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Journal of Nanobiotechnology May 2024Chemotherapy, as a conventional strategy for tumor therapy, often leads to unsatisfied therapeutic effect due to the multi-drug resistance and the serious side effects....
Chemotherapy, as a conventional strategy for tumor therapy, often leads to unsatisfied therapeutic effect due to the multi-drug resistance and the serious side effects. Herein, we genetically engineered a thermal-responsive murine Ferritin (mHFn) to specifically deliver mitoxantrone (MTO, a chemotherapeutic and photothermal agent) to tumor tissue for the chemotherapy and photothermal combined therapy of colorectal cancer, thanks to the high affinity of mHFn to transferrin receptor that highly expressed on tumor cells. The thermal-sensitive channels on mHFn allowed the effective encapsulation of MTO in vitro and the laser-controlled release of MTO in vivo. Upon irradiation with a 660 nm laser, the raised temperature triggered the opening of the thermal-sensitive channel in mHFn nanocage, resulting in the controlled and rapid release of MTO. Consequently, a significant amount of reactive oxygen species was generated, causing mitochondrial collapse and tumor cell death. The photothermal-sensitive controlled release, low systemic cytotoxicity, and excellent synergistic tumor eradication ability in vivo made mHFn@MTO a promising candidate for chemo-photothermal combination therapy against colorectal cancer.
Topics: Animals; Colorectal Neoplasms; Mice; Ferritins; Photothermal Therapy; Humans; Mitoxantrone; Lasers; Cell Line, Tumor; Reactive Oxygen Species; Mice, Inbred BALB C; Antineoplastic Agents; Mice, Nude; Female
PubMed: 38812019
DOI: 10.1186/s12951-024-02566-6 -
Scientific Reports May 2024Chronic Heart Failure (CHF) is a significant global public health issue, with high mortality and morbidity rates and associated costs. Disease modules, which are...
Chronic Heart Failure (CHF) is a significant global public health issue, with high mortality and morbidity rates and associated costs. Disease modules, which are collections of disease-related genes, offer an effective approach to understanding diseases from a biological network perspective. We employed the multi-Steiner tree algorithm within the NeDRex platform to extract CHF disease modules, and subsequently utilized the Trustrank algorithm to rank potential drugs for repurposing. The constructed disease module was then used to investigate the mechanism by which Panax ginseng ameliorates CHF. The active constituents of Panax ginseng were identified through a comprehensive review of the TCMSP database and relevant literature. The Swiss target prediction database was utilized to determine the action targets of these components. These targets were then cross-referenced with the CHF disease module in the STRING database to establish protein-protein interaction (PPI) relationships. Potential action pathways were uncovered through Gene Ontology (GO) and KEGG pathway enrichment analyses on the DAVID platform. Molecular docking, the determination of the interaction of biological macromolecules with their ligands, and visualization were conducted using Autodock Vina, PLIP, and PyMOL, respectively. The findings suggest that drugs such as dasatinib and mitoxantrone, which have low docking scores with key disease proteins and are reported in the literature as effective against CHF, could be promising. Key components of Panax ginseng, including ginsenoside rh4 and ginsenoside rg5, may exert their effects by targeting key proteins such as AKT1, TNF, NFKB1, among others, thereby influencing the PI3K-Akt and calcium signaling pathways. In conclusion, drugs like dasatinib and midostaurin may be suitable for CHF treatment, and Panax ginseng could potentially mitigate the progression of CHF through a multi-component-multi-target-multi-pathway approach. Disease module analysis emerges as an effective strategy for exploring drug repurposing and the mechanisms of traditional Chinese medicine in disease treatment.
Topics: Panax; Heart Failure; Humans; Drug Repositioning; Molecular Docking Simulation; Protein Interaction Maps; Signal Transduction; Chronic Disease; Ginsenosides; Drugs, Chinese Herbal
PubMed: 38802411
DOI: 10.1038/s41598-024-61926-2 -
Multiple Sclerosis Journal -... 2024The use of non-specific immunosuppressants (NSIS) to treat multiple sclerosis (MS) remains prevalent in certain geographies despite safety concerns, likely due to...
BACKGROUND
The use of non-specific immunosuppressants (NSIS) to treat multiple sclerosis (MS) remains prevalent in certain geographies despite safety concerns, likely due to resource limitations.
OBJECTIVE
To use MSBase registry data to compare real-world outcomes in adults with relapsing-remitting MS (RRMS) treated with dimethyl fumarate (DMF) or NSIS (azathioprine, cyclosporine, cyclophosphamide, methotrexate, mitoxantrone or mycophenolate mofetil) between January 1, 2014 and April 1, 2022.
METHODS
Treatment outcomes were compared using inverse probability of treatment weighting (IPTW) Cox regression. Outcomes were annualized relapse rates (ARRs), time to discontinuation, time to first relapse (TTFR) and time to 24-week confirmed disability progression (CDP) or 24-week confirmed disability improvement (CDI; in patients with baseline Expanded Disability Status Scale [EDSS] score ≥2).
RESULTS
After IPTW, ARR was similar for DMF (0.13) and NSIS (0.16; = 0.29). There was no difference in TTFR between cohorts (hazard ratio [HR]: 0.98; = 0.84). The DMF cohort experienced longer times to discontinuation (HR: 0.75; = 0.001) and CDP (HR: 0.53; = 0.001), and shorter time to CDI (HR: 1.99; < 0.008), versus the NSIS cohort.
CONCLUSION
This analysis supports the use of DMF to treat patients with relapsing forms of MS, and may have implications for MS practices in countries where NSIS are commonly used to treat RRMS.
PubMed: 38800132
DOI: 10.1177/20552173241247182 -
Frontiers in Pharmacology 2024ATP-binding cassette transporters represent a superfamily of dynamic membrane-based proteins with diverse yet common functions such as use of ATP hydrolysis to efflux...
ATP-binding cassette transporters represent a superfamily of dynamic membrane-based proteins with diverse yet common functions such as use of ATP hydrolysis to efflux substrates across cellular membranes. Three major transporters-P-glycoprotein (P-gp or ABCB1), multidrug resistance protein 1 (MRP1 or ABCC1), and breast cancer resistance protein (BCRP or ABCG2) are notoriously involved in therapy resistance in cancer patients. Despite exhaustive individual characterizations of each of these transporters, there is a lack of understanding in terms of the functional role of mutations in substrate binding and efflux, leading to drug resistance. We analyzed clinical variations reported in endometrial cancers for these transporters. For ABCB1, the majority of key mutations were present in the membrane-facing region, followed by the drug transport channel and ATP-binding regions. Similarly, for ABCG2, the majority of key mutations were located in the membrane-facing region, followed by the ATP-binding region and drug transport channel, thus highlighting the importance of membrane-mediated drug recruitment and efflux in ABCB1 and ABCG2. On the other hand, for ABCC1, the majority of key mutations were present in the inactive nucleotide-binding domain, followed by the drug transport channel and membrane-facing regions, highlighting the importance of the inactive nucleotide-binding domain in facilitating indirect drug efflux in ABCC1. The identified key mutations in endometrial cancer and mapped common mutations present across different types of cancers in ABCB1, ABCC1, and ABCG2 will facilitate the design and discovery of inhibitors targeting unexplored structural regions of these transporters and re-engineering of these transporters to tackle chemoresistance.
PubMed: 38766631
DOI: 10.3389/fphar.2024.1380371 -
Journal of Nanobiotechnology May 2024Chemotherapy, the mainstay treatment for metastatic cancer, presents serious side effects due to off-target exposure. In addition to the negative impact on patients'...
BACKGROUND
Chemotherapy, the mainstay treatment for metastatic cancer, presents serious side effects due to off-target exposure. In addition to the negative impact on patients' quality of life, side effects limit the dose that can be administered and thus the efficacy of the drug. Encapsulation of chemotherapeutic drugs in nanocarriers is a promising strategy to mitigate these issues. However, avoiding premature drug release from the nanocarriers and selectively targeting the tumour remains a challenge.
RESULTS
In this study, we present a pioneering method for drug integration into nanoparticles known as mesoporous organosilica drugs (MODs), a distinctive variant of periodic mesoporous organosilica nanoparticles (PMOs) in which the drug is an inherent component of the silica nanoparticle structure. This groundbreaking approach involves the chemical modification of drugs to produce bis-organosilane prodrugs, which act as silica precursors for MOD synthesis. Mitoxantrone (MTO), a drug used to treat metastatic breast cancer, was selected for the development of MTO@MOD nanomedicines, which demonstrated a significant reduction in breast cancer cell viability. Several MODs with different amounts of MTO were synthesised and found to be efficient nanoplatforms for the sustained delivery of MTO after biodegradation. In addition, FeO NPs were incorporated into the MODs to generate magnetic MODs to actively target the tumour and further enhance drug efficacy. Importantly, magnetic MTO@MODs underwent a Fenton reaction, which increased cancer cell death twofold compared to non-magnetic MODs.
CONCLUSIONS
A new PMO-based material, MOD nanomedicines, was synthesised using the chemotherapeutic drug MTO as a silica precursor. MTO@MOD nanomedicines demonstrated their efficacy in significantly reducing the viability of breast cancer cells. In addition, we incorporated FeO into MODs to generate magnetic MODs for active tumour targeting and enhanced drug efficacy by ROS generation. These findings pave the way for the designing of silica-based multitherapeutic nanomedicines for cancer treatment with improved drug delivery, reduced side effects and enhanced efficacy.
Topics: Humans; Breast Neoplasms; Female; Cell Survival; Organosilicon Compounds; Antineoplastic Agents; Mitoxantrone; Cell Line, Tumor; Drug Carriers; Silicon Dioxide; Porosity; Drug Liberation; Nanoparticles; MCF-7 Cells; Nanomedicine; Reactive Oxygen Species
PubMed: 38745193
DOI: 10.1186/s12951-024-02522-4 -
American Journal of Cancer Research 2024Mitoxantrone Hydrochloride Injection for Tracing (MHI), a modified new drug marketed in China, has been approved by the National Medical Products Administration for...
Safety, tolerability, and pharmacokinetics of mitoxantrone hydrochloride injection for tracing in patients with gastric cancer: a single-blind, single-center, phase I clinical trial.
Mitoxantrone Hydrochloride Injection for Tracing (MHI), a modified new drug marketed in China, has been approved by the National Medical Products Administration for lymph node tracing in thyroid cancer and sentinel lymph node biopsy in breast cancer. This single-center, single-blind, dose-escalation phase I clinical trial aimed to investigate the safety of MHI on lymph node tracing in gastric cancer. In this study, four dose groups (1.0 mL, 1.5 mL, 2.0 mL, and 3.0 mL) with 3 gastric cancer patients in each group were set. The safety, tolerability, pharmacokinetics and preliminary efficacy of different doses were investigated. Results showed that none of the patients experienced dose-limiting toxicity or developed serious adverse events or adverse drug reactions. Pharmacokinetic analyses revealed minimal absorption of the tracer, resulting in low and transient blood drug concentrations across all participants. The mean time to peak concentration was (0.561 ± 0.3728) h (with mean peak concentration (C) of 10.300 ng/mL), (0.500 ± 0.0167) h (mean C of 13.687 ng/mL), (0.494 ± 0.0096) h (mean C of 30.933 ng/mL), and (0.661 ± 0.2791) h (mean C of 21.067 ng/mL) in the 1.0 mL, 1.5 mL, 2.0 mL, and 3.0 mL dose groups, respectively. The mean lymph node staining rates were 21.0%, 24.7%, 32.5%, and 44.5%, and the mean metastatic lymph node staining rates were 20.6%, 36.1%, 42.4%, and 21.0% in each group. This study confirmed that MHI was safe, well-tolerated, and had low systemic effects when used for lymphatic tracing of gastric cancer, and the tracing effect was better in the 3 mL dose group. This trail was registered on the website of Centre for Drug Evaluation State Drug and Food Administration (http://www.chinadrugtrials.org.cn/index.html) with the name of clinical study of lymphatic tracer in lymph node tracing of gastric cancer, the code was CTR20201906.
PubMed: 38726280
DOI: 10.62347/LSDV5580 -
Animals : An Open Access Journal From... Apr 2024Mammary cancer is a frequent disease in female dogs, where a high proportion of cases correspond to malignant tumors that may exhibit drug resistance. Within the mammary...
Mammary cancer is a frequent disease in female dogs, where a high proportion of cases correspond to malignant tumors that may exhibit drug resistance. Within the mammary tumor microenvironment, there is a cell subpopulation called cancer stem cells (CSCs), which are capable of forming spheres in vitro and resisting anti-tumor treatments, partly explaining the recurrence of some tumors. Previously, it has been described that spheres derived from canine mammary carcinoma cells CF41.Mg and REM 134 exhibit stemness characteristics. Melatonin has shown anti-tumor effects on mammary tumor cells; however, its effects have been poorly evaluated in canine mammary CSCs. This study aimed to analyze the effect of melatonin on the chemoresistance exhibited by stem-like neoplastic cells derived from canine mammary carcinoma to cytotoxic drugs such as doxorubicin and mitoxantrone. CF41.Mg and REM 134 cells were cultured in high-glucose DMEM supplemented with fetal bovine serum and L-glutamine. The spheres were cultured in ultra-low attachment plates in DMEM/F12 medium without fetal bovine serum and with different growth factors. The CD44/CD24 phenotype was analyzed by flow cytometry. The viability of sphere-derived cells (MTS reduction) was studied in the presence of melatonin (0.1 or 1 mM), doxorubicin, mitoxantrone, and luzindole. In addition, the gene (RT-qPCR) of the multidrug resistance bombs and were analyzed in the presence of melatonin. Both cell types expressed the gene, which encodes the melatonin receptor MT1. Melatonin 1 mM does not modify the CD44/CD24 phenotype; however, the hormone reduced viability ( < 0.0001) only in CF41.Mg spheres, without inducing an additive effect when co-incubated with cytotoxic drugs. These effects were independent of the binding of the hormone to its receptor MT1, since, by pharmacologically inhibiting them, the effect of melatonin was not blocked. In CF41.Mg spheres, the relative gene expression of and was decreased in response to the hormone ( < 0.001). These results indicate that melatonin negatively modulates the cell survival of spheres derived from CF41.Mg cells, in a way that is independent of its MT1 receptor. These effects did not counteract the resistance to doxorubicin and mitoxantrone, even though the hormone negatively regulates the gene expression of and .
PubMed: 38672378
DOI: 10.3390/ani14081229 -
Journal of Feline Medicine and Surgery Apr 2024The aim of this study was to determine response rates, median progression-free intervals (PFIs) and median survival times (MSTs) for cats with intermediate-large cell...
Evaluation of a multiagent chemotherapy protocol combining vincristine, cyclophosphamide, mitoxantrone and prednisolone (CMOP) for treatment of feline intermediate-large cell lymphoma.
OBJECTIVES
The aim of this study was to determine response rates, median progression-free intervals (PFIs) and median survival times (MSTs) for cats with intermediate-large cell lymphoma treated with a vincristine, cyclophosphamide, mitoxantrone and prednisolone (CMOP) protocol. A secondary objective was to determine the tolerability of mitoxantrone used within this multiagent protocol.
METHODS
The medical records of 31 cats treated at a single institution between 2009 and 2022 were reviewed to identify suitable cases. Cats were included in the study if they had a confirmed diagnosis of intermediate-large cell lymphoma, had received a CMOP protocol as first-line treatment and had completed at least one 4-week cycle of this protocol. Modifications allowed in the protocol included the use of l-asparaginase, vinblastine substitution for vincristine, chlorambucil substitution for cyclophosphamide and dexamethasone or methylprednisolone substitution for prednisolone.
RESULTS
The overall response rate was 74% (n = 23), with 45% (n = 14) achieving complete remission (CR), 29% (n = 9) achieving partial remission (PR) and 26% (n = 8) achieving stable disease (SD). The Kaplan-Meier median PFI and MST were 139 days and 206 days, respectively. Responders (CR or PR) had a significantly longer ( <0.001) median PFI and MST compared with non-responders (SD) (176 days vs 62 days, and 251 days vs 61 days, respectively). Cats that achieved CR had a significantly longer median PFI and MST ( <0.001) at 178 days and 1176 days, respectively. The 6-month and 1- and 2-year survival rates in cats with CR were 64%, 57% and 35%, respectively. Treatment with mitoxantrone was generally well tolerated, with no cats experiencing Veterinary Cooperative Oncology Group adverse effects above grade 2.
CONCLUSIONS AND RELEVANCE
The CMOP protocol is an alternative and well-tolerated treatment for cats with intermediate-large cell lymphoma. As demonstrated with previous chemotherapy protocols, cats that respond to treatment, particularly those that achieve CR, are likely to have more durable responses.
Topics: Animals; Cats; Mitoxantrone; Cat Diseases; Vincristine; Cyclophosphamide; Antineoplastic Combined Chemotherapy Protocols; Prednisolone; Male; Female; Retrospective Studies; Treatment Outcome
PubMed: 38647264
DOI: 10.1177/1098612X241234614 -
ACS Infectious Diseases May 2024Host-acting compounds are emerging as potential alternatives to combating antibiotic resistance. Here, we show that bosutinib, an FDA-approved chemotherapeutic for...
Host-acting compounds are emerging as potential alternatives to combating antibiotic resistance. Here, we show that bosutinib, an FDA-approved chemotherapeutic for treating chronic myelogenous leukemia, does not possess any antibiotic activity but enhances macrophage responses to bacterial infection. In vitro, bosutinib stimulates murine and human macrophages to kill bacteria more effectively. In a murine wound infection with vancomycin-resistant , a single intraperitoneal bosutinib injection or multiple topical applications on the wound reduce the bacterial load by approximately 10-fold, which is abolished by macrophage depletion. Mechanistically, bosutinib stimulates macrophage phagocytosis of bacteria by upregulating surface expression of bacterial uptake markers Dectin-1 and CD14 and promoting actin remodeling. Bosutinib also stimulates bacterial killing by elevating the intracellular levels of reactive oxygen species. Moreover, bosutinib drives NF-κB activation, which protects infected macrophages from dying. Other Src kinase inhibitors such as DMAT and tirbanibulin also upregulate expression of bacterial uptake markers in macrophages and enhance intracellular bacterial killing. Finally, cotreatment with bosutinib and mitoxantrone, another chemotherapeutic in clinical use, results in an additive effect on bacterial clearance in vitro and in vivo. These results show that bosutinib stimulates macrophage clearance of bacterial infections through multiple mechanisms and could be used to boost the host innate immunity to combat drug-resistant bacterial infections.
Topics: Nitriles; Phagocytosis; Animals; Quinolines; Macrophages; Aniline Compounds; Mice; Humans; Enterococcus faecalis; Reactive Oxygen Species; Anti-Bacterial Agents; Mice, Inbred C57BL; NF-kappa B; Cell Survival; Gram-Positive Bacterial Infections
PubMed: 38602352
DOI: 10.1021/acsinfecdis.4c00086