAE) is an animal model of multiple sclerosis, a T-cell-mediated disease. Active T-cells differentiate into the Th9 and Th17 subsets, which are controlled by NF-kB and produce the proinflammatory cytokines IL9 and IL17. Because these cytokines are crucial to the pathophysiology of EAE, they have been used as targets for MS therapy. Caffeic acid phenethyl ester (CAPE) is an active ingredient of propolis that has been shown to have immunomodulatory and anti-inflammatory activities. Mitoxantrone is a synthetic antineoplastic agent and cytotoxic immunosuppressive effect used to treat MS. The study aimed to determine whether the two medications have superior efficacy and effect in the treatment of EAE mouse model MS compared to the other. After inducing EAE in mice, CAPE and mitoxantrone were administered to evaluate this therapeutic effectiveness. ELISA was used to measure IL9, IL17 levels and the activity of NF-kBp56. H&E was used to evaluate cell infiltration T lymphocytes for histopathology of spinal cord tissue. Molecular docking was performed to predict the interaction between CAPE and a cytokine. We found that CAPE has a sufficient effect of reducing the level of IL9, IL17, active NF-kBp56, and inflammatory cell infiltration T-lymphocytes in all groups of mice EAE treated with CAPE. In contrast, mitoxantrone reduced cytokines and cell infiltration, so EAE mice treated with both compounds were observed more improvement than other groups. Based on our findings, two medications demonstrated the same efficacy and effect in EAE mice model MS., whereas CAPE did not statistically reach a significant value. While the combination of two medications has the optimal effect. [ABSTRACT FROM AUTHOR]

Introduction. Breast cancer resistance protein (BCRP) is an efflux membrane transporter that controls the pharmacokinetics of a large number of drugs. Its activity may change when taking some endo- and exogenous substances, thus making it a link in drug interactions.Aim. The aim of the study was to develop a method for testing of drugs for belonging to BCRP substrates and inhibitors in vitro.Materials and methods. The work was performed on Caco-2 cells overexpressing BCRP, the cultivation was performed in a transwell-system consisting of the apical and basolateral chambers. Cells were seeded at the bottom of the apical chamber, which is a semipermeable membrane. Primarily, the transport of BCRP substrates: methotrexate, mitoxantrone and quercetin was evaluated in the concentration range of 1, 5, 10, and 50 μM in the direction from the basal chamber to the apical one (Papp b-a) and in the opposite direction (Papp a-b). The ratio Papp b-a / Papp a-b more than «2» characterizes the participation of transporter proteins in the transcellular transport of substances. To confirm the participation of BCRP in their transport the experiment was carried out with the addition of a transporter inhibitor, reserpine, to the transport medium at a concentration of 50 μM. The concentration of substrates in the chambers was analyzed by HPLC-MS/MS.Results and their discussion. The addition of methotrexate (1 μM), mitoxantrone (1 μM), and quercetin (1–10 μM) to both the apical or basolateral chambers of the transwell-system, their content in the recipient chamber was not detected. When methotrexate concentration became 5 μM the Papp b-a / Papp a-b ratio was 3.38 ± 0.08, which indicates the involvement of transporters in its transfer. The addition of methotrexate to the donor chamber at concentrations of 10 and 50 μM, Papp b-a / Papp a-b decreased to values below «2». At mitoxantrone concentration of 5 μM Papp b-a / Papp a-b was 2.72 ± 0.16. An increase in the concentration to 10 μM led to an increase in Papp b-a / Papp a-b to 6.18 ± 0.08. With a substance content of 50 μM the indicator decreased but remained above the value «2». In the quercetin concentration of 50 microns, Papp b-a / Papp was below "2". Reserpine reduced Papp b-a / Papp a-b of methotrexate by 3.31 times (p = 0.0002), which indicates the elimination of asymmetry in the transport of the substance. At a mitoxantrone concentration of 10 microns, reserpine reduced its Papp b-a / Papp a-b by 3.36 times (p < 0.0001). The results indicate the participation of BCRP in the control of the transfer of both substances through the cellular monolayer.Conclusion. A method of testing drugs belonging to BCRP substrates and inhibitors using methotrexate (5 μM) and mitoxantrone (10 μM) as marker substrates and reserpine (50 μM) as inhibitor was developed and tested on Caco-2 cells.

Abstract Bone metastasis is the main cause of death in patients with prostate cancer (PCa), but there lacks effective treatment method. Immunotherapy shows new hopes for bone metastatic PCa patients, while the efficacy is still unsatisfactory and limited by the unique immunosuppressive microenvironment in metastatic bone site. Here, we developed a bone-targeted nano-delivery system as a nano-regulator to enhance the immunotherapy of bone metastatic PCa. The nanosystem was assembled via coordination between phytic acid (PA) and Fe3+ to form nano-sized metal–organic framework (MOF), through which mitoxantrone (MTO) was encapsulated. At cellular level, the nanosystem showed selective cytotoxicity towards RM-1 PCa cells over immune cells, and could induce tumor cells immunogenic cell death (ICD) to improve the immunogenicity of the tumor. Moreover, the nanosystem was able to induce ubiquitination of TGFβ receptor (TβR) on immune cells to promote its degradation, thus serving as a nano-regulator to block the functions of TGF-β, an abundant cytokine that has a systematically immunosuppressive effect in the tumor microenvironment. Upon intravenous injection, the nanoparticle showed pro-longed blood circulation and targeting accumulation into bone metastatic site, and imposed robust anti-tumor effect in combination with αCTLA-4. In addition, bone destruction was significantly alleviated after treatment to reduce the skeletal-related events. Overall, this work provides a biocompatible nanomedicine to restore immune sensitivity of bone metastatic tumor for enhanced immunotherapy by blocking TGF-β signaling pathway.

Objective(s): Conventional methods of cancer treatment include surgery, chemotherapy, radiation therapy, and immunotherapy. Chemotherapy, as one of the main methods of cancer treatment, due to the lack of targeted distribution of the drug in tumor tissues, is not able to destroy cancer cells and also affects healthy tissues and causes serious side effects in patients. Sonodynamic therapy (SDT) is a promising strategy for non-invasive treatment of deep solid cancer tumors. In this study, for the first time, the sono-sensitive activity of mitoxantrone was investigated and then mitoxantrone (MTX) was conjugated to hollow gold nanostructure (HGN) to improve the efficiency of in vivo SDT. Materials and Methods: Firstly, after the synthesis of hollow gold nanoshells and the PEGylation process, conjugation of MTX was performed. Then, after evaluating the toxicity of the treatment groups in vitro, in order to perform an in vivo study, 56 male Balb/c mice that had been tumorized by subcutaneous injection of 4T1 cells were divided into eight groups of breast tumor model. Ultrasonic irradiation (US) conditions including intensity of 1.5 W/cm2 (with a frequency of 800 kHz, 5 min), MTX concentration of 2 μM, and HGN dose of 2.5 mg/kg (unit of animal weight) were used.Results: The results show that administration of PEG-HGN-MTX caused a slight reduction in tumor size and growth compared with free MTX. Ultrasound also improved the therapeutic effect of the gold nanoshell in treated groups, and the HGN-PEG-MTX-US treated groups were able to significantly reduce and control tumor size and growth. Conclusion: The findings also show that MTX and HGN can be used as sonosensitizers in SDT. Also, HGN-PEG-MTX can act as a sono-chemotherapy agent for the combination of sonodynamic therapy and chemotherapy for in vivo breast tumors.

Mitoxantrone is a marker substrate of breast cancer resistance protein (BCRP). BCRP is involved in a number of pharmacokinetic drug-drug interactions. The transporter’s possible saturability makes it advisable to use low concentrations of mitoxantrone for in vitro studies. Consequently, mitoxantrone quantification requires a method with high sensitivity.The aim of the study was to develop and validate a procedure for mitoxantrone quantification in Caco-2 culture media by HPLC-MS/MS.Materials and methods. The authors used an Ultimate 3000 HPLC system and a TSQ Fortis triple quadrupole mass spectrometer by Thermo Fisher Scientific and a Selectra C18 column (4.6×100 mm, 5 μm, 100 Å) by United Chemical Technologies. The elution ran in a gradient mode with a mobile phase of 1% formic acid solution and methanol. Experimental parameters were as follows: eluent flow rate, 0.3 mL/min; separation column temperature, 35 °C; injection volume, 5 μL; ana lysis time, 10 min; approximate mitoxantrone retention time, 5.51 min. The sample preparation involved protein precipitation from the culture medium with methanol, followed by centrifugation at 13,000 g for 10 min. The detection was performed using electrospray ionisation in the positive ion mode. Detection parameters were as follows: electrospray voltage, 3700 V; sheath gas flow rate, 50 L/min; auxiliary gas flow rate, 10 L/min; sweep gas flow rate, 1 L/min; ion-transfer tube temperature, 300 °C; and evaporator temperature, 350 °C. The detection was set at mass transitions of m/z 455 to 88.2 and m/z 455 to 358.1, with the collision energy for these transitions amounting to 25 V and 18 V, respectively. The source fragmentation was at 0, and the CID gas pressure was at 2 mTorr.Results. The analytical procedure showed selectivity, high sensitivity (limit of detection, 10 nmol/L; lower limit of quantification, 50 nmol/L), accuracy, precision, and linearity in the concentration range of 50–1000 nmol/L. The authors observed no carryover or matrix effects. A simulation of real-life storage conditions demonstrated high stability of mitoxantrone samples. Thus, the analytical procedure enables preclinical evaluation of medicinal product effects on the functional activity of BCRP, based on assessing the transcellular mitoxantrone transport in the presence of a test product.Conclusion. The authors developed and validated the analytical procedure for mitoxantrone quantification in Caco-2 culture media by HPLC-MS/MS.

Glioblastoma Multiforme (GBM) tumors contain a small population of glioma stem-like cells (GSCs) among the various differentiated GBM cells (d-GCs). GSCs drive tumor recurrence, and resistance to Temozolomide (TMZ), the standard of care (SoC) for GBM chemotherapy. In order to investigate a potential link between GSC specific mitochondria function and SoC resistance, two patient-derived GSC lines were evaluated for differences in their mitochondrial metabolism. In both the lines, GSCs had significantly lower mitochondrial -content, and -function compared to d-GCs. In vitro, the standard mitochondrial-specific inhibitors oligomycin A, antimycin A, and rotenone selectively inhibited GSC proliferation to a greater extent than d-GCs and human primary astrocytes. These findings indicate that mitochondrial inhibition can be a potential GSC-targeted therapeutic strategy in GBM with minimal off-target toxicity. Mechanistically the standard mitochondrial inhibitors elicit their GSC-selective cytotoxic effects through the induction of apoptosis or autophagy pathways. We tested for GSC proliferation in the presence of 3 safe FDA-approved drugs--trifluoperazine, mitoxantrone, and pyrvinium pamoate, all of which are also known mitochondrial-targeting agents. The SoC GBM therapeutic TMZ did not trigger cytotoxicity in glioma stem cells, even at 100 μM concentration. By contrast, trifluoperazine, mitoxantrone, and pyrvinium pamoate exerted antiproliferative effects in GSCs about 30-50 fold more effectively than temozolomide. Thus, we hereby demonstrate that FDA-approved mitochondrial inhibitors induce GSC-selective cytotoxicity, and targeting mitochondrial function could present a potential therapeutic option for GBM treatment.

Objective: NRF2 is a master transcription factor that regulates the stress response. NRF2 is frequently mutated and activated in human esophageal squamous cell carcinoma (ESCC), which drives resistance to chemotherapy and radiation therapy. Therefore, a great need exists for NRF2 inhibitors for targeted therapy of NRF2high ESCC. Design: We performed high-throughput screening of two compound libraries from which hit compounds were further validated in human ESCC cells and a genetically modified mouse model. The mechanism of action of one compound was explored by biochemical assays. Results: Using high-throughput screening of two small molecule compound libraries, we identified 11 hit compounds as potential NRF2 inhibitors with minimal cytotoxicity at specified concentrations. We then validated two of these compounds, pyrimethamine and mitoxantrone, by demonstrating their dose- and time-dependent inhibitory effects on the expression of NRF2 and its target genes in two NRF2Mut human ESCC cells (KYSE70 and KYSE180). RNAseq and qPCR confirmed the suppression of global NRF2 signaling by these two compounds. Mechanistically, pyrimethamine reduced NRF2 half-life by promoting NRF2 ubiquitination and degradation in KYSE70 and KYSE180 cells. Expression of an Nrf2E79Q allele in mouse esophageal epithelium (Sox2CreER;LSL-Nrf2E79Q/+) resulted in an NRF2high phenotype, which included squamous hyperplasia, hyperkeratinization, and hyperactive glycolysis. Treatment with pyrimethamine (30 mg/kg/day, p.o.) suppressed the NRF2high esophageal phenotype with no observed toxicity. Conclusion: We have identified and validated pyrimethamine as an NRF2 inhibitor that may be rapidly tested in the clinic for NRF2high ESCC.

Background: The dual technique using blue dye in combination with a radioisotope is considered the gold standard for identifying sentinel lymph nodes (SLNs) in patients with breast cancer. Unfortunately, not all cancer centres have access to radioactive material, which jeopardizes the SLN identification rate and patient safety. Aim: We aimed to assess the safety and efficacy of mitoxantrone hydrochloride injection (MHI) for identifying axillary SLNs in patients with primary breast cancer. Patients and methods: We have conducted a prospective non-randomized analysis of patients diagnosed with invasive breast cancer who agreed to participate in the study between December 2019 and December 2022. We have used the patient's medical records to collect the data. We have used the SLN intraoperative identification rate as a marker for the efficacy of the technique and both the immediate and delayed complication rates and routine blood tests as markers for the safety of the technique. Results: Out of the 296 patients, 289 (97.6%) had their SLNs identified using MHI, while seven patients (2.3%) had four-node sampling carried out because the SLNs were not identified. Liver functions were not significantly affected by MHI, and there was no technique-related readmission or reported morbidity or mortality. Conclusion: We have found that the MHI technique is still inferior to the combined radioactive directed technique and patent blue V dye in SLN identification. Yet, it may serve as a safe and reliable alternative in cases where the radioactive technique is unavailable. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer is the second most frequently occurring cancer in men, and patients with advanced prostate cancer have poor long-term survival. Chemotherapy is the cornerstone of systemic therapy for advanced prostate cancer and can prolong survival, both in castration-sensitive and castration-resistant disease. In this review, we summarize the data that underlie the integration of chemotherapy into the management of advanced prostate cancer, including data supporting the combination of chemotherapy with next generation androgen receptor signaling inhibitors. Prostate cancer is the second most common cancer among men. Despite advances in diagnosis and management, prostate cancer led to more than 300,000 deaths globally in 2020. Chemotherapy is a cornerstone of therapy for advanced prostate cancer and can prolong survival of patients with both castration-sensitive and castration-resistant disease. Herein, we present a comprehensive review of the data supporting implementation of chemotherapy in the modern treatment of advanced prostate cancer, with special attention to the use of chemotherapy for aggressive variant prostate cancer (e.g., neuroendocrine prostate cancer) and the combination of chemotherapy with androgen signaling inhibitors. As the field of prostate cancer research continues to rapidly evolve yielding novel agents and treatment modalities, chemotherapy continues to play an essential role in prolonging the survival of patients with advanced and metastatic prostate cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Meloxicam is a readily available non-steroidal anti-inflammatory medication that is commonly used in clinical practice. It has been associated with a low incidence of gastrointestinal adverse effects in comparison to other non-steroidal anti-inflammatory medications and it has also demonstrated anti-tumour activity in vitro. In this study we describe the efficacy of meloxicam in combination with either mitoxantrone or vinblastine as a first-line treatment for non-resectable canine urothelial cell carcinoma (UCC), as well as the incidence of gastrointestinal adverse effects associated with this treatment combination. The results of this study suggest that meloxicam in combination with mitoxantrone or vinblastine, as a first-line treatment for non-resectable UCC, is well-tolerated and potentially effective in inducing cancer response. Cyclooxygenase (COX) inhibitors have been demonstrated to have antitumour activity in canine urothelial cell carcinoma (UCC), given as a sole treatment or in combination with chemotherapy. The purpose of this retrospective multi-institutional study was to assess the efficacy of meloxicam in combination with mitoxantrone or vinblastine as a first-line treatment for non-resectable canine UCC. Gastrointestinal adverse effects (AEs) of these treatment combinations were also assessed. A total of 28 dogs met the inclusion criteria, 21/28 dogs received mitoxantrone and meloxicam, and 7/28 received vinblastine and meloxicam. Tumour response (TR) and AE were evaluated according to Veterinary Co-Operative Oncology Group (VCOG) criteria. The endpoint of the study was the time to tumour progression (TTP). The mitoxantrone-group induced 24% partial response and 62% stable disease, while the vinblastine-group induced 14% and 86%, respectively. Median TTP was 84 days (mitoxantrone and meloxicam, 70 days; and vinblastine and meloxicam, 178 days). The presence of metastatic disease significantly decreased TTP (p = 0.007). Gastrointestinal AEs were reported in 21.4% of the patients, with the most common being VCOG grade 1–2 diarrhoea. Meloxicam is a well-tolerated NSAID when combined with mitoxantrone or vinblastine as first-line treatment for non-resectable canine UCC. [ABSTRACT FROM AUTHOR]

(1) The treatment of metastatic or drug-resistant melanoma is still a significant therapeutic problem. The aim of this study was to evaluate the anticancer potential of daphnetin (7,8-dihydroxycoumarin) and its combinations with five different cytostatic drugs (mitoxantrone, docetaxel, vemurafenib, epirubicin and cisplatin). (2) The viability, proliferation and cytotoxicity of daphnetin against four human malignant melanoma cell lines were evaluated. The interactions were assessed using isobolographic analysis for the combinations of daphnetin with each of the five cytostatic drugs. (3) Daphnetin showed anticancer activity against malignant melanoma, with IC50 values ranging from 40.48 ± 10.90 µM to 183.97 ± 18.82 µM, depending on the cell line. The combination of daphnetin with either vemurafenib or epirubicin showed an antagonistic interaction. Moreover, additive interactions were observed for the combinations of daphnetin with cisplatin and docetaxel. The most desirable synergistic interactions for human melanoma metastatic cell lines were observed for the combination of daphnetin with mitoxantrone. (4) The obtained results suggest that daphnetin should not be combined with vemurafenib or epirubicin in the treatment of malignant melanoma due to the abolition of their anticancer effects. The combination of daphnetin with mitoxantrone is beneficial in the treatment of metastatic melanoma due to their synergistic interaction. [ABSTRACT FROM AUTHOR]

Doxorubicin (DOX) and mitoxantrone (MTX) are classical chemotherapeutic agents used in cancer that induce similar clinical cardiotoxic effects, although it is not clear if they share similar underlying molecular mechanisms. We aimed to assess the effects of DOX and MTX on the cardiac remodeling, focusing mainly on metabolism and autophagy. Adult male CD-1 mice received pharmacologically relevant cumulative doses of DOX (18 mg/kg) and MTX (6 mg/kg). Both DOX and MTX disturbed cardiac metabolism, decreasing glycolysis, and increasing the dependency on fatty acids (FA) oxidation, namely, through decreased AMP-activated protein kinase (AMPK) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH) content and decreased free carnitine (C0) and increased acetylcarnitine (C2) concentration. Additionally, DOX heavily influenced glycolysis, oxidative metabolism, and amino acids turnover by exclusively decreasing phosphofructokinase (PFKM) and electron transfer flavoprotein-ubiquinone oxidoreductase (ETFDH) content, and the concentration of several amino acids. Conversely, both drugs downregulated autophagy given by the decreased content of autophagy protein 5 (ATG5) and microtubule-associated protein light chain 3 (LC3B), with MTX having also an impact on Beclin1. These results emphasize that DOX and MTX modulate cardiac remodeling differently, despite their clinical similarities, which is of paramount importance for future treatments. [ABSTRACT FROM AUTHOR]

Patients with triple‐negative breast cancer (TNBC) have the worst clinical outcomes when compared to other subtypes of breast cancer. Nanotechnology‐assisted photothermal therapy (PTT) opens new opportunities for precise cancer treatment. However, thermoresistance caused by PTT, as well as uncertainty in the physiological metabolism of existing phototherapeutic nanoformulations, severely limit their clinical applications. Herein, based on the clinically chemotherapeutic drug mitoxantrone (MTO), a multifunctional nanoplatform (MTO‐micelles) is developed to realize mutually synergistic mild‐photothermal chemotherapy. MTO with excellent near‐infrared absorption (≈669 nm) can function not only as a chemotherapeutic agent but also as a photothermal transduction agent with elevated photothermal conversion efficacy (ƞ = 54.62%). MTO‐micelles can accumulate at the tumor site through the enhanced permeability and retention effect. Following local near‐infrared irradiation, mild hyperthermia (<50 °C) assists MTO in binding tumor cell DNA, resulting in chemotherapeutic sensitization. In addition, downregulation of heat shock protein 70 (HSP70) expression due to enhanced DNA damage can in turn weaken tumor thermoresistance, boosting the efficacy of mild PTT. Both in vitro and in vivo studies indicate that MTO‐micelles possess excellent synergetic tumor inhibition effects. Therefore, the mild‐photothermal chemotherapy strategy based on MTO‐micelles has a promising prospect in the clinical transformation of TNBC treatment. [ABSTRACT FROM AUTHOR]

We developed a custom-designed liposome carrier for codelivery of a potent immunogenic cell death (ICD) stimulus plus an inhibitor of the indoleamine 2,3-dioxygenase (IDO-1) pathway to establish a chemo-immunotherapy approach for solid tumors in syngeneic mice. The carrier was constructed by remote import of the anthraquinone chemotherapeutic agent, mitoxantrone (MTO), into the liposomes, which were further endowed with a cholesterol-conjugated indoximod (IND) prodrug in the lipid bilayer. For proof-of-principle testing, we used IV injection of the MTO/IND liposome in a CT26 colon cancer model to demonstrate the generation of a robust immune response, characterized by the appearance of ICD markers (CRT and HMGB-1) as well as evidence of cytotoxic cancer cell death, mediated by perforin and granzyme B. Noteworthy, the cytotoxic effects involved natural killer (NK) cell, which suggests a different type of ICD response. The immunotherapy response was significantly augmented by codelivery of the IND prodrug, which induced additional CRT expression, reduced number of Foxp3+ Treg, and increased perforin release, in addition to extending animal survival beyond the effect of an MTO-only liposome. The outcome reflects the improved pharmacokinetics of MTO delivery to the cancer site by the carrier. In light of the success in the CT26 model, we also assessed the platform efficacy in further breast cancer (EMT6 and 4T1) and renal cancer (RENCA) models, which overexpress IDO-1. Encapsulated MTO delivery was highly effective for inducing chemo-immunotherapy responses, with NK participation, in all tumor models. Moreover, the growth inhibitory effect of MTO was enhanced by IND codelivery in EMT6 and 4T1 tumors. All considered, our data support the use of encapsulated MTO delivery for chemo-immunotherapy, with the possibility to boost the immune response by codelivery of an IDO-1 pathway inhibitor.

PurposeTreatment failure from drug resistance is the primary reason for relapse in acute lymphoblastic leukemia (ALL). Improving outcomes by targeting mechanisms of drug resistance is a potential solution.Patients and methodsWe report results investigating the epigenetic modulators decitabine and vorinostat with vincristine, dexamethasone, mitoxantrone, and PEG-asparaginase for pediatric patients with relapsed or refractory B-cell ALL (B-ALL). Twenty-three patients, median age 12 years (range, 1-21) were treated in this trial.ResultsThe most common grade 3-4 toxicities included hypokalemia (65%), anemia (78%), febrile neutropenia (57%), hypophosphatemia (43%), leukopenia (61%), hyperbilirubinemia (39%), thrombocytopenia (87%), neutropenia (91%), and hypocalcemia (39%). Three subjects experienced dose-limiting toxicities, which included cholestasis, steatosis, and hyperbilirubinemia (n = 1); seizure, somnolence, and delirium (n = 1); and pneumonitis, hypoxia, and hyperbilirubinemia (n = 1). Infectious complications were common with 17 of 23 (74%) subjects experiencing grade ≥3 infections including invasive fungal infections in 35% (8/23). Nine subjects (39%) achieved a complete response (CR + CR without platelet recovery + CR without neutrophil recovery) and five had stable disease (22%). Nine (39%) subjects were not evaluable for response, primarily due to treatment-related toxicities. Correlative pharmacodynamics demonstrated potent in vivo modulation of epigenetic marks, and modulation of biologic pathways associated with functional antileukemic effects.ConclusionsDespite encouraging response rates and pharmacodynamics, the combination of decitabine and vorinostat on this intensive chemotherapy backbone was determined not feasible in B-ALL due to the high incidence of significant infectious toxicities. This study is registered at http://www.clinicaltrials.gov as NCT01483690.

Improvements in survival rates with gonad-sparing protocols for childhood and adolescence cancer have increased the optimism of survivors to become parents after treatment. Findings in rodents indicate that chromosomal aberrations can be induced in male germ cells by genotoxic exposures and transmitted to offspring and future generations with effects on development, fertility and health. Thus, there is a need for effective technologies to identify human sperm carrying chromosomal aberrations to assess the germ-line risks, especially for cancer survivors who have received genotoxic therapies. The time-dependent changes in the burden of sperm carrying structural chromosomal aberrations were assessed for the first time in a cancer setting, using the AM8 sperm FISH protocol which simultaneously detects abnormalities in chromosomal structure and number in sperm. Nine Hodgkin lymphoma (HL) patients provided 20 semen samples before, during, and after NOVP therapy (Novantrone, Oncovin, Velban and Prednisone) and radiation therapy that produced scattered gonadal doses from

Neoadjuvant chemotherapy has become an indispensable weapon against high-risk resectable cancers, which benefits from tumor downstaging. However, the utility of chemotherapeutics alone as a neoadjuvant agent is incapable of generating durable therapeutic benefits to prevent postsurgical tumor metastasis and recurrence. Herein, a tactical nanomissile (TALE), equipped with a guidance system (PD-L1 monoclonal antibody), ammunition (mitoxantrone, Mit), and projectile bodies (tertiary amines modified azobenzene derivatives), is designed as a neoadjuvant chemo-immunotherapy setting, which aims at targeting tumor cells, and fast-releasing Mit owing to the intracellular azoreductase, thereby inducing immunogenic tumor cells death, and forming an in situ tumor vaccine containing damage-associated molecular patterns and multiple tumor antigen epitopes to mobilize the immune system. The formed in situ tumor vaccine can recruit and activate antigen-presenting cells, and ultimately increase the infiltration of CD8+ T cells while reversing the immunosuppression microenvironment. Moreover, this approach provokes a robust systemic immune response and immunological memory, as evidenced by preventing 83.3% of mice from postsurgical metastasis or recurrence in the B16–F10 tumor mouse model. Collectively, our results highlight the potential of TALE as a neoadjuvant chemo-immunotherapy paradigm that can not only debulk tumors but generate a long-term immunosurveillance to maximize the durable benefits of neoadjuvant chemotherapy.

Occurrence of non-canonical G-quadruplex (G4) DNA structures in the genome have been recognized as key factors in gene regulation and several other cellular processes. The mosR and ndhA genes involved in pathways of oxidation sensing regulation and ATP generation, respectively, make Mycobacterium tuberculosis (Mtb) bacteria responsible for oxidative stress inside host macrophage cells. Circular Dichroism spectra demonstrate stable hybrid G4 DNA conformations of mosR/ndhA DNA sequences. Real-time binding of mitoxantrone to G4 DNA with an affinity constant ~105–107 M−1, leads to hypochromism with a red shift of ~18 nm, followed by hyperchromism in the absorption spectra. The corresponding fluorescence is quenched with a red shift ~15 nm followed by an increase in intensity. A change in conformation of the G4 DNA accompanies the formation of multiple stoichiometric complexes with a dual binding mode. The external binding of mitoxantrone with a partial stacking with G-quartets and/or groove binding induces significant thermal stabilization, ~20–29 °C in ndhA/mosR G4 DNA. The interaction leads to a two/four-fold downregulation of transcriptomes of mosR/ndhA genes apart from the suppression of DNA replication by Taq polymerase enzyme, establishing the role of mitoxantrone in targeting G4 DNA, as an alternate strategy for effective anti-tuberculosis action in view of deadly multi-drug resistant tuberculosis disease causing bacterial strains t that arise from existing therapeutic treatments. [ABSTRACT FROM AUTHOR]

The PI3K/Akt/mTOR pathway is one of the important pathways in many cancers. Akt is a serine-threonine kinase protein identified as a drug target for cancer treatment. Therefore, anticancer drugs are essential therapeutic targets for this pathway. In the current study, the inhibitory effect of two anticancer molecules, XFE and mitoxantrone, on AKT1 protein that can impact the activity of the AKT1 protein was investigated by using molecular docking and molecular dynamics (MD) simulations. The molecular docking results presented a relatively higher binding affinity of the mitoxantrone molecule in interaction with AKT1 than the XFE molecule. These results were validated by the MM/PBSA technique that was performed on obtained trajectories of 25 ns MD simulations. The mitoxantrone molecule has an intense binding energy of − 880.536 kcal/mol with AKT1 protein, while the XFE molecule shows a binding energy value of − 83.569 kcal/mol. Our findings from molecular dynamics simulations indicated that both molecules have favorite interactions with AKT1 protein. Other analyses, such as RMSF and hydrogen binding on trajectories obtained from MD simulations, indicated that the mitoxantrone molecule could be a relatively potent inhibitor for AKT1. Based on the results of this study and the structure of mitoxantrone, it is expected to be a good candidate for cancer treatment as a (PI3K)/Akt/mTOR inhibitor. [ABSTRACT FROM AUTHOR]

Bone metastasis is the main cause of death in patients with prostate cancer (PCa), but there lacks effective treatment method. Immunotherapy shows new hopes for bone metastatic PCa patients, while the efficacy is still unsatisfactory and limited by the unique immunosuppressive microenvironment in metastatic bone site. Here, we developed a bone-targeted nano-delivery system as a nano-regulator to enhance the immunotherapy of bone metastatic PCa. The nanosystem was assembled via coordination between phytic acid (PA) and Fe3+ to form nano-sized metal–organic framework (MOF), through which mitoxantrone (MTO) was encapsulated. At cellular level, the nanosystem showed selective cytotoxicity towards RM-1 PCa cells over immune cells, and could induce tumor cells immunogenic cell death (ICD) to improve the immunogenicity of the tumor. Moreover, the nanosystem was able to induce ubiquitination of TGFβ receptor (TβR) on immune cells to promote its degradation, thus serving as a nano-regulator to block the functions of TGF-β, an abundant cytokine that has a systematically immunosuppressive effect in the tumor microenvironment. Upon intravenous injection, the nanoparticle showed pro-longed blood circulation and targeting accumulation into bone metastatic site, and imposed robust anti-tumor effect in combination with αCTLA-4. In addition, bone destruction was significantly alleviated after treatment to reduce the skeletal-related events. Overall, this work provides a biocompatible nanomedicine to restore immune sensitivity of bone metastatic tumor for enhanced immunotherapy by blocking TGF-β signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Asparaginase-based treatment regimen for acute lymphocytic leukemia (ALL) is considered as feasible, but there is still a lack of data. In this study, considering the results of other regimen that were not optimum in previous studies. Here, we aimed to investigate the feasibility of PETHEMA ALL-96 treatment regimen. Materials and Methods: This is a retrospective feasibility study that was performed in 2019-2021 on 13 patients diagnosed with B-cell ALL. Patients were treated by PETHEMA ALL-96 regimen during induction, consolidation, reinduction, and maintenance phases. Patients were followed for 2 years after initiation of PETHEMA ALL-96 regimen for disease-free survival (DFS) and overall survival (OS) of all patients were evaluated after 2 years. Results: Data of 11 patients were analyzed. Within 28 days after treatments, all patients (100%) had no blasts in the bone marrow that was considered as complete remission (CR). The CR rate was 100% within 6 months and 12 months and 81.8% within 2 years after the treatments. Evaluation of OS, CR, and DFS regarding 6, 12, and 24 months showed 100% for all items after 6 and 12 months. After 24 months, the CR was 90.9%, the OS was 81.8% and the DFS was 90.9%. None of the patients died during the induction phase and during the 12 months study. No side effects were observed. Conclusion: The PETHEMA ALL-96 had high feasibility and survival rates with no side effects during the study course. It is believed that PETHEMA ALL-96 regimen has beneficial outcomes in young patients with ALL. [ABSTRACT FROM AUTHOR]

Heparan sulfate proteoglycans (HSPGs) possess various functions driving malignancy of tumors. However, their impact on tumor cell sensitivity to cytotoxic treatment is far less understood. Aiming to investigate this, we depleted HSPGs by downregulating Exostosin 1 (EXT1), a key enzyme in HS formation, or upregulating heparanase in human MV3 human melanoma cells, and investigated their response to cytotoxic drugs. Cytotoxicity of trametinib, doxorubicin, and mitoxantrone was detected by MTT assay. Insights into intracellular signaling was provided by kinome protein profiler array, and selected kinases were inhibited to investigate their impact on cell sensitization and migratory dynamics. EXT1 knockdown (EXT1kd) in MV3 cells affected the activity of doxorubicin and mitoxantrone, significantly increasing EC50 values two- or fourfold, respectively. Resistance formation was scarcely related to HSPG deficiency, suggested by enzymatic cleavage of HSPG in control cells. Notably, EXT1kd induced an upregulation of EGFR signaling via JNK and MEK/ERK, and hence blocking these kinases returned resistance to a sensitive level. JNK appeared as a key signal component, also inducing higher migratory activity of EXT1kd cells. Furthermore, EXT1kd upregulated thrombotic properties of MV3 cells, indicated by tissue factor and PAR-1 expression, functionally reflected by a stronger activation of platelet aggregation. EXT1 was confirmed to act as a tumor suppressor, shown here for the first time to affect chemosensitivity of melanoma cells. [ABSTRACT FROM AUTHOR]

Objective(s): Conventional methods of cancer treatment include surgery, chemotherapy, radiation therapy, and immunotherapy. Chemotherapy, as one of the main methods of cancer treatment, due to the lack of targeted distribution of the drug in tumor tissues, is not able to destroy cancer cells and also affects healthy tissues and causes serious side effects in patients. Sonodynamic therapy (SDT) is a promising strategy for non-invasive treatment of deep solid cancer tumors. In this study, for the first time, the sono-sensitive activity of mitoxantrone was investigated and then Mitoxantrone (MTX) was conjugated to hollow gold nanostructure (HGN) to improve the efficiency of in vivo SDT. Materials and Methods: Firstly, after the synthesis of hollow gold nanoshells and the PEGylation process, conjugation of MTX was performed. Then, after evaluating the toxicity of the treatment groups in vitro, in order to perform an in vivo study, 56 male Balb/c mice that had been tumorized by subcutaneous injection of 4T1 cells were divided into eight groups of breast tumor model. Ultrasonic irradiation (US) conditions including intensity of 1.5 W/cm2 (with a frequency of 800 kHz, 5 min), MTX concentration of 2 μM, and HGN dose of 2.5 mg/kg (unit of animal weight) were used. Results: The results show that administration of PEG-HGN-MTX caused a slight reduction in tumor size and growth compared with free MTX. Ultrasound also improved the therapeutic effect of the gold nanoshell in treated groups, and the HGN-PEG-MTX-US treated groups were able to significantly reduce and control tumor size and growth. Conclusion: The findings also show that MTX and HGN can be used as sonosensitizers in SDT. Also, HGN-PEG-MTX can act as a sono-chemotherapy agent for the combination of sonodynamic therapy and chemotherapy for in vivo breast tumors. [ABSTRACT FROM AUTHOR]

Nuclear ubiquitous casein and cyclin-dependent kinase substrate 1 (NUCKS1) is highly expressed in a variety of malignant tumors and functions as an oncogene; however, its role in colorectal cancer (CRC) remains unclear. We aimed to explore the function and regulatory mechanisms of NUCKS1 and potential therapeutic agents targeting NUCKS1 in CRC. We knocked down and overexpressed NUCKS1 in CRC cells and explored its effects in vitro and in vivo. Flow cytometry, CCK-8, Western blotting, colony formation, immunohistochemistry, in vivo tumorigenic, and transmission electron microscopy analyses were performed to determine the effects of NUCKS1 on CRC cell function. LY294002 was used to examine the mechanism of NUCKS1 expression in CRC cells. Potential therapeutic agents for NUCKS1-high CRC patients were analyzed using the CTRP and PRISM datasets, and the function of selected agents was determined by CCK-8 and Western blotting. We revealed that NUCKS1 was highly expressed in CRC tissues and clinically correlated with poor prognosis in CRC patients. NUCKS1 knockdown induces cell cycle arrest, inhibits CRC cell proliferation, and promotes apoptosis and autophagy. These results were reversed when NUCKS1 was overexpressed. Mechanistically, NUCKS1 exerts a cancer-promoting function by activating the PI3K/AKT/mTOR signaling pathway. This was reversed when LY294002 was used to inhibit the PI3K/AKT pathway. Furthermore, we determined that mitoxantrone exhibited high drug sensitivity in NUCKS1-overexpressing CRC cells. This work demonstrated NUCKS1 plays a crucial role in CRC progression via the PI3K/AKT/mTOR signaling pathway. Additionally, mitoxantrone may be a potential therapeutic agent for CRC treatment. Therefore, NUCKS1 represents a promising anti-tumor therapeutic target. [ABSTRACT FROM AUTHOR]

Abstract Patients with triple‐negative breast cancer (TNBC) have the worst clinical outcomes when compared to other subtypes of breast cancer. Nanotechnology‐assisted photothermal therapy (PTT) opens new opportunities for precise cancer treatment. However, thermoresistance caused by PTT, as well as uncertainty in the physiological metabolism of existing phototherapeutic nanoformulations, severely limit their clinical applications. Herein, based on the clinically chemotherapeutic drug mitoxantrone (MTO), a multifunctional nanoplatform (MTO‐micelles) is developed to realize mutually synergistic mild‐photothermal chemotherapy. MTO with excellent near‐infrared absorption (≈669 nm) can function not only as a chemotherapeutic agent but also as a photothermal transduction agent with elevated photothermal conversion efficacy (ƞ = 54.62%). MTO‐micelles can accumulate at the tumor site through the enhanced permeability and retention effect. Following local near‐infrared irradiation, mild hyperthermia (

Mitoxantrone (MTX) is a drug employed in breast cancer treatment, but its application is largely limited due to side effects. A controlled delivery approach can potentially reduce the side effects. In this study, two zirconium (Zr)-based MOFs, UiO-66 and UiO-66-NH2, were studied for a more controlled delivery of MTX with a 40% and 21% loading capacity, respectively. Characterisation via powder X-ray diffraction, thermogravimetric analysis, Fourier transform infrared spectrometry, scanning electron microscopy, and dynamic light scattering confirmed the integrity of structure post-MTX loading. UV–vis spectrophotometry revealed distinctive release profiles, with UiO-66-MTX exhibiting a 25% cumulative release after 96 h in water and 120 h in PBS +10% FBS. UiO-66-NH2-MTX displayed a more sustained release, reaching 62% in water and 47% in PBS +10% FBS after 168 h. The interaction between MTX and the MOFs was also proposed based on computational modelling, suggesting a stronger interaction of UiO-66NH2 and MTX, and an optimised interaction of MTX in the tetrahedral and octahedral pores of the MOFs. The study also reports the release profile of the drug and antiproliferative activity against a panel of breast cancer cell lines (MDA-MB-231, MDA-MB-468, and MCF7) and a normal breast epithelial cell line (MCF10A). MTX-encapsulated MOFs were thoroughly characterised, and their biological activity was assessed in vitro. MTT cell viability assay indicated a higher IC50 value for MTX-loaded MOFs compared to free MTX in physiological conditions, albeit with a slower release profile. These findings suggest the potential of these MTX-loaded MOFs as an alternative avenue for formulation to mitigate side effects.

The effect of an extremely low frequency alternating magnetic field (ELF AMF) at frequencies of 17, 48, and 95 Hz at 100 mT on free and internalized 4T1 breast cancer cell submicron magnetic mineral carriers with an anticancer drug, mitoxantrone, was shown. The alternating magnetic field (100 mT; 17, 48, 95 Hz; time of treatment—10.5 min with a 30 s delay) does not lead to the significant destruction of carrier shells and release of mitoxantrone or bovine serum albumin from them according to the data of spectrophotometry, or the heating of carriers in the process of exposure to magnetic fields. The most optimal set of factors that would lead to the suppression of proliferation and survival of cells with anticancer drug carriers on the third day (in comparison with the control and first day) is exposure to an alternating magnetic field of 100 mT in a pulsed mode with a frequency of 95 Hz. The presence of magnetic nanocarriers in cell lines was carried out by a direct label-free method, space-resolved Brillouin light scattering (BLS) spectrometry, which was realized for the first time. The analysis of the series of integrated BLS spectra showed an increase in the magnetic phase in cells with a growth in the number of particles per cell (from 10 to 100) after their internalization. The safety of magnetic carriers in the release of their constituent ions has been evaluated using atomic absorption spectrometry.