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Frontiers in Pharmacology 2024Cervical cancer (CC) ranks as the fourth most prevalent malignant tumor among women worldwide, and is the fourth leading cause of cancer-related mortality. GuiErBai...
Cervical cancer (CC) ranks as the fourth most prevalent malignant tumor among women worldwide, and is the fourth leading cause of cancer-related mortality. GuiErBai (GEB), a compound preparation developed by our research team, is derived from the ancient Chinese medicine of the Miao nationality and is comprised of podophyllotoxin (PTOX), imperatorin, isoimperatorin, and alkaloids. These individual components have demonstrated notable efficacy in tumor treatment. However, the specific anti-tumor effect of the compound Chinese medicine GEB in the context of CC has yet to be validated. HeLa and SiHa cell lines were utilized for experiments and treated with 5 mg/mL and 10 mg/mL GEB concentrations, respectively. The cell cycle changes after GEB treatment were assessed using flow cytometry. Transmission electron microscopy was employed to observe autophagic bodies and apoptotic bodies, while MDC staining evaluated the occurrence of autophagy. CCK-8 was used to observe the effect of GEB on cell proliferation, and Transwell assays assessed cell migration and invasion. Western blotting detected cell cycle and apoptosis-related protein expression, along with the expression level of autophagy-related protein LC3I/II. Changes in ROS and mitochondrial membrane potential in cervical cancer cells following GEB treatment were determined using ROS detection and mitochondrial membrane potential detection kits. For the experiment, a nude mouse model of cervical cancer transplantation based on HeLa cells was established. Experimental animals were divided into negative control, positive control, high-dose GEB (10 mg/mL), and low-dose GEB (5 mg/mL) groups. In HeLa and SiHa cell lines, the G0/G1 phase of tumor cells significantly decreased ( < 0.001), while the G2/M phase increased notably ( < 0.001) following various GEB treatments. Electron microscopy showed GEB promoted apoptotic body and autophagosome formation in both cell lines. Compared to untreated HeLa and SiHa cells, GEB-treated cells exhibited significantly reduced caspase3 protein expression, and substantially increased autophagy-related protein LC3I/II expression. GEB treatment significantly reduced migration and invasion capabilities in both cell lines ( < 0.001), while ROS content and mitochondrial membrane potential were significantly elevated ( < 0.001). GEB effectively inhibited cervical cancer cell proliferation, with the optimal concentration being 10 mg/mL. A successful nude mouse model of cervical cancer transplantation was established using HeLa cells. Post-GEB treatment, the tumor volume and weight in nude mice significantly decreased ( < 0.001), with diminished expression of CD34, VEGF, and caspase3 proteins in tumor tissues. GEB exhibits a robust antitumor effect against cervical cancer, both and , in a concentration-dependent manner, by regulating autophagy and apoptosis of tumor cells.
PubMed: 38915466
DOI: 10.3389/fphar.2024.1296588 -
Oncology Letters Aug 2024One of the lignans isolated from plants within the genus is podophyllotoxin (PPT). PPT and its derivatives are pharmacologically active compounds with potential...
One of the lignans isolated from plants within the genus is podophyllotoxin (PPT). PPT and its derivatives are pharmacologically active compounds with potential antiproliferative properties in several kinds of tumors. Although these compounds have been used to treat other malignancies, no PPT derivative-based chemotherapeutic agent has been used to cure tamoxifen (TAM)-resistant breast cancer in clinical trials, to the best of our knowledge. Thus, using TAM-resistant breast cancer as a disease model, the present study assessed the effects of a recently synthesized PPT derivative, bromosulfonamidine amino-PPT (BSAPPT), on TAM-resistant breast cancer. Using the tamoxifen-resistant breast cancer cell model (MCF-7/TAMR) , Cell Counting Kit-8 and colony formation assays were adopted to evaluate the effect of BSAPPT on cell proliferation. Cell apoptosis and cell cycle assays were used to assess the influence of BSAPPT on cell apoptosis and the cell cycle in MCF-7/TAMR. The targets of the potential mechanism of action were analyzed by RT-qPCR and western blotting. The present study demonstrated that BSAPPT suppressed MCF-7/TAMR cell proliferation in a dose-dependent manner. By modulating the level of expression of genes linked to both apoptosis and the cell cycle, BSAPPT triggered MCF-7/TAMR cells to undergo apoptosis and prevented them from entering the cell cycle. Consequently, BSAPPT blocked these cells from proliferating, thereby halting the malignant advancement of TAM-resistant breast cancer. Therefore, these findings indicate that new therapeutic agents involving BSAPPT may be developed to facilitate the treatment of TAM-resistant breast cancer.
PubMed: 38910903
DOI: 10.3892/ol.2024.14506 -
Medicine Jun 2024Hemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening syndrome for which early recognition and treatment are essential for improving outcomes. HLH...
INTRODUCTION
Hemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening syndrome for which early recognition and treatment are essential for improving outcomes. HLH is characterized by uncontrolled immune activation leading to fever, cytopenias, hepatosplenomegaly, coagulation abnormalities, and elevated typical markers. This condition can be genetic or secondary, with the latter often triggered by infections. Here, we present a unique case of HLH secondary to acute otitis media (AOM), a common ear infection.
PATIENT CONCERNS
We describe a 4-year-old boy who initially presented with a high fever and otalgia, later diagnosed with bilateral AOM. Despite antibiotic treatment, his condition deteriorated.
DIAGNOSIS
The patient fulfilled diagnostic criteria for HLH.
INTERVENTIONS
Aggressive treatment by using combination therapy with immunoglobulins, intravenous steroids (dexamethasone), cyclosporine, and etoposide was performed.
OUTCOMES
After 1 month of treatment, improvement in the otologic symptoms was observed, and hematological findings gradually improved and normalized.
LESSIONS
The link between AOM and HLH may be associated with inflammatory responses and immunological mechanisms, highlighting the importance of considering HLH in severe infection cases. This case emphasizes the need for prompt diagnosis and management, especially in secondary HLH scenarios, to improve patient outcomes. It is imperative to be aware of the potential correlation between these 2 conditions, and healthcare professionals should consider the likelihood of HLH.
Topics: Humans; Lymphohistiocytosis, Hemophagocytic; Male; Child, Preschool; Otitis Media; Acute Disease; Dexamethasone; Cyclosporine; Etoposide; Immunoglobulins, Intravenous
PubMed: 38905364
DOI: 10.1097/MD.0000000000038616 -
Biological & Pharmaceutical Bulletin 2024Although carboplatin (CBDCA) is classified as a moderately emetogenic agent, the majority of guidelines recommend the use of a neurokinin-1 receptor antagonist in...
Although carboplatin (CBDCA) is classified as a moderately emetogenic agent, the majority of guidelines recommend the use of a neurokinin-1 receptor antagonist in addition to a 5-hydroxytryptamine type 3 receptor antagonist with dexamethasone (DEX) for CBDCA-containing chemotherapy because of its higher emetogenic risk. However, the additional efficacy of aprepitant (APR) in CBDCA-containing treatment remains controversial, and data on multiple-day treatments are limited. Etoposide (ETP) was administered on days 1-3 in the CBDCA + ETP regimen, and it is important to evaluate suitable antiemetic therapy for the regimen. Therefore, we evaluated the efficacy of additional APR in CBDCA + ETP. Patients were divided into two groups and retrospectively evaluated. One was the control group, which was prophylactically administered palonosetron (PALO) and DEX, and the other was the APR group, which received APR orally with PALO and DEX. The primary endpoint was complete response (CR) between the groups. The overall CR rates were 75.0 and 76.4% in the control and APR groups, respectively, with no significant difference (p = 1.00). In the acute phase, it was 88.9 and 97.2%, respectively, and 86.1 and 79.2% in the delayed phase, respectively, without significant differences (p = 0.10 and 0.38, respectively). The incidence and severity of nausea, vomiting, and anorexia were not significantly different between the two groups in the acute and delayed phases. Our findings suggest that combining APR with PALO and DEX does not improve the CR rate in CBDCA + ETP therapy.
Topics: Aprepitant; Carboplatin; Humans; Dexamethasone; Palonosetron; Male; Etoposide; Antiemetics; Female; Middle Aged; Vomiting; Aged; Nausea; Retrospective Studies; Adult; Drug Therapy, Combination; Antineoplastic Combined Chemotherapy Protocols; Quinuclidines; Morpholines; Antineoplastic Agents; Isoquinolines; Treatment Outcome
PubMed: 38897969
DOI: 10.1248/bpb.b24-00046 -
International Journal of Molecular... May 2024Podophyllotoxin (PPT) is an active pharmaceutical ingredient (API) with established antitumor potential. However, due to its systemic toxicity, its use is restricted to...
Cellular Distribution and Ultrastructural Changes in HaCaT Cells, Induced by Podophyllotoxin and Its Novel Fluorescent Derivative, Supported by the Molecular Docking Studies.
Podophyllotoxin (PPT) is an active pharmaceutical ingredient (API) with established antitumor potential. However, due to its systemic toxicity, its use is restricted to topical treatment of anogenital warts. Less toxic PPT derivatives (e.g., etoposide and teniposide) are used intravenously as anticancer agents. PPT has been exploited as a scaffold of new potential therapeutic agents; however, fewer studies have been conducted on the parent molecule than on its derivatives. We have undertaken a study of ultrastructural changes induced by PPT on HaCaT keratinocytes. We have also tracked the intracellular localization of PPT using its fluorescent derivative (PPT-FL). Moreover, we performed molecular docking of both PPT and PPT-FL to compare their affinity to various binding sites of tubulin. Using the Presto blue viability assay, we established working concentrations of PPT in HaCaT cells. Subsequently, we have used selected concentrations to determine PPT effects at the ultrastructural level. Dynamics of PPT distribution by confocal microscopy was performed using PPT-FL. Molecular docking calculations were conducted using Glide. PPT induces a time-dependent cytotoxic effect on HaCaT cells. Within 24 h, we observed the elongation of cytoplasmic processes, formation of cytoplasmic vacuoles, progressive ER stress, and shortening of the mitochondrial long axis. After 48 h, we noticed disintegration of the cell membrane, progressive vacuolization, apoptotic/necrotic vesicles, and a change in the cell nucleus's appearance. PPT-FL was detected within HaCaT cells after ~10 min of incubation and remained within cells in the following measurements. Molecular docking confirmed the formation of a stable complex between tubulin and both PPT and PPT-FL. However, it was formed at different binding sites. PPT is highly toxic to normal human keratinocytes, even at low concentrations. It promptly enters the cells, probably via endocytosis. At lower concentrations, PPT causes disruptions in both ER and mitochondria, while at higher concentrations, it leads to massive vacuolization with subsequent cell death. The novel derivative of PPT, PPT-FL, forms a stable complex with tubulin, and therefore, it is a useful tracker of intracellular PPT binding and trafficking.
Topics: Humans; Molecular Docking Simulation; Podophyllotoxin; HaCaT Cells; Tubulin; Keratinocytes; Cell Survival; Mitochondria; Fluorescent Dyes; Binding Sites; Endoplasmic Reticulum Stress
PubMed: 38892135
DOI: 10.3390/ijms25115948 -
Frontiers in Immunology 2024SMARCA4-deficient undifferentiated tumor (SMARCA4-dUT) is a devastating subtype of thoracic tumor with SMARCA4 inactivation and is characterized by rapid progression,...
SMARCA4-deficient undifferentiated tumor (SMARCA4-dUT) is a devastating subtype of thoracic tumor with SMARCA4 inactivation and is characterized by rapid progression, poor prognosis, and high risk of postoperative recurrence. However, effective treatments for SMARCA4-dUT are lacking. Herein, we describe a patient with SMARCA4-dUT who exhibited an impressive response to the anti-programmed cell death protein-1 (PD-1) antibody (tislelizumab) in combination with conventional chemotherapy (etoposide and cisplatin). To the best of our knowledge, this is the first case of SMARCA4-dUT treated with chemotherapy, comprising etoposide and cisplatin, combined with anti-PD-1 inhibitors. Immunotherapy combined with etoposide and cisplatin may be a promising strategy to treat SMARCA4-dUT.
Topics: Humans; Antibodies, Monoclonal, Humanized; DNA Helicases; Antineoplastic Combined Chemotherapy Protocols; Transcription Factors; Nuclear Proteins; Etoposide; Male; Cisplatin; Treatment Outcome; Female
PubMed: 38881888
DOI: 10.3389/fimmu.2024.1371379 -
Ecotoxicology and Environmental Safety Jul 2024Podophyllotoxin (PPT) is a lignan derived from the roots and stems of the Podophyllum plant. However, its enterotoxicity restricts its clinical application. The...
Podophyllotoxin (PPT) is a lignan derived from the roots and stems of the Podophyllum plant. However, its enterotoxicity restricts its clinical application. The underlying mechanisms by which PPT exerts its action remain largely elusive. This study aimed to evaluate the molecular mechanisms underlying PPT-induced enterotoxicity utilizing the concept of toxicological evidence chain. Changes in body weight, behavior, and histopathological and biochemical markers in rats were observed. Additionally, microbiome, metabolome, and transcriptome analyses were integrated to identify potential microorganisms, metabolic markers, and major pathways using a co-occurrence network. Our findings suggested that PPT induced pathological changes in rats, including weight loss, diarrhea, and inflammation accompanied by increased levels of IFN-γ, IL-5, IL-6, GRO/KC, and IL-12p70. The decrease in butyrate levels in the PPT group may be related to the enrichment of Firmicutes. The reduction of butyrate levels may impair the expression of PPARγ, subsequently promoting Escherichia-Shigella proliferation. Additionally, the suppression of PPARs pathway may result in the increased production of inflammatory factors, contributing to enterotoxicity. This study offers a novel understanding of the molecular mechanisms underlying PPT-induced enterotoxicity, making a significant contribution to developing strategies to mitigate PPT toxicity and prevent associated diseases.
Topics: Animals; Podophyllotoxin; Rats; Male; Gastrointestinal Microbiome; Rats, Sprague-Dawley; Peroxisome Proliferator-Activated Receptors; PPAR gamma; Microbiota
PubMed: 38850705
DOI: 10.1016/j.ecoenv.2024.116548 -
Medicine Jun 2024Lung cancer is one of the most malignant tumors with fastest morbidity and mortality. Small cell lung cancer (SCLC) is the most malignant pathological type of lung... (Observational Study)
Observational Study
The predictive value of delta-like3 and serum NSE in evaluating chemotherapy response and prognosis in patients with advanced small cell lung carcinoma: An observational study.
Lung cancer is one of the most malignant tumors with fastest morbidity and mortality. Small cell lung cancer (SCLC) is the most malignant pathological type of lung cancer with early metastasis and poor prognosis. At present, there is a lack of effective indicators to predict prognosis of SCLC patients. Delta-like 3 protein (DLL3) is selectively expressed on the surface of SCLC and is involved in proliferation and invasion. Neuron-specific enolase (NSE) is an enolase isoenzyme that is generally regarded as a biomarker for SCLC and may correlate with stage of SCLC, prognosis and chemotherapy response. NSE can be influenced by different types of factors. To explore the associations between expression levels of DLL3 in tumor tissues with platinum/etoposide chemotherapy response, and assess the prognostic values of DLL3, NSE and other potential prognostic factors in advanced SCLC patients were herein studied. Ninety-seven patients diagnosed with SCLC in Zhongda Hospital from 2014 to 2020 were enrolled in the study. Serum NSE levels were tested using ELISA methods before any treatment. The expression of DLL3 in tumor tissue was detected by Immunohistochemistry (IHC). We investigated the relationship of DLL3 expression with chemotherapy and survival. Progression free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Multivariate Cox-proportional hazard regression was used to identify predictors of PFS and OS. DLL3 was detected in 84.5% (82/97) of all patients' tumor samples by IHC, mainly located on the surface of SCLC cells. Lower DLL3 expression was associated with longer PFS and better chemotherapy response. OS had no significant differences. Multivariate analysis by Cox Hazard model showed that, high DLL3 expression and maximum tumor size >5 cm were independent risk factors for PFS, where NSE < 35 ng/mL and age < 70 were independent prognostic factors for OS. Early stage was independent prognostic factors for PFS and OS (P < .05 log-rank). DLL3 was expressed in the most of SCLCs. DLL3 expression level in the tumor and NSE level in the serum may be useful biomarkers to predict the prognosis of SCLC. DLL3 may be a potential therapeutic target for SCLC in the future.
Topics: Humans; Small Cell Lung Carcinoma; Male; Female; Phosphopyruvate Hydratase; Lung Neoplasms; Middle Aged; Prognosis; Biomarkers, Tumor; Aged; Membrane Proteins; Intracellular Signaling Peptides and Proteins; Etoposide; Adult; Antineoplastic Combined Chemotherapy Protocols; Predictive Value of Tests; Kaplan-Meier Estimate
PubMed: 38847733
DOI: 10.1097/MD.0000000000038487 -
Life Science Alliance Aug 2024RNA-binding proteins are frequently deregulated in cancer and emerge as effectors of the DNA damage response (DDR). The non-POU domain-containing octamer-binding protein...
RNA-binding proteins are frequently deregulated in cancer and emerge as effectors of the DNA damage response (DDR). The non-POU domain-containing octamer-binding protein NONO/p54 is a multifunctional RNA-binding protein that not only modulates the production and processing of mRNA, but also promotes the repair of DNA double-strand breaks (DSBs). Here, we investigate the impact of deletion in the murine KP ( , ) cell-based lung cancer model. We show that the deletion of Nono impairs the response to DNA damage induced by the topoisomerase II inhibitor etoposide or the radiomimetic drug bleomycin. Nono-deficient KP (KPN) cells display hyperactivation of DSB signalling and high levels of DSBs. The defects in the DDR are accompanied by reduced RNA polymerase II promoter occupancy, impaired nascent RNA synthesis, and attenuated induction of the DDR factor growth arrest and DNA damage-inducible beta (Gadd45b). Our data characterise Gadd45b as a putative Nono-dependent effector of the DDR and suggest that Nono mediates a genome-protective crosstalk of the DDR with the RNA metabolism via induction of Gadd45b.
Topics: Animals; DNA Repair; Mice; RNA-Binding Proteins; DNA Damage; DNA Breaks, Double-Stranded; Antigens, Differentiation; Bleomycin; DNA-Binding Proteins; Etoposide; Signal Transduction; Lung Neoplasms; Tumor Suppressor Protein p53; Cell Line, Tumor; RNA Polymerase II; Humans; GADD45 Proteins
PubMed: 38843934
DOI: 10.26508/lsa.202302555 -
International Journal of Molecular... May 2024Triple-negative breast cancer (TNBC) remains the most lethal subtype of breast cancer, characterized by poor response rates to current chemotherapies and a lack of...
Triple-negative breast cancer (TNBC) remains the most lethal subtype of breast cancer, characterized by poor response rates to current chemotherapies and a lack of additional effective treatment options. While approximately 30% of patients respond well to anthracycline- and taxane-based standard-of-care chemotherapy regimens, the majority of patients experience limited improvements in clinical outcomes, highlighting the critical need for strategies to enhance the effectiveness of anthracycline/taxane-based chemotherapy in TNBC. In this study, we report on the potential of a DNA-PK inhibitor, peposertib, to improve the effectiveness of topoisomerase II (TOPO II) inhibitors, particularly anthracyclines, in TNBC. Our in vitro studies demonstrate the synergistic antiproliferative activity of peposertib in combination with doxorubicin, epirubicin and etoposide in multiple TNBC cell lines. Downstream analysis revealed the induction of ATM-dependent compensatory signaling and p53 pathway activation under combination treatment. These in vitro findings were substantiated by pronounced anti-tumor effects observed in mice bearing subcutaneously implanted tumors. We established a well-tolerated preclinical treatment regimen combining peposertib with pegylated liposomal doxorubicin (PLD) and demonstrated strong anti-tumor efficacy in cell-line-derived and patient-derived TNBC xenograft models in vivo. Taken together, our findings provide evidence that co-treatment with peposertib has the potential to enhance the efficacy of anthracycline/TOPO II-based chemotherapies, and it provides a promising strategy to improve treatment outcomes for TNBC patients.
Topics: Triple Negative Breast Neoplasms; Humans; Animals; Female; Mice; Topoisomerase II Inhibitors; Cell Line, Tumor; Xenograft Model Antitumor Assays; Doxorubicin; Drug Synergism; DNA-Activated Protein Kinase; Sulfones; Cell Proliferation; Antineoplastic Combined Chemotherapy Protocols; Polyethylene Glycols; Etoposide; DNA Topoisomerases, Type II; Epirubicin
PubMed: 38791158
DOI: 10.3390/ijms25105120