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Journal of Biomolecular Structure &... Mar 2024Cervical cancer poses a significant global health challenge, ranking as the fourth most common cancer among women worldwide and resulting in approximately 300,000 deaths...
Cervical cancer poses a significant global health challenge, ranking as the fourth most common cancer among women worldwide and resulting in approximately 300,000 deaths yearly, predominantly caused by high-risk human papillomavirus strains (HPV), mainly types 16 and 18. The scenario poses the urgent need of the hour to develop effective treatment strategies that can address the complexity of cervical cancer and multitargeted inhibitor designing that holds promise as it can simultaneously target multiple proteins and pathways involved in its progression and have the potential to enhance treatment efficacy, reduce the likelihood of drug resistance. In this study, we have performed multitargeted molecular docking of FDA-approved drugs against cervical cancer replication and maintenance proteins- Xenopus kinesin-like protein-2 (3KND), cell division cycle protein-20 (4N14), MCM2-histone complex (4UUZ) and MCM6 Minichromosome maintenance (2KLQ) with HTVS, SP and XP algorithms and have obtained the docking and MM\GBSA score ranging from -8.492 to -5.189 Kcal/mol and -58.16 to -39.07 Kcal/mol. Further, the molecular interaction fingerprints identified ALA, THR, SER, ASN, LEU, and ILE were among the most interacted residues, leaning towards hydrophobic and polar amino acids. The pharmacokinetics and DFT of the compound have shown promising results. The complexes were simulated for 100 ns to study the stability by computing the deviation, fluctuations, and intermolecular interactions formed during the simulation. This study produced promising results, satisfying the criteria that Mitoxantrone 2HCl can be a multitargeted inhibitor against cervical cancer proteins-however, experimental validation is a must before human use.Communicated by Ramaswamy H. Sarma.
PubMed: 38517073
DOI: 10.1080/07391102.2024.2329796 -
Zhonghua Yi Xue Za Zhi Mar 2024To investigate the effect of dual fluorescence imaging in identifying central lymph nodes and parathyroid glands during thyroid cancer surgery. This study was a...
To investigate the effect of dual fluorescence imaging in identifying central lymph nodes and parathyroid glands during thyroid cancer surgery. This study was a cross-sectional study. Patients who underwent surgery for papillary thyroid cancer (PTC) at the Department of Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University between January 2022 and September 2023 were included. All patients underwent thyroid lobectomy or total resection, and central lymph node dissection was performed at the same time. During the operation, tracing injection of mitoxantrone hydrochloride and 785 nm and 660 nm dual fluorescence imaging technique were used to measure the fluorescence intensity (FI) of parathyroid glands, central lymph nodes and background. After correcting to obtain the standardized FI, the paired -test was used to compare the standardized FI of the parathyroid glands and central lymph nodes, and the Spearman's rank correlation analysis was used to analyze the relationship between the standardized FI and various clinical indicators. The study included 30 patients (8 males and 22 females), with a mean age of (41.8±10.4) years. A total of 76 parathyroid glands and 234 central lymph nodes were identified under dual fluorescence imaging, and the standardized FI of parathyroid glands was less than that of central lymph nodes (44.7±16.8 vs 99.5±28.4, <0.001). The visualization rate, false rate and miscut rate of parathyroid glands under 785 nm wavelength excitation light were 98.7% (76/77), 0 (0/77) and 1.3% (1/77), respectively (one case with no visualization and miscutting parathyroid gland was the encapsulated type). The visualization rate of central lymph nodes under 660 nm wavelength excitation light was 98.7% (234/237). There was no significant correlation between FI and clinical indicators such as gender, age, height, weight, body mass index, preoperative thyroid stimulating hormone, thyroglobulin antibody, thyroid microsomal antibody, serum calcium, parathyroid hormone level and surgical procedure (all >0.05). Dual fluorescence imaging of central lymph nodes and parathyroid glands can improve the ability to identify parathyroid gland while assisting central lymph node dissection.
Topics: Male; Female; Humans; Adult; Middle Aged; Parathyroid Glands; Cross-Sectional Studies; Thyroid Neoplasms; Lymph Nodes; Neck Dissection; Thyroidectomy; Optical Imaging
PubMed: 38514342
DOI: 10.3760/cma.j.cn112137-20231016-00762 -
International Journal of Pharmaceutics Apr 2024Combination therapy exhibits higher efficacy than any single therapy, inspiring various nanocarrier-assisted multi-drug co-delivery systems for the combined treatment of...
Mitoxantrone encapsulated photosensitizer nanomicelle as carrier-free theranostic nanomedicine for near-infrared fluorescence imaging-guided chemo-photodynamic combination therapy on cancer.
Combination therapy exhibits higher efficacy than any single therapy, inspiring various nanocarrier-assisted multi-drug co-delivery systems for the combined treatment of cancer. However, most nanocarriers are inert and non-therapeutic and have potential side effects. Herein, an amphiphilic polymer composed of a hydrophobic photosensitizer and hydrophilic poly(ethylene glycol) was employed as the nanocarriers and photosensitizers to encapsulate the chemotherapeutic drug mitoxantrone for chemo-photodynamic combination therapy. The resulting nanodrug consisted solely of pharmacologically active ingredients, thus avoiding potential toxicity induced by inert excipients. This multifunctional nanoplatform demonstrated significantly superior treatment performance compared to monotherapy for colorectal cancer, both in vitro and in vivo, achieving near-infrared fluorescence imaging-mediated chemo-photodynamic combined eradication of malignancy.
Topics: Humans; Photosensitizing Agents; Mitoxantrone; Theranostic Nanomedicine; Nanoparticles; Photochemotherapy; Neoplasms; Optical Imaging; Cell Line, Tumor
PubMed: 38513816
DOI: 10.1016/j.ijpharm.2024.124025 -
Bioorganic Chemistry May 2024The breast cancer resistance protein (BCRP/ABCG2) transporter mediates the efflux of numerous antineoplastic drugs, playing a central role in multidrug resistance...
The breast cancer resistance protein (BCRP/ABCG2) transporter mediates the efflux of numerous antineoplastic drugs, playing a central role in multidrug resistance related to cancer. The absence of successful clinical trials using specific ABCG2 inhibitors reveals the urge to identify new compounds to attend this critical demand. In this work, a series of 13 magnolol derivatives was tested as ABCG2 inhibitors. Only two compounds, derivatives 10 and 11, showed partial and complete ABCG2 inhibitory effect, respectively. This inhibition was selective toward ABCG2, since none of the 13 compounds inhibited neither P-glycoprotein nor MRP1. Both inhibitors (10 and 11) were not transported by ABCG2 and demonstrated a low cytotoxic profile even at high concentrations (up to 100 µM). 11 emerged as the most promising compound of the series, considering the ratio between cytotoxicity (IG) and ABCG2 inhibition potency (IC), showing a therapeutic ratio (TR) higher than observed for 10 (10.5 versus 1.6, respectively). This derivative showed a substrate-independent and a mixed type of inhibition. The effect of compound 11 on the ABCG2 ATPase activity and thermostability revealed allosteric protein changes. This compound did not affect the expression levels of ABCG2 and increased the binding of the conformational-sensitive antibody 5D3. A docking study showed that 11 did not share the same binding site with ABCG2 substrate mitoxantrone. Finally, 11 could revert the chemoresistance to SN-38 mediated by ABCG2.
Topics: Humans; Female; ATP Binding Cassette Transporter, Subfamily G, Member 2; Drug Resistance, Neoplasm; Neoplasm Proteins; Antineoplastic Agents; Breast Neoplasms; Biphenyl Compounds; Lignans
PubMed: 38513324
DOI: 10.1016/j.bioorg.2024.107283 -
The Journal of Pharmacology and... Apr 2024DNA topoisomerase II (TOP2/180; 180 kDa) is a nuclear enzyme that regulates DNA topology by generation of short-lived DNA double-strand breaks, primarily during...
DNA topoisomerase II (TOP2/180; 180 kDa) is a nuclear enzyme that regulates DNA topology by generation of short-lived DNA double-strand breaks, primarily during transcription. TOP2/180 can be a target for DNA damage-stabilizing anticancer drugs, whose efficacy is often limited by chemoresistance. Our laboratory previously demonstrated reduced levels of TOP2/180 (and the paralog TOP2/170) in an acquired etoposide-resistant human leukemia (K562) clonal cell line, K/VP.5, in part due to overexpression of microRNA-9-3p/5p impacting post-transcriptional events. To evaluate the effect on drug sensitivity upon reduction/elimination of TOP2/180, a premature stop codon was generated at the TOP2/180 gene exon 19/intron 19 boundary (AA//GTAA→AA//GTAA) in parental K562 cells (which contain four TOP2/180 alleles) by CRISPR/Cas9 editing with homology-directed repair to disrupt production of full-length TOP2/180. Gene-edited clones were identified and verified by quantitative polymerase chain reaction and Sanger sequencing, respectively. Characterization of TOP2/180 gene-edited clones, with one or all four TOP2/180 alleles mutated, revealed partial or complete loss of TOP2 mRNA/protein, respectively. The loss of TOP2/180 protein correlated with decreased (2-{4-[(7-chloro-2-quinoxalinyl)oxy]phenoxy}propionic acid)-induced DNA damage and partial resistance in growth inhibition assays. Partial resistance to mitoxantrone was also noted in the gene-edited clone with all four TOP2/180 alleles modified. No cross-resistance to etoposide or mAMSA was noted in the gene-edited clones. Results demonstrated the role of TOP2/180 in drug sensitivity/resistance in K562 cells and revealed differential paralog activity of TOP2-targeted agents. SIGNIFICANCE STATEMENT: Data indicated that CRISPR/Cas9 editing of the exon 19/intron 19 boundary in the TOP2β/180 gene to introduce a premature stop codon resulted in partial to complete disruption of TOP2β/180 expression in human leukemia (K562) cells depending on the number of edited alleles. Edited clones were partially resistant to mitoxantrone and XK469, while lacking resistance to etoposide and mAMSA. Results demonstrated the import of TOP2β/180 in drug sensitivity/resistance in K562 cells and revealed differential paralog activity of TOP2-targeted agents.
Topics: Humans; Etoposide; K562 Cells; DNA Topoisomerases, Type II; Mitoxantrone; CRISPR-Cas Systems; Codon, Nonsense; Antineoplastic Agents; Leukemia; DNA; Phenotype
PubMed: 38508753
DOI: 10.1124/jpet.123.002038 -
Heart (British Cardiac Society) Apr 2024We assessed the prevalence and diagnostic value of ECG abnormalities for cardiomyopathy surveillance in childhood cancer survivors.
BACKGROUND
We assessed the prevalence and diagnostic value of ECG abnormalities for cardiomyopathy surveillance in childhood cancer survivors.
METHODS
In this cross-sectional study, 1381 survivors (≥5 years) from the Dutch Childhood Cancer Survivor Study part 2 and 272 siblings underwent a long-term follow-up ECG and echocardiography. We compared ECG abnormality prevalences using the Minnesota Code between survivors and siblings, and within biplane left ventricular ejection fraction (LVEF) categories. Among 880 survivors who received anthracycline, mitoxantrone or heart radiotherapy, logistic regression models using least absolute shrinkage and selection operator identified ECG abnormalities associated with three abnormal LVEF categories (<52% in male/<54% in female, <50% and <45%). We assessed the overall contribution of these ECG abnormalities to clinical regression models predicting abnormal LVEF, assuming an absence of systolic dysfunction with a <1% threshold probability.
RESULTS
16% of survivors (52% female, mean age 34.7 years) and 14% of siblings had major ECG abnormalities. ECG abnormalities increased with decreasing LVEF. Integrating selected ECG data into the baseline model significantly improved prediction of sex-specific abnormal LVEF (c-statistic 0.66 vs 0.71), LVEF <50% (0.66 vs 0.76) and LVEF <45% (0.80 vs 0.86). While no survivor met the preset probability threshold in the first two models, the third model used five ECG variables to predict LVEF <45% and was applicable for ruling out (sensitivity 93%, specificity 56%, negative predictive value 99.6%). Calibration and internal validation tests performed well.
CONCLUSION
A clinical prediction model with ECG data (left bundle branch block, left atrial enlargement, left heart axis, Cornell's criteria for left ventricular hypertrophy and heart rate) may aid in ruling out LVEF <45%.
Topics: Humans; Female; Male; Cancer Survivors; Electrocardiography; Cross-Sectional Studies; Adult; Stroke Volume; Neoplasms; Cardiomyopathies; Child; Netherlands; Echocardiography; Ventricular Function, Left; Prevalence; Adolescent; Young Adult; Child, Preschool; Predictive Value of Tests
PubMed: 38503487
DOI: 10.1136/heartjnl-2023-323474 -
Journal of Chromatographic Science Mar 2024The concentration of mitoxantrone in the blood of mice was determined by a high-performance liquid chromatography-ultraviolet method with aloe-emodin as the internal...
The concentration of mitoxantrone in the blood of mice was determined by a high-performance liquid chromatography-ultraviolet method with aloe-emodin as the internal standard. The separation was performed on a Hypersil BDS2 column (4.6 × 250 mm, 5 μm) as the analytical column, the mobile Phase A was acetonitrile, and B was 20-mM potassium dihydrogen phosphate (adding 1% triethylamine and adjusting the pH to 2.8 with phosphoric acid) and 4.6-mM sodium octyl sulfonate. The flow rate was 1.0 mL·min-1, the detection wavelength was 243 nm, the column temperature is 25 ± 5°C and the injection amount was 20 μL. Finally, the linear range of mitoxantrone was 5-200 μg·mL-1, and the correlation coefficient was r = 0.9999. The recovery rate of the method was 91.93-105.5%, and the extraction recovery rate was 91.45-105.5%. The intraday precision and interday precision were <3.29% (limit of detection = 0.3 μg·mL-1). The HPLC method established in this paper was simple, rapid, sensitive and accurate, and can be used to determine the content of mitoxantrone in mouse plasma after tail vein injection.
PubMed: 38493310
DOI: 10.1093/chromsci/bmae007 -
Nano Letters Mar 2024Prodrug nanoassemblies are emerging as a novel drug delivery system for chemotherapy, comprising four fundamental modules: a drug module, a modification module, a...
Prodrug nanoassemblies are emerging as a novel drug delivery system for chemotherapy, comprising four fundamental modules: a drug module, a modification module, a response module, and a surface functionalization module. Among these modules, surface functionalization is an essential process to enhance the biocompatibility and stability of the nanoassemblies. Here, we selected mitoxantrone (MTO) as the drug module and DSPE-PEG as surface functionalization module to develop MTO prodrug nanoassemblies. We systematically evaluated the effect of surface functionalization module ratios (10%, 20%, 40%, and 60% of prodrug, /) on the prodrug nanoassemblies. The results indicated that 40% NPs significantly improved the self-assembly stability and cellular uptake of prodrug nanoassemblies. Compared with MTO solution, 40% NPs showed better tumor specificity and pharmacokinetics, resulting in potent antitumor activity with a good safety profile. These findings highlighted the pivotal role of the surface functionalization module in regulating the performance of mitoxantrone prodrug nanoassemblies for cancer treatment.
Topics: Prodrugs; Mitoxantrone; Cell Line, Tumor; Drug Delivery Systems; Nanoparticles; Antineoplastic Agents
PubMed: 38478977
DOI: 10.1021/acs.nanolett.4c00300 -
Human Cell May 2024Giant cell tumor of bone (GCTB) is a rare osteolytic bone tumor consisting of mononuclear stromal cells, macrophages, and osteoclast-like giant cells. Although GCTB...
Giant cell tumor of bone (GCTB) is a rare osteolytic bone tumor consisting of mononuclear stromal cells, macrophages, and osteoclast-like giant cells. Although GCTB predominantly exhibits benign behavior, the tumor carries a significant risk of high local recurrence. Furthermore, GCTB can occasionally undergo malignant transformation and distal metastasis, making it potentially fatal. The standard treatment is complete surgical resection; nonetheless, an optimal treatment strategy for advanced GCTB remains unestablished, necessitating expanded preclinical research to identify appropriate therapeutic options. However, only one GCTB cell line is publicly available from a cell bank for research use worldwide. The present study reports the establishment of two novel cell lines, NCC-GCTB8-C1 and NCC-GCTB9-C1, derived from the primary tumor tissues of two patients with GCTB. Both cell lines maintained the hallmark mutation in the H3-3A gene, which is associated with tumor formation and development in GCTB. Characterization of these cell lines revealed their steady growth, spheroid-formation capability, and invasive traits. Potential therapeutic agents were identified via extensive drug screening of the two cell lines and seven previously established GCTB cell lines. Among the 214 antitumor agents tested, romidepsin, a histone deacetylase inhibitor, and mitoxantrone, a topoisomerase inhibitor, were identified as potential therapeutic agents against GCTB. Conclusively, the establishment of NCC-GCTB8-C1 and NCC-GCTB9-C1 provides novel and crucial resources that are expected to advance GCTB research and potentially revolutionize treatment strategies.
Topics: Humans; Giant Cell Tumor of Bone; Cell Line, Tumor; Antineoplastic Agents; Bone Neoplasms
PubMed: 38466561
DOI: 10.1007/s13577-024-01042-5 -
Leukemia Research Apr 2024Most patients with acute myeloid leukemia (AML) develop relapsed or refractory (R/R) disease after receiving initial induction chemotherapy. Salvage chemotherapy...
BACKGROUND/RATIONALE
Most patients with acute myeloid leukemia (AML) develop relapsed or refractory (R/R) disease after receiving initial induction chemotherapy. Salvage chemotherapy followed by allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only curative therapy for R/R AML. Mitoxantrone, etoposide, and cytarabine (MEC) is the current standard of care salvage regimen for R/R AML at Cleveland Clinic. The primary objective was to determine the overall remission rate (ORR: defined as patients achieving complete remission (CR) or complete remission with incomplete hematologic recovery (CRi)) in R/R AML patients who received MEC.
METHODS
Adult patients with R/R AML treated with MEC between July 1, 2014 and September 30, 2022 were included. ORR and its association with baseline characteristics were determined. Secondary outcomes included overall survival (OS), event-free survival (EFS), relapse-free survival (RFS), and safety.
RESULTS
Sixty patients were evaluated. The ORR was 51.7% (33.3% CR and 18.3% CRi). The median time from receipt of MEC to CR/CRi was 7.7 weeks. Patients with bone marrow blasts ≤20% and peripheral blood blasts ≤30% at MEC initiation were more than twice as likely to achieve CR/CRi compared to those with a higher blast burden. The median OS was 6.3 months. Twenty-four (40.0%) patients proceeded to alloHSCT. Twenty-one (35.0%) patients were transferred to the intensive care unit (ICU) during their admission.
CONCLUSIONS
MEC is an effective salvage regimen for patients with R/R AML, especially among those with low disease burden at initiation. Febrile neutropenia, infections, and severe oral mucositis were common with MEC administration.
Topics: Adult; Humans; Mitoxantrone; Etoposide; Cytarabine; Antineoplastic Combined Chemotherapy Protocols; Leukemia, Myeloid, Acute
PubMed: 38460433
DOI: 10.1016/j.leukres.2024.107468