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Pediatric Blood & Cancer Aug 2024Metronomic chemotherapy-based combinations have received interest for relapsed/refractory malignancies. Preclinical and clinical studies showed activity of metronomic...
Metronomic chemotherapy-based combinations have received interest for relapsed/refractory malignancies. Preclinical and clinical studies showed activity of metronomic etoposide and axitinib. We report our retrospective experience in six children treated with axitinib and metronomic etoposide for refractory/relapsed brain tumors as an "off-label" combination. Three patients with medulloblastoma experienced partial response; one patient with atypical teratoid rhabdoid tumor (ATRT) displays an ongoing stable disease (12 months); two patients with medulloblastoma had progressive disease. Grade 3-4 toxicities were observed in two patients (thrombocytopenia, anemia, diarrhea, fatigue). The axitinib-etoposide combination shows signals of efficacy in heavily pretreated patients with relapsed/refractory brain tumors. These results were based on real-world observation and will need formal evaluation in a phase I/II trial.
Topics: Humans; Male; Retrospective Studies; Female; Etoposide; Antineoplastic Combined Chemotherapy Protocols; Child; Axitinib; Brain Neoplasms; Child, Preschool; Neoplasm Recurrence, Local; Adolescent; Administration, Metronomic; Administration, Oral; Follow-Up Studies; Prognosis; Infant
PubMed: 38778441
DOI: 10.1002/pbc.31076 -
Molecular and Cellular Biology 2024Cellular senescence is a dynamic biological process triggered by sublethal cell damage and driven by specific changes in gene expression programs. We recently identified...
Cellular senescence is a dynamic biological process triggered by sublethal cell damage and driven by specific changes in gene expression programs. We recently identified ANKRD1 (ankyrin repeat domain 1) as a protein strongly elevated after triggering senescence in fibroblasts. Here, we set out to investigate the mechanisms driving the elevated production of ANKRD1 in the early stages of senescence. Our results indicated that the rise in ANKRD1 levels after triggering senescence using etoposide (Eto) was the result of moderate increases in transcription and translation, and robust mRNA stabilization. Antisense oligomer (ASO) pulldown followed by mass spectrometry revealed a specific interaction of the RNA-binding protein RBMS1 with mRNA that was confirmed by ribonucleoprotein immunoprecipitation analysis. RBMS1 abundance decreased in the nucleus and increased in the cytoplasm during Eto-induced senescence; in agreement with the hypothesis that RBMS1 may participate in post-transcriptional stabilization of mRNA, silencing RBMS1 reduced, while overexpressing RBMS1 enhanced mRNA half-life after Eto treatment. A segment proximal to the coding region was identified as binding RBMS1 and conferring RBMS1-dependent increased expression of a heterologous reporter. We propose that RBMS1 increases expression of ANKRD1 during the early stages of senescence by stabilizing mRNA.
Topics: Humans; Cellular Senescence; RNA Stability; RNA-Binding Proteins; Nuclear Proteins; Repressor Proteins; RNA, Messenger; Etoposide; Fibroblasts; Cell Nucleus; Cell Line; Muscle Proteins
PubMed: 38769646
DOI: 10.1080/10985549.2024.2350540 -
European Journal of Pharmacology Jul 2024The emergence of chemoresistance poses a significant challenge to the efficacy of DNA-damaging agents in cancer treatment, in part due to the inherent DNA repair...
The emergence of chemoresistance poses a significant challenge to the efficacy of DNA-damaging agents in cancer treatment, in part due to the inherent DNA repair capabilities of cancer cells. The Ku70/80 protein complex (Ku) plays a central role in double-strand breaks (DSBs) repair through the classical non-homologous end joining (c-NHEJ) pathway, and has proven to be one of the most promising drug target for cancer treatment when combined with radiotherapy or chemotherapy. In this study, we conducted a high-throughput screening of small-molecule inhibitors targeting the Ku complex by using a fluorescence polarization-based DNA binding assay. From a library of 11,745 small molecules, UMI-77 was identified as a potent Ku inhibitor, with an IC value of 2.3 μM. Surface plasmon resonance and molecular docking analyses revealed that UMI-77 directly bound the inner side of Ku ring, thereby disrupting Ku binding with DNA. In addition, UMI-77 also displayed potent inhibition against MUS81-EME1, a key player in homologous recombination (HR), demonstrating its potential for blocking both NHEJ- and HR-mediated DSB repair pathways. Further cell-based studies showed that UMI-77 could impair bleomycin-induced DNA damage repair, and significantly sensitized multiple cancer cell lines to the DNA-damaging agents. Finally, in a mouse xenograft tumor model, UMI-77 significantly enhanced the chemotherapeutic efficacy of etoposide with little adverse physiological effects. Our work offers a new avenue to combat chemoresistance in cancer treatment, and suggests that UMI-77 could be further developed as a promising candidate in cancer treatment.
Topics: Humans; Ku Autoantigen; Animals; Cell Line, Tumor; Mice; Antineoplastic Agents; DNA Damage; Molecular Docking Simulation; Xenograft Model Antitumor Assays; DNA End-Joining Repair; Etoposide; Drug Discovery; DNA Breaks, Double-Stranded; Drug Resistance, Neoplasm
PubMed: 38754534
DOI: 10.1016/j.ejphar.2024.176647 -
Scientific Reports May 2024Research on the relationships between oligoelements (OE) and the development of cancer or its prevention is a field that is gaining increasing relevance. The aim was to...
Research on the relationships between oligoelements (OE) and the development of cancer or its prevention is a field that is gaining increasing relevance. The aim was to evaluate OE and their interactions with oncology treatments (cytarabine or etoposide) to determine the effects of this combination on biogenic amines and oxidative stress biomarkers in the brain regions of young Wistar rats. Dopamine (DA), 5-Hydroxyindoleacetic acid (5-Hiaa), Glutathione (Gsh), Tiobarbituric acid reactive substances (TBARS) and Ca, Mg ATPase enzyme activity were measured in brain regions tissues using spectrophometric and fluorometric methods previously validated. The combination of oligoelements and cytarabine increased dopamine in the striatum but decreased it in cerebellum/medulla-oblongata, whereas the combination of oligoelements and etoposide reduced lipid peroxidation. These results suggest that supplementation with oligoelements modifies the effects of cytarabine and etoposide by redox pathways, and may become promising therapeutic targets in patients with cancer.
Topics: Animals; Etoposide; Oxidative Stress; Cytarabine; Dopamine; Rats; Rats, Wistar; Brain; Male; Lipid Peroxidation; Dietary Supplements; Glutathione
PubMed: 38736022
DOI: 10.1038/s41598-024-61766-0 -
International Journal of Molecular... Apr 2024When new antitumor therapy drugs are discovered, it is essential to address new target molecules from the point of view of chemical structure and to carry out efficient...
When new antitumor therapy drugs are discovered, it is essential to address new target molecules from the point of view of chemical structure and to carry out efficient and systematic evaluation. In the case of natural products and derived compounds, it is of special importance to investigate chemomodulation to further explore antitumoral pharmacological activities. In this work, the compound podophyllic aldehyde, a cyclolignan derived from the chemomodulation of the natural product podophyllotoxin, has been evaluated for its viability, influence on the cell cycle, and effects on intracellular signaling. We used functional proteomics characterization for the evaluation. Compared with the FDA-approved drug etoposide (another podophyllotoxin derivative), we found interesting results regarding the cytotoxicity of podophyllic aldehyde. In addition, we were able to observe the effect of mitotic arrest in the treated cells. The use of podophyllic aldehyde resulted in increased cytotoxicity in solid tumor cell lines, compared to etoposide, and blocked the cycle more successfully than etoposide. High-throughput analysis of the deregulated proteins revealed a selective antimitotic mechanism of action of podophyllic aldehyde in the HT-29 cell line, in contrast with other solid and hematological tumor lines. Also, the apoptotic profile of podophyllic aldehyde was deciphered. The cell death mechanism is activated independently of the cell cycle profile. The results of these targeted analyses have also shown a significant response to the signaling of kinases, key proteins involved in signaling cascades for cell proliferation or metastasis. Thanks to this comprehensive analysis of podophyllic aldehyde, remarkable cytotoxic, antimitotic, and other antitumoral features have been discovered that will repurpose this compound for further chemical transformations and antitumoral analysis.
Topics: Humans; Podophyllotoxin; Proteomics; Cell Cycle; Cell Line, Tumor; Apoptosis; Etoposide; Antineoplastic Agents; HT29 Cells; Cell Proliferation; Cell Survival
PubMed: 38731850
DOI: 10.3390/ijms25094631 -
Pediatric Blood & Cancer Aug 2024The addition of rituximab to standard regimens for primary mediastinal large B-cell lymphoma (PMBCL) has significantly improved overall survival. However, the optimal...
The addition of rituximab to standard regimens for primary mediastinal large B-cell lymphoma (PMBCL) has significantly improved overall survival. However, the optimal management of isolated central nervous system (CNS) relapse and role of CNS prophylaxis remains undefined. We present cases of two adolescents with PMBCL who developed isolated CNS relapses. While isolated CNS relapse may be managed with high-dose chemotherapy and autologous stem cell transplant with or without CNS radiotherapy, review of these cases and the literature highlight the need for further work to define risk factors for CNS relapse, and identify patients who may benefit from CNS prophylaxis.
Topics: Humans; Mediastinal Neoplasms; Adolescent; Lymphoma, Large B-Cell, Diffuse; Antineoplastic Combined Chemotherapy Protocols; Central Nervous System Neoplasms; Male; Rituximab; Vincristine; Etoposide; Doxorubicin; Cyclophosphamide; Female; Prednisone; Neoplasm Recurrence, Local
PubMed: 38721853
DOI: 10.1002/pbc.31065 -
Molecular Pharmacology Jun 2024DNA topoisomerase II (TOP2; 170 kDa, TOP2/170) is an essential enzyme for proper chromosome dysjunction by producing transient DNA double-stranded breaks and is an...
DNA topoisomerase II (TOP2; 170 kDa, TOP2/170) is an essential enzyme for proper chromosome dysjunction by producing transient DNA double-stranded breaks and is an important target for DNA damage-stabilizing anticancer agents, such as etoposide. Therapeutic effects of TOP2 poisons can be limited due to acquired drug resistance. We previously demonstrated decreased TOP2/170 levels in an etoposide-resistant human leukemia K562 subline, designated K/VP.5, accompanied by increased expression of a C-terminal truncated TOP2 isoform (90 kDa; TOP2/90), which heterodimerized with TOP2/170 and was a determinant of resistance by exhibiting dominant-negative effects against etoposide activity. Based on 3'-rapid amplification of cDNA ends, we confirmed TOP2/90 as the translation product of a TOP2 mRNA in which a cryptic polyadenylation site (PAS) harbored in intron 19 (I19) was used. In this report, we investigated whether the resultant intronic polyadenylation (IPA) would be attenuated by blocking or mutating the I19 PAS, thereby circumventing acquired drug resistance. An antisense morpholino oligonucleotide was used to hybridize/block the PAS in TOP2 pre-mRNA in K/VP.5 cells, resulting in decreased TOP2/90 mRNA/protein levels in K/VP.5 cells and partially circumventing drug resistance. Subsequently, CRISPR/CRISPR-associated protein 9 with homology-directed repair was used to mutate the cryptic I19 PAS (AAA→AAA) to prevent IPA. Gene-edited clones exhibited increased TOP2/170 and decreased TOP2/90 mRNA/protein and demonstrated restored sensitivity to etoposide and other TOP2-targeted drugs. Together, results indicated that blocking/mutating a cryptic I19 PAS in K/VP.5 cells reduced IPA and restored sensitivity to TOP2-targeting drugs. SIGNIFICANCE STATEMENT: The results presented in this study indicate that CRISPR/CRISPR-associated protein 9 gene editing of a cryptic polyadenylation site (PAS) within I19 of the TOP2α gene results in the reversal of acquired resistance to etoposide and other TOP2-targeted drugs. An antisense morpholino oligonucleotide targeting the PAS also partially circumvented resistance.
Topics: Humans; Etoposide; DNA Topoisomerases, Type II; Drug Resistance, Neoplasm; K562 Cells; Polyadenylation; Introns; CRISPR-Cas Systems
PubMed: 38719474
DOI: 10.1124/molpharm.124.000868 -
Scientific Reports May 2024The aim of the study was to investigate the prognostic significance of the advanced lung cancer inflammation index (ALI) in patients with limited-stage small-cell lung...
The aim of the study was to investigate the prognostic significance of the advanced lung cancer inflammation index (ALI) in patients with limited-stage small-cell lung cancer (LS-SCLC) undergoing definite chemo-radiotherapy (CRT). We included 87 patients with LS-SCLC from South Korea, treated between 2005 and 2019 with definite CRT. ALI was calculated using body mass index, serum albumin, and neutrophil-lymphocyte ratio. We categorized 38 patients into the high ALI group (ALI ≥ 44.3) and 48 into the low ALI group (ALI < 44.3). Patients in the high ALI group exhibited longer overall survival (OS) than patients in the low ALI group. In multivariate analysis, prophylactic cranial irradiation (hazard ratio [HR] = 0.366, 95% confidence interval [CI] 0.20-0.66, P = 0.0008), and high ALI (HR = 0.475, 95% CI 0.27-0.84, P = 0.0103) were identified as independent prognostic factors for predicting better OS. Notably, a high ALI score was particularly indicative of longer survival in patients treated with the combination of etoposide and cisplatin. In conclusion, this study demonstrated that a high pretreatment ALI was significantly associated with better OS in patients with LS-SCLC undergoing definite CRT. This suggests that ALI could be a useful tool for predicting prognosis and guiding chemotherapy regimen selections in clinical practice for LS-SCLC.
Topics: Humans; Small Cell Lung Carcinoma; Female; Male; Lung Neoplasms; Chemoradiotherapy; Middle Aged; Aged; Prognosis; Inflammation; Cisplatin; Etoposide; Neoplasm Staging; Neutrophils; Retrospective Studies; Antineoplastic Combined Chemotherapy Protocols; Adult; Clinical Relevance
PubMed: 38710892
DOI: 10.1038/s41598-024-61145-9 -
Biosensors & Bioelectronics Aug 2024Therapeutic drug monitoring (TDM) serves as a potent tool for adjusting drug concentration within a reasonable range. However, continuous monitoring of anticancer drugs...
Therapeutic drug monitoring (TDM) serves as a potent tool for adjusting drug concentration within a reasonable range. However, continuous monitoring of anticancer drugs in-vivo presents a significant challenge. Herein, we propose a needle-in-needle electrochemical sensor based on an acupuncture needle electrode, capable of monitoring the anticancer drug etoposide in the peritoneal cavity of living rats. The acupuncture needle was modified with Au nanoparticles and etoposide-templated molecularly imprinted polymer (MIP), resulting in high sensitivity and selectivity in the electrochemical detection of etoposide. The modified acupuncture needle (0.16 mm diameter) was anchored inside a syringe needle (1.40 mm diameter), allowing the outer syringe needle to protect the modified materials of the inner acupuncture needle during skin piercing. Due to the unique needle-in-needle design, high stability was obtained during in-vivo etoposide monitoring. Connecting to a smartphone-controlled portable electrochemical workstation, the needle-in-needle sensor offers great convenience in point-of-care TDM. Moreover, the electrode materials on the acupuncture needle were carefully characterized and optimized. Under the optimized conditions, low detection limits and wide linear range were achieved. This work provides new insights into acupuncture needle electrochemical sensors and further expands the feasibility for real-time and in-vivo detection.
Topics: Etoposide; Animals; Needles; Rats; Biosensing Techniques; Gold; Drug Monitoring; Electrochemical Techniques; Antineoplastic Agents; Metal Nanoparticles; Molecularly Imprinted Polymers; Limit of Detection; Electrodes; Rats, Sprague-Dawley; Equipment Design
PubMed: 38710143
DOI: 10.1016/j.bios.2024.116348 -
Medicine May 2024Trophoblastic neoplasms are often associated with pregnancy, and nongestational trophoblastic neoplasms are extremely rare. Nongestational ovarian choriocarcinoma (NGCO)... (Review)
Review
INTRODUCTION
Trophoblastic neoplasms are often associated with pregnancy, and nongestational trophoblastic neoplasms are extremely rare. Nongestational ovarian choriocarcinoma (NGCO) is a highly aggressive germ cell-derived tumor frequently presenting with early hematogenous metastasis.
PATIENT CONCERNS
Herein, we report a case of a 28-year-old unmarried woman with regular menstruation who experienced vaginal bleeding 1 week after her last menstrual cycle. Doppler ultrasound revealed bilateral adnexal masses and elevated serum human chorionic gonadotropin (hCG) levels. The patient was initially misdiagnosed as presenting an ectopic pregnancy.
DIAGNOSIS
The final pathology confirmed an International Federation of Gynecology and Obstetrics stage IA NGCO with bilateral mature teratoma of the ovary. This is an extraordinary instance of ovarian choriocarcinoma which emerged without any prior gestation, and the patient's lack of a history of pregnancy made the diagnosis ignored.
INTERVENTIONS
After initial surgery and 1 cycle of bleomycin, etoposide, and cisplatin (BEP) chemotherapy, a laparoscopic fertility-preserving comprehensive staging surgery was performed. Two cycles of chemotherapy with BEP were administered as supplemental therapy postsurgery, and leuprorelin was administered to protect ovarian function.
OUTCOMES
Menstruation resumed 4 months after chemotherapy completion, and tumor indicators were within the normal range. No signs of recurrence were observed at the 36-month follow-up.
CONCLUSION
NGCO should be considered if a female patient exhibits irregular vaginal bleeding and masses in the adnexal area. The present case and our literature review also highlighted that fertility-sparing surgery and multidrug chemotherapy are effective methods for treating NGCO.
Topics: Humans; Female; Adult; Ovarian Neoplasms; Teratoma; Choriocarcinoma, Non-gestational; Antineoplastic Combined Chemotherapy Protocols; Etoposide; Pregnancy; Bleomycin
PubMed: 38701311
DOI: 10.1097/MD.0000000000036996