RESUMEN

Metastasis contributes to the increased mortality rate of cancer, but the intricate mechanisms remain unclear. Cancer cells from a primary tumor invade nearby tissues and access the lymphatic or circulatory system. If these cells manage to survive and extravasate from the vasculature into distant tissues and ultimately adapt to survive, they will proliferate and facilitate malignant tumor formation. Traditional two-dimensional (2D) cell cultures offer a rapid and convenient method for validating the efficacy of anticancer drugs within a reasonable cost range, but their utility is limited because of tumors' high heterogeneity in vivo and spatial complexities. Three-dimensional (3D) cell cultures that mimic the physiological conditions of cancer cells in vivo have gained considerable interest. In these cultures, cells assemble into spheroids through gravity, magnetic forces, or their low-adhesion to the plates. Although these approaches address some of the limitations of 2D cultures, they often require a considerable amount of time and cost. Therefore, this study aims to enhance the effectiveness of 3D culture techniques by using microfluidic systems to provide a high-throughput and sensitive pipeline for drug screening. Using these systems, we studied the effects of lanthanide elements, which have garnered interest in cancer treatment, on spheroid formation and cell spreading. Our findings suggest that these elements alter the compactness of cell spheroids and decrease cell mobility.

Asunto(s)

Elementos de la Serie de los Lantanoides , Esferoides Celulares , Esferoides Celulares/efectos de los fármacos , Humanos , Elementos de la Serie de los Lantanoides/toxicidad , Elementos de la Serie de los Lantanoides/farmacología , Técnicas de Cultivo de Célula/métodos , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Técnicas Analíticas Microfluídicas/instrumentación , Técnicas Analíticas Microfluídicas/métodos , Supervivencia Celular/efectos de los fármacos , Técnicas de Cultivo Tridimensional de Células/métodos , Ensayos de Selección de Medicamentos Antitumorales/métodos

RESUMEN

Cisplatin is a common anticancer drug, but its frequent nephrotoxicity limits its clinical use. Small GTP-binding protein GDP dissociation stimulator (smgGDS), a small GTPase chaperone protein, was considerably downregulated during cisplatin-induced acute kidney injury (CDDP-AKI), especially in renal tubular epithelial cells. SmgGDS-knockdown mice was established and found that smgGDS knockdown promoted CDDP-AKI, as demonstrated by an increase in serum creatine, blood urea nitrogen levels and the appearance of tubular patterns. RNA sequencing suggested that protein kinase RNA-like ER kinase (PERK), which bridges mitochondria-associated ER membranes, was involved in smgGDS knockdown following CDDP-AKI, and then identified that smgGDS knockdown increased phosphorylated-PERK in vivo and in vitro. Furthermore, we confirmed that smgGDS deficiency aggravated apoptosis and ER stress in vivo and in vitro. And the ER stress inhibitor 4-Phenylbutyric acid and the inhibition of PERK phosphorylation mitigated smgGDS deficiency-induced ER stress related apoptosis following cisplatin treatment, while the eIF2α phosphorylation inhibitor could not reverse the smgGDS deficiency accelerated cell death. Furthermore, the over-expression of smgGDS could reverse the ER stress and apoptosis caused by CDDP. Overall, smgGDS regulated PERK-dependent ER stress and apoptosis, thereby influencing renal damage. This study identified a target for diagnosing and treating cisplatin-induced acute kidney injury.

Asunto(s)

Lesión Renal Aguda , Cisplatino , Estrés del Retículo Endoplásmico , eIF-2 Quinasa , Cisplatino/efectos adversos , Cisplatino/toxicidad , Animales , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Lesión Renal Aguda/patología , Lesión Renal Aguda/genética , eIF-2 Quinasa/metabolismo , eIF-2 Quinasa/genética , Estrés del Retículo Endoplásmico/efectos de los fármacos , Ratones , Masculino , Apoptosis/efectos de los fármacos , Ratones Endogámicos C57BL , Antineoplásicos/efectos adversos , Antineoplásicos/toxicidad , Fosforilación

RESUMEN

This study aimed to investigate the effects and possible mechanisms of adenylate cyclase 1 (ADCY1) on pirarubicin-induced cardiomyocyte injury. HL-1 cells were treated with pirarubicin (THP) to induce intracellular toxicity, and the extent of damage to mouse cardiomyocytes was assessed using CCK-8, Edu, flow cytometry, ROS, ELISA, RT-qPCR and western blotting. THP treatment reduced the viability of HL-1 cells, inhibited proliferation, induced apoptosis and triggered oxidative stress. In addition, the RT-qPCR results revealed that ADCY1 expression was significantly elevated in HL-1 cells, and molecular docking showed a direct interaction between ADCY1 and THP. Western blotting showed that ADCY1, phospho-protein kinase A and GRIN2D expression were also significantly elevated. Knockdown of ADCY1 attenuated THP-induced cardiotoxicity, possibly by regulating the ADCY1/PKA/GRIN2D pathway.

Asunto(s)

Adenilil Ciclasas , Cardiotoxicidad , Doxorrubicina , Técnicas de Silenciamiento del Gen , Miocitos Cardíacos , Adenilil Ciclasas/metabolismo , Adenilil Ciclasas/genética , Animales , Ratones , Cardiotoxicidad/genética , Doxorrubicina/toxicidad , Doxorrubicina/farmacología , Doxorrubicina/análogos & derivados , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismo , Línea Celular , Apoptosis/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Simulación del Acoplamiento Molecular , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/toxicidad

RESUMEN

BACKGROUND: Peripheral neuropathy (PN) constitutes a dose-limiting side effect of oxaliplatin chemotherapy that often compromises the efficacy of antineoplastic treatments. Sensory neurons damage in dorsal root ganglia (DRG) are the cellular substrate of PN complex molecular origin. Dehydropeptidase-1 (DPEP1) inhibitors have shown to avoid platin-induced nephrotoxicity without compromising its anticancer efficiency. The objective of this study was to describe DPEP1 expression in rat DRG in health and in early stages of oxaliplatin toxicity. To this end, we produced and characterized anti-DPEP1 polyclonal antibodies and used them to define the expression, and cellular and subcellular localization of DPEP1 by immunohistochemical confocal microscopy studies in healthy controls and short term (six days) oxaliplatin treated rats. RESULTS: DPEP1 is expressed mostly in neurons and in glia, and to a lesser extent in endothelial cells. Rats undergoing oxaliplatin treatment developed allodynia. TNF-𝛼 expression in DRG revealed a pattern of focal and at different intensity levels of neural cell inflammatory damage, accompanied by slight variations in DPEP1 expression in endothelial cells and in nuclei of neurons. CONCLUSIONS: DPEP1 is expressed in neurons, glia and endothelial cells of DRG. Oxaliplatin caused allodynia in rats and increased TNF-α expression in DRG neurons. The expression of DPEP1 in neurons and other cells of DRG suggest this protein as a novel strategic molecular target in the prevention of oxaliplatin-induced acute neurotoxicity.

Asunto(s)

Antineoplásicos , Ganglios Espinales , Oxaliplatino , Enfermedades del Sistema Nervioso Periférico , Animales , Oxaliplatino/toxicidad , Ganglios Espinales/metabolismo , Ganglios Espinales/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Enfermedades del Sistema Nervioso Periférico/metabolismo , Enfermedades del Sistema Nervioso Periférico/prevención & control , Enfermedades del Sistema Nervioso Periférico/patología , Masculino , Antineoplásicos/toxicidad , Ratas , Hiperalgesia/inducido químicamente , Hiperalgesia/metabolismo , Hiperalgesia/prevención & control , Factor de Necrosis Tumoral alfa/metabolismo , Neuroglía/efectos de los fármacos , Neuroglía/metabolismo , Ratas Sprague-Dawley , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Inflamación/metabolismo , Inflamación/inducido químicamente

RESUMEN

Neurotoxicity is characterized by the accumulation of harmful chemicals such as heavy metals and drugs in neural tissue, resulting in subsequent neuronal death. Among chemicals platinum-based cancer drugs are frequently used due to their antineoplastic effects, but this drug is also known to cause a wide range of toxicities, such as neurotoxicity. The nuclear-factor-erythroid 2-related factor-2 (NRF2) is crucial in combating oxidative stress and maintaining cellular homeostasis. This study thoroughly explores the protective effects of extracellular vesicles derived from NRF2 gene overexpressed neural progenitor cells (NEVs) on cisplatin-induced neurotoxicity. Therefore, extracellular vesicles derived from neural progenitor cells were isolated and characterized. The Cisplatin neurotoxicity dose was 75 µM in mature, post-mitotic neurons. 1.25 µM of tert-butyl hydroquinone that induces NRF2/ARE pathway was used as the positive control. The effects of extracellular vesicles (EVs) were investigated using functional and molecular assays such as PCR and protein-based assays. Here, we observed that NEVs dose-dependently protected post-mitotic neuron cells in response to cisplatin. The study also examined whether the effect was EV-induced by limiting EV biogenesis. The molecular basis of preventive treatment was established. When pre-administered, 1×108 particles/ml of NEVs maintained antioxidant and detoxifying gene and protein expression levels similar to control cell levels. Furthermore, NEVs reduced both cellular and mitochondrial ROS levels and preserved mitochondrial membrane potential. In addition, Catalase and SOD levels were found higher in NEV-treated cells compared to cisplatin control. The findings in NRF2-based protection of cisplatin-induced neurotoxicity may provide further evidence for the relationship between EVs and inhibition of neuronal stress through the NRF2/ARE pathway, increasing the understanding of neuroprotective responses and the development of gene-engineered EV therapy options for peripheral neuropathy or other neurodegenerative diseases. This is the first study in the literature to investigate the neutralizing potency of NRF2 overexpressed neural EVs against cisplatin-induced neurotoxicity.

Asunto(s)

Antineoplásicos , Cisplatino , Vesículas Extracelulares , Factor 2 Relacionado con NF-E2 , Células-Madre Neurales , Transducción de Señal , Cisplatino/toxicidad , Factor 2 Relacionado con NF-E2/metabolismo , Vesículas Extracelulares/efectos de los fármacos , Vesículas Extracelulares/metabolismo , Animales , Antineoplásicos/toxicidad , Antineoplásicos/farmacología , Células-Madre Neurales/efectos de los fármacos , Células-Madre Neurales/metabolismo , Transducción de Señal/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Síndromes de Neurotoxicidad/prevención & control , Síndromes de Neurotoxicidad/metabolismo , Síndromes de Neurotoxicidad/etiología , Elementos de Respuesta Antioxidante/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Células Cultivadas

RESUMEN

Nephrotoxicity, including electrolytic disorders and acute kidney injury (AKI), limits the clinical dosage and utility of platinated antineoplastics such as cisplatin. Cisplatin nephrotoxicity embodies a tubulopathy involving the medullary S2 and S3 segments of the proximal and the distal tubules. Higher dosage extends damage over the cortical S1 segment and intensifies overall injury. However, the standard diagnosis based on plasma creatinine as well as novel injury biomarkers lacks enough pathophysiological specificity. Further granularity in the detection of renal injury would help understand the implications of individual damage patterns needed for personalized patient handling. In this article, we studied the association of urinary ganglioside GM2 activator protein (GM2AP) with the patterns of tubular damage produced by 5 and 10 mg/kg cisplatin in rats. Our results show that GM2AP appears in the urine only following damage to the cortical segment of the proximal tubule. The information provided by GM2AP is not redundant with but distinct and complementary to that provided by urinary neutrophil gelatinase-associated lipocalin (NGAL). Similarly, treatment with 150 mg/kg/day gentamicin damages the renal cortex and increases GM2AP urinary excretion; whereas renal ischemia, which does not affect the cortex, has no effect on GM2AP. Because of the key role of the cortical proximal tubule in renal function, we contend GM2AP as a potential diagnostic biomarker to stratify AKI patients according to the underlying damage and follow their evolution and prognosis. Prospectively, urinary GM2AP may help grade the severity of platinated antineoplastic nephrotoxicity by forming part of a non-invasive liquid biopsy.

Asunto(s)

Lesión Renal Aguda , Antineoplásicos , Biomarcadores , Cisplatino , Proteína Activadora de G (M2) , Corteza Renal , Cisplatino/toxicidad , Animales , Masculino , Ratas , Biomarcadores/orina , Antineoplásicos/toxicidad , Corteza Renal/efectos de los fármacos , Corteza Renal/patología , Corteza Renal/metabolismo , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/patología , Lesión Renal Aguda/orina , Gentamicinas/toxicidad , Ratas Sprague-Dawley , Lipocalina 2/orina , Índice de Severidad de la Enfermedad

RESUMEN

The irreversible pan-HER tyrosine kinase inhibitor neratinib is approved for patients with HER2-positive, early-stage and metastatic breast cancer (BC). Neratinib-associated diarrhea is the most common reason for early discontinuation. Preclinical studies identified mechanisms of neratinib-induced diarrhea and rationale for prophylactic and preventive measures. We studied effects of neratinib on rat intestines and conducted a phase 2 study of colon pathogenesis in patients with HER2-positive BC treated with neratinib (NCT04366713). Colon samples from female albino Wistar rats receiving neratinib or vehicle were examined for histopathological changes. Patients with HER2-positive BC received neratinib 240 mg once daily for up to 1 year. Colonoscopy biopsies were collected at baseline and at Day 28 to identify changes consistent with rat pathologies. Rat colons were markedly altered in appearance, with similar short circuit currents (Isc) and responses to carbachol and forskolin. Mucosal barrier loss and/or significant increase in secretory propensity in neratinib- versus control-treated animals were not seen. Two of four endpoint-evaluable patients presented with mild pathological changes, largely comparable with the rat model. Preclinical evidence supports an inflammatory component of neratinib-induced diarrhea without mucosal barrier function loss. Colonoscopy findings in patients with BC indicate mild or no pathological changes in the colon due to neratinib treatment.

Asunto(s)

Neoplasias de la Mama , Colonoscopía , Diarrea , Quinolinas , Ratas Wistar , Receptor ErbB-2 , Animales , Femenino , Diarrea/inducido químicamente , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Quinolinas/farmacología , Quinolinas/uso terapéutico , Ratas , Proyectos Piloto , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Humanos , Persona de Mediana Edad , Colon/patología , Colon/efectos de los fármacos , Colon/metabolismo , Anciano , Antineoplásicos/efectos adversos , Antineoplásicos/toxicidad

RESUMEN

BACKGROUND: Bufonis Venenum (BV) is a traditional animal-based Chinese medicine with therapeutic effects against cancer. However, its clinical use is significantly restricted due to associated cardiovascular risks. BV's value in China's market is typically assessed based on "content priority," focusing on indicator components. However, these components of BV possess both antitumor activity and toxicity, and the correlation between the antitumor activity and toxicity of BV has not yet been elucidated. PURPOSE: This study employs an integrated multi-omics approach to identify bufadienolide Q-markers and explore the correlation between BV's antitumor activity and toxicity. The aim is to establish a more comprehensive method for BV's quality. METHODS: Normal zebrafish and HepG2 xenograft zebrafish were chosen as activity and toxicity evaluation models. Ultra-high performance liquid chromatography (UHPLC) coupled with a linear ion trap orbitrap (LTQ-Orbitrap) mass spectrometry was used to quantify eight batches of BV and key "toxic and effective" components were screened out. Transcriptomic and metabolomic analyses were performed to elucidate the regulatory mechanisms underlying the antitumor activity and cardiovascular toxicity of the key components in BV. RESULTS: Eight key "toxic and effective" compounds were identified: resibufogenin, cinobufagin, arenobufagin, bufotalin, bufalin, gamabufotalin, desacetylcinobufagin, and telocinobufagin. The findings showed that bufalin and cinobufagin interfered with calcium homeostasis through CaV and CaSR, induced cardiotoxicity, and upregulated CASP9 to activate myocardial cell apoptosis. However, desacetylcinobufagin exhibited greater potential in terms of anti-tumor effects. Combining the results of untargeted and targeted metabolomics revealed that desacetylcinobufagin could have a callback effect on differential lipids and correct abnormal energy and amino acid metabolism caused by cancer, similar to cinobufagin and bufalin. Microscale thermophoresis (MST) ligand binding measurements also showed that the binding of desacetylcinobufagin to GPX4 has a more potent ability to induce ferroptosis in tumor cells compared to cinobufagin. CONCLUSION: An innovative evaluation method based on the zebrafish was developed to investigate the relationship between the toxicity and efficacy of BV. This study identified toxicity and activity Q-markers and explored the mechanism between the two effects of BV. The research data could offer valuable insights into the efficacy of BV. Additionally, desacetylcinobufagin, an active ingredient with low toxicity, was found to enhance the quality of BV.

Asunto(s)

Bufanólidos , Pez Cebra , Animales , Bufanólidos/farmacología , Bufanólidos/toxicidad , Humanos , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Células Hep G2 , Cromatografía Líquida de Alta Presión/métodos , Cardiotoxicidad , Biomarcadores/metabolismo , Metabolómica , Venenos de Anfibios/farmacología , Venenos de Anfibios/química , Multiómica

RESUMEN

OBJECTIVE: To systematically identify early biomarkers of cisplatin-induced acute kidney injury (AKI) in rats. STUDY DESIGN: An experimental study. Place and Duration of the Study: Experimental Animal Laboratory of Lanzhou University, Gansu, China, and the Department of Pharmacy, The First Hospital of Lanzhou University, Gansu, China, from July 2022 to October 2023. METHODOLOGY: In this study, an AKI model was established by continuously injecting cisplatin into rats at a dose of 1 mg/kg once a day for control group and for 2, 3, 4, and 5 days to other four groups, respectively. Subsequently, rat plasma samples were collected for metabolomics analysis to identify early differentiated metabolites in the plasma prior to creatinine elevation. Furthermore, accurate HPLC-MS/MS methods were developed to validate the biomarker variation in other AKI models. RESULTS: The occurrence of time-dependent renal cortical injury and significant alterations of creatinine (Cr) concentration were observed on day-4 and 5, which demonstrated successful model construction. Sixty-six compounds changed on Day-2 while 61 compounds changed on Day-3. Eleven compounds with variable importance in projection (VIP) >1.5 and false discover rate (FDR) <0.2 were selected and identified by HPLC-MS/MS. Among these, N-acetylglutamine and citramalic acid changed earlier than serum creatinine (sCr) in the AKI model. CONCLUSION: N-acetylglutamine and citramalic acid may serve as early biomarker of cisplatin-induced AKI. KEY WORDS: Acute kidney injury, Biomarker, Cisplatin, Metabolomics, LC-MS/MS, Rats.

Asunto(s)

Lesión Renal Aguda , Biomarcadores , Cisplatino , Metabolómica , Animales , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/sangre , Ratas , Biomarcadores/sangre , Metabolómica/métodos , Masculino , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Antineoplásicos/efectos adversos , Antineoplásicos/toxicidad , Espectrometría de Masas en Tándem , Cromatografía Líquida de Alta Presión , Creatinina/sangre

RESUMEN

Cisplatin-induced nephrotoxicity restricts its clinical use against solid tumors. The present study elucidated the pharmacological effects of Renogrit, a plant-derived prescription medicine, using cisplatin-induced human renal proximal tubular (HK-2) cells and Caenorhabditis elegans. Quantification of phytochemicals in Renogrit was performed on HPTLC and UHPLC platforms. Renogrit was assessed in vitro in HK-2 cells post-exposure to clinically relevant concentration of cisplatin. It was observed that renoprotective properties of Renogrit against cisplatin-induced injury stem from its ability to regulate renal injury markers (KIM-1, NAG levels; NGAL mRNA expression), redox imbalance (ROS generation; GST levels), and mitochondrial dysfunction (mitochondrial membrane potential; SKN-1, HSP-60 expression). Renogrit was also found to modulate apoptosis (EGL-1 mRNA expression; protein levels of p-ERK, p-JNK, p-p38, c-PARP1), necroptosis (intracellular calcium accumulation; RIPK1, RIPK3, MLKL mRNA expression), mitophagy (lysosome population; mRNA expression of PINK1, PDR1; protein levels of p-PINK1, LC3B), and inflammation (IL-1ß activity; protein levels of LXR-α). More importantly, Renogrit treatment did not hamper normal anti-proliferative effects of cisplatin as observed from cytotoxicity analysis on MCF-7, A549, SiHa, and T24 human cancer cells. Taken together, Renogrit could be a potential clinical candidate to mitigate cisplatin-induced nephrotoxicity without compromising the anti-neoplastic properties of cisplatin.

Asunto(s)

Apoptosis , Caenorhabditis elegans , Cisplatino , Mitofagia , Cisplatino/efectos adversos , Cisplatino/toxicidad , Animales , Humanos , Mitofagia/efectos de los fármacos , Caenorhabditis elegans/efectos de los fármacos , Caenorhabditis elegans/metabolismo , Apoptosis/efectos de los fármacos , Línea Celular , Extractos Vegetales/farmacología , Túbulos Renales/efectos de los fármacos , Túbulos Renales/metabolismo , Túbulos Renales/patología , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Antineoplásicos/efectos adversos , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología

RESUMEN

A systematic review of the literature found fifteen articles on the effect of a botulinum toxin on neoplastic cell lines and eight articles on in vivo neoplasms. The reported in vitro effects rely on high doses or the mechanical disruption of cell membranes to introduce the botulinum neurotoxin into the cell cytoplasm. The potency of the botulinum neurotoxin to intoxicate non-neuronal cells (even cell lines expressing an appropriate protein receptor) is several orders of magnitude lower compared to that to intoxicate the primary neurons. The data suggest that the botulinum toxin disrupts the progression of cancer cells, with some studies reporting apoptotic effects. A majority of the data in the in vivo studies also showed similar results. No safety issues were disclosed in the in vivo studies. Limited studies have suggested similar anti-neoplastic potential for the clostridium difficile. New modes of delivery have been tested to enhance the in vivo delivery of the botulinum toxin to neoplastic cells. Careful controlled studies are necessary to demonstrate the efficacy and safety of this mode of anti-neoplastic treatment in humans.

Asunto(s)

Toxinas Botulínicas , Neoplasias , Animales , Humanos , Antineoplásicos/uso terapéutico , Antineoplásicos/toxicidad , Toxinas Botulínicas/uso terapéutico , Toxinas Botulínicas/toxicidad , Línea Celular Tumoral , Neoplasias/tratamiento farmacológico

RESUMEN

Chemotherapy-induced premature ovarian insufficiency (CIPOI) triggers gonadotoxicity in women undergoing cancer treatment, leading to loss of ovarian reserves and subfertility, with no effective therapies available. In our study, fecal microbiota transplantation in a cisplatin-induced POI mouse model reveals that a dysbiotic gut microbiome negatively impacts ovarian health in CIPOI. Multi-omics analyses show a significant decrease in Limosilactobacillus reuteri and its catabolite, ß-resorcylic acid , in the CIPOI group in comparison to healthy controls. Supplementation with L. reuteri or ß-RA mitigates cisplatin-induced hormonal disruptions, morphological damages, and reductions in follicular reserve. Most importantly, ß-RA pre-treatment effectively preserves oocyte function, embryonic development, and fetus health, thereby protecting against chemotherapy-induced subfertility. Our results provide evidence that ß-RA suppresses the nuclear accumulation of sex-determining region Y-box 7, which in turn reduces Bcl-2-associated X activation and inhibits granulosa cell apoptosis. These findings highlight the therapeutic potential of targeting the gut-ovary axis for fertility preservation in CIPOI.

Asunto(s)

Cisplatino , Limosilactobacillus reuteri , Ovario , Insuficiencia Ovárica Primaria , Femenino , Animales , Cisplatino/efectos adversos , Cisplatino/toxicidad , Ratones , Insuficiencia Ovárica Primaria/inducido químicamente , Insuficiencia Ovárica Primaria/patología , Ovario/efectos de los fármacos , Ovario/patología , Ovario/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Apoptosis/efectos de los fármacos , Trasplante de Microbiota Fecal , Oocitos/efectos de los fármacos , Oocitos/metabolismo , Ratones Endogámicos C57BL , Antineoplásicos/toxicidad , Antineoplásicos/efectos adversos , Células de la Granulosa/efectos de los fármacos , Células de la Granulosa/metabolismo , Modelos Animales de Enfermedad , Infertilidad

RESUMEN

HYPOTHESIS: Memantine, an N -methyl- d -aspartate receptor antagonist, is widely used to treat Alzheimer's disease and has been found to have potential neuroprotective effects. In this study, we evaluated the protective effects of memantine against cisplatin-induced ototoxicity. BACKGROUND: Cisplatin is a widely used anticancer drug for various cancers; however, its use is limited by its side effects, including ototoxicity. Several drugs have been developed to reduce cisplatin toxicity. In this study, we treated cisplatin-damaged cochlear hair cells with memantine and evaluated its protective effects. METHOD: House Ear Institute Organ of Corti 1 (HEI-OC1) cells and cochlear explants were treated with cisplatin or memantine. Cell viability, apoptotic patterns, reactive oxygen species (ROS) production, Bcl-2/caspase-3 activity, and cell numbers were measured to evaluate the anti-apoptotic and antioxidative effects of memantine. RESULT: Memantine treatment significantly improved cell viability and reduced cisplatin-induced apoptosis in auditory cells. Bcl-2/caspase-3 activity was also significantly increased, suggesting anti-apoptotic effects against cisplatin-induced ototoxicity. CONCLUSION: Our results suggest that memantine protects against cisplatin-induced ototoxicity in vitro, providing a potential new strategy for preventing hearing loss in patients undergoing cisplatin chemotherapy.

Asunto(s)

Antineoplásicos , Apoptosis , Supervivencia Celular , Cisplatino , Memantina , Ototoxicidad , Especies Reactivas de Oxígeno , Memantina/farmacología , Cisplatino/toxicidad , Cisplatino/efectos adversos , Animales , Ototoxicidad/prevención & control , Apoptosis/efectos de los fármacos , Antineoplásicos/toxicidad , Antineoplásicos/efectos adversos , Supervivencia Celular/efectos de los fármacos , Ratones , Especies Reactivas de Oxígeno/metabolismo , Células Ciliadas Auditivas/efectos de los fármacos , Células Ciliadas Auditivas/patología , Caspasa 3/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Fármacos Neuroprotectores/farmacología , Órgano Espiral/efectos de los fármacos , Órgano Espiral/patología , Cóclea/efectos de los fármacos , Cóclea/patología , Antagonistas de Aminoácidos Excitadores/farmacología , Línea Celular

RESUMEN

Cisplatin (CDDP) often leads to kidney impairment, limiting its effectiveness in cancer treatment. The lack of mitophagy in proximal tubules exacerbates this issue. Hence, targeting SIRT-3 and PGC1-α shows promise in mitigating CDDP-induced kidney damage. The potential renoprotective effects of linagliptin, however, remain poorly understood. This study represents the first exploration of linagliptin's impact on CDDP-induced kidney impairment in rats, emphasizing its potential role in mitophagic pathways. The experiment involved four rat groups: Group (I) received saline only, Group (II) received a single intraperitoneal injection of CDDP at 6 mg/kg. Groups (III) and (IV) received linagliptin at 6 and 10 mg/kg p.o., respectively, seven days before CDDP administration, continuing for an additional four days. Various parameters, including renal function tests, oxidative stress, TNF-α, IL-1ß, IL-6, PGC-1α, FOXO-3a, p-ERK1, and the gene expression of SIRT-3 and P62 in renal tissue, were assessed. Linagliptin improved renal function, increased antioxidant enzyme activity, and decreased IL-1ß, TNF-α, and IL-6 expression. Additionally, linagliptin significantly upregulated PGC-1α and PINK-1/Parkin-2 expression while downregulating P62 expression. Moreover, linagliptin activated FOXO-3a and SIRT-3, suggesting a potential enhancement of mitophagy. Linagliptin demonstrated a positive impact on various factors related to kidney health in the context of CDDP-induced impairment. These findings suggest a potential role for linagliptin in improving cancer treatment outcomes. Clinical trials are warranted to further investigate and validate its efficacy in a clinical setting.

Asunto(s)

Cisplatino , Linagliptina , Mitofagia , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Ubiquitina-Proteína Ligasas , Animales , Linagliptina/farmacología , Cisplatino/toxicidad , Mitofagia/efectos de los fármacos , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Masculino , Ratas , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Sirtuina 3/metabolismo , Sirtuina 3/genética , Proteínas Quinasas/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/patología , Ratas Wistar , Antineoplásicos/toxicidad , Estrés Oxidativo/efectos de los fármacos , Enfermedades Renales/inducido químicamente , Enfermedades Renales/prevención & control , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Sirtuinas

RESUMEN

Cisplatin is a chemotherapeutic agent widely used to treat solid tumors. However, it can also be highly ototoxic, resulting in high-frequency hearing loss. Cisplatin causes degeneration of hair cells (HCs) and spiral ganglion neurons (SGNs) in the inner ear, which are essential components of the hearing process and cannot be regenerated in mammals. As the affected cells primarily die by apoptosis, we tested several anti-apoptotic small molecules to protect these cells from drug-induced toxicity. We found that the general caspase inhibitor Emricasan could significantly counteract the toxic effects of cisplatin in House Ear Institute-Organ of Corti 1 (HEI-OC1) cells, phoenix auditory cells, and primary SGNs. Importantly, the anti-cytotoxic effect in neuronal cells was even more pronounced than the effect of sodium thiosulfate (STS), which is currently the only approved prevention option for cisplatin-induced ototoxicity. Finally, we tested the protective effect of Emricasan treatment in the context of another ototoxic drug, i.e., the aminoglycoside antibiotic neomycin, and again found a significant increase in cell viability when the cultures were co-treated with Emricasan. These results suggest a promising strategy to prevent ototoxicity in patients by temporarily blocking the apoptotic pathway when applying cisplatin or aminoglycoside antibiotics. KEY MESSAGES: Anti-apoptotic small molecules can reduce cisplatin-induced toxicity. Emricasan can effectively exert its anti-apoptotic effect on cochlear cells. Strong protection from cisplatin- and neomycin-induced cytotoxicity with Emricasan. Sodium thiosulfate and Emricasan provide similar protective effects to cisplatin-treated cells. Emricasan is more potent than sodium thiosulfate in reducing neomycin-induced cytotoxicity.

Asunto(s)

Inhibidores de Caspasas , Cisplatino , Neomicina , Cisplatino/efectos adversos , Cisplatino/toxicidad , Cisplatino/farmacología , Animales , Neomicina/farmacología , Neomicina/toxicidad , Inhibidores de Caspasas/farmacología , Ratones , Apoptosis/efectos de los fármacos , Cóclea/efectos de los fármacos , Cóclea/citología , Supervivencia Celular/efectos de los fármacos , Células Ciliadas Auditivas/efectos de los fármacos , Ganglio Espiral de la Cóclea/efectos de los fármacos , Ototoxicidad/etiología , Ototoxicidad/prevención & control , Antineoplásicos/farmacología , Antineoplásicos/toxicidad , Línea Celular , Células Cultivadas

RESUMEN

Acute kidney injury (AKI) is a worldwide public health problem with high morbidity and mortality. Cisplatin is a widely used chemotherapeutic agent for treating solid tumors, but the induction of AKI restricts its clinical application. In this study, the effect of cisplatin on the expression of organic ion transporters was investigated through in vivo and in vitro experiments. Targeted metabolomics techniques were used to measure the levels of selected endogenous substances in serum. Transmission electron microscopy was used to observe the microstructure of renal tubular epithelial cells. Our results show that the toxicity of cisplatin on HK-2 cells or HEK-293 cells was time- and dose-dependent. Administration of cisplatin decreased the expression of OAT1/3 and OCT2 and increased the expression of MRP2/4. Mitochondrial damage induced by cisplatin lead to renal tubular epithelial cell injury. In addition, administration of cisplatin resulted in significant changes in endogenous substance levels in serum, including amino acids, carnitine, and fatty acids. These serum amino acids and metabolites (α-aminobutyric acid, proline, and alanine), carnitines (tradecanoylcarnitine, hexanylcarnitine, octanoylcarnitine, 2-methylbutyroylcarnitine, palmitoylcarnitine, and linoleylcarnitine) and fatty acids (9E-tetradecenoic acid) represent endogenous substances with diagnostic potential for cisplatin-induced AKI.

Asunto(s)

Lesión Renal Aguda , Cisplatino , Cisplatino/toxicidad , Humanos , Animales , Células HEK293 , Masculino , Lesión Renal Aguda/inducido químicamente , Lesión Renal Aguda/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Antineoplásicos/toxicidad , Transportadores de Anión Orgánico/metabolismo , Transportadores de Anión Orgánico/genética , Transportador 2 de Cátion Orgánico/metabolismo , Transportador 2 de Cátion Orgánico/genética , Proteínas de Transporte de Catión Orgánico/metabolismo , Proteínas de Transporte de Catión Orgánico/genética , Carnitina/análogos & derivados , Carnitina/farmacología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo

RESUMEN

Prenatal exposure to toxins can adversely affect long-term health outcomes of the offspring. Though chemotherapeutics are now standard of care for treating cancer patients during pregnancy, certain compounds are known to cross the placenta and harm placental tissue. The consequences for the fetus are largely unexplored. Here we examined the responses of newborn cord blood mononuclear cells in tissue culture to two chemotherapeutic drugs, cyclophosphamide and epirubicin, when either directly exposed to these drugs, or indirectly after crossing a placenta trophoblast bilayer barrier. Cord blood mononuclear cells exposed to the conditioned media obtained from cyclophosphamide-exposed trophoblast barriers showed a significant 2.4-fold increase of nuclear ROS levels compared to direct exposure to cyclophosphamide. Indirect exposure to epirubicine-exposed trophoblast barriers not only enhanced nuclear ROS levels but also significantly increased the fraction of cord blood cells with double strand breaks, relative to directly exposed cells. Neither apoptosis nor proliferation markers were affected in cord mononuclear blood cells upon direct or indirect exposure to cyclophosphamide or epirubicin. Our data suggests that trophoblast cells exposed to cyclophosphamide or epirubicine may induce an indirect 'bystander' effect and can aggravate genotoxicity in the fetal compartment.

Asunto(s)

Ciclofosfamida , Epirrubicina , Sangre Fetal , Placenta , Humanos , Sangre Fetal/citología , Sangre Fetal/metabolismo , Femenino , Embarazo , Ciclofosfamida/toxicidad , Ciclofosfamida/efectos adversos , Epirrubicina/efectos adversos , Placenta/efectos de los fármacos , Placenta/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Trofoblastos/efectos de los fármacos , Trofoblastos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Daño del ADN/efectos de los fármacos , Apoptosis/efectos de los fármacos , Recién Nacido , Antineoplásicos/toxicidad , Antineoplásicos/farmacología , Antineoplásicos/efectos adversos , Células Cultivadas

RESUMEN

Different organs respond differently to cisplatin (CDDP)-induced toxicity. Oleuropein (OLE) is a natural phenolic antioxidant. The purpose of this study was to determine the potential protective effect of OLE against CDDP-induced ototoxicity by evaluating expression of genes associated with deoxyribonucleic acid (DNA) damage and repair in cochlear cells. House Ear Institute-Organ of Corti 1 (HEI-OC1) cells were treated using CDDP, OLE, and OLE-CDDP. The water-soluble tetrazolium salt assay was used for monitoring cell viability. Deoxyribonucleic acid damage in cells due to the CDDP, OLE, and combination treatments was determined using a flow-cytometric kit. The change in the expression of 84 genes associated with CCDP, OLE, and OLE-CDDP treatments that induced DNA damage was tested using the reverse transcription polymerase chain reaction array. Changes ≥3-fold were considered significant. House Ear Institute-Organ of Corti 1 cell viability was significantly reduced by CDDP. The OLE-CDDP combination restored the cell viability. Cisplatin increased the H2AX ratio, while OLE-CDDP combination decreased it. Some of the DNA damage-associated genes whose expression was upregulated with CDDP were downregulated with OLE-CDDP, while the expression of genes such as Gadd45g and Rev1 was further downregulated. The expression of DNA repair-related Abl1, Dbd2, Rad52, and Trp53 genes was downregulated with CDDP, whereas their expression was upregulated with OLE-CDDP treatment. In cochlear cells, the OLE-CDDP combination downregulated DNA damage-associated gene expression relative to that upregulated mainly by CDDP. The results revealed that OLE has a potential protective effect on CDDP-induced ototoxicity in cochlear cells by altering the expression of DNA damage-related genes.

Asunto(s)

Supervivencia Celular , Cisplatino , Cóclea , Daño del ADN , Glucósidos Iridoides , Ototoxicidad , Cisplatino/toxicidad , Glucósidos Iridoides/farmacología , Daño del ADN/efectos de los fármacos , Animales , Cóclea/efectos de los fármacos , Cóclea/metabolismo , Cóclea/patología , Supervivencia Celular/efectos de los fármacos , Ototoxicidad/prevención & control , Ratones , Iridoides/farmacología , Antineoplásicos/toxicidad , Antioxidantes/farmacología , Humanos , Línea Celular , Expresión Génica/efectos de los fármacos

RESUMEN

With the postponement of female reproductive age and the higher incidence of cancer in young people, fertility preservation has become increasingly important in childbearing age. Chemotherapy during pregnancy is crucial for maternal cancer treatments and fetal outcomes. It is a need to further study ovarian damage caused by chemotherapy drug combinations and long-term effects on offspring development, and a detailed understanding of side effects of chemotherapy drugs. In this study, chemotherapy drug combinations significantly impacted on ovarian function, especially epirubicin/cyclophosphamide (EC) combination led to an unbalance in the development of the left and right ovary. Exposure to EC and cisplatin/paclitaxel (TP) increased the number of progenitor follicles while decreased the count of antral follicles and corpora luteum. As to the estrus cycle, EC exposure resulted in a longer estrus period and diestrus period, while TP exposure only extended the diestrus period. EC and TP affected steroid biosynthesis by reducing the expression of SF1 and P450arom.γ-H2AX was detected in both EC and TP exposure groups. As to the impact on the offspring from 4T1 tumor-bearing pregnant mice injected with EC, no significant difference was observed in the physical and neurological development compared to the control, but the ovarian weights, estrus cycles of the offspring were significantly different. Chemotherapy drug combinations exhibit ovarian toxicity, not only causing direct damage on the follicle cells but also disrupting steroid biosynthesis. The reproductive system of offspring from maternal tumor-bearing mice exposed to chemotherapy drugs was observed disorder, but the concrete mechanism still needs further exploration.

Asunto(s)

Cisplatino , Ciclofosfamida , Epirrubicina , Ovario , Femenino , Animales , Ciclofosfamida/toxicidad , Ciclofosfamida/efectos adversos , Embarazo , Ovario/efectos de los fármacos , Cisplatino/efectos adversos , Cisplatino/toxicidad , Epirrubicina/efectos adversos , Epirrubicina/toxicidad , Paclitaxel/efectos adversos , Paclitaxel/toxicidad , Ratones , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ratones Endogámicos BALB C , Antineoplásicos/efectos adversos , Antineoplásicos/toxicidad

RESUMEN

Targeting cancer cells through drug-based treatment or combination therapy protocols involving chemical compounds can be challenging due to multiple factors, including their resistance to bioactive compounds and the potential of drugs to damage healthy cells. This study aims to investigate the relationship between the structure of novel sulfur-containing shikonin oxime compounds and the corresponding cytotoxicity against four cancer types, namely colon, gastric, liver, and breast cancers, through computational chemistry tools. This investigation is suggested to help build insights into how the structure of the compounds influences their activity and understand the mechanisms behind it and subsequently might be used in multi-cancer drug design process to propose novel optimized compounds that potentially exhibit the desired activity. The findings showed that the cytotoxic activity against the four cancer types was accurately predictable (R2 > 0.7, NRMSE <20%) by a combination of search and machine learning algorithms, based on the information on the structure of the compounds, including their lipophilicity, surface area, and volume. Overall, this study is supposed to play a crucial role in effective multi-cancer drug design in cancer research areas.

Asunto(s)

Antineoplásicos , Naftoquinonas , Oximas , Relación Estructura-Actividad Cuantitativa , Humanos , Naftoquinonas/química , Naftoquinonas/farmacología , Naftoquinonas/toxicidad , Oximas/química , Oximas/farmacología , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/toxicidad , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Azufre/química , Aprendizaje Automático , Neoplasias/tratamiento farmacológico