ABSTRACT
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.
Subject(s)
Acute Kidney Injury , Cisplatin , Endoplasmic Reticulum Stress , eIF-2 Kinase , Cisplatin/adverse effects , Cisplatin/toxicity , Animals , Acute Kidney Injury/chemically induced , Acute Kidney Injury/metabolism , Acute Kidney Injury/pathology , Acute Kidney Injury/genetics , eIF-2 Kinase/metabolism , eIF-2 Kinase/genetics , Endoplasmic Reticulum Stress/drug effects , Mice , Male , Apoptosis/drug effects , Mice, Inbred C57BL , Antineoplastic Agents/adverse effects , Antineoplastic Agents/toxicity , PhosphorylationABSTRACT
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.
Subject(s)
Adenylyl Cyclases , Cardiotoxicity , Doxorubicin , Gene Knockdown Techniques , Myocytes, Cardiac , Adenylyl Cyclases/metabolism , Adenylyl Cyclases/genetics , Animals , Mice , Cardiotoxicity/genetics , Doxorubicin/toxicity , Doxorubicin/pharmacology , Doxorubicin/analogs & derivatives , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Cell Line , Apoptosis/drug effects , Oxidative Stress/drug effects , Oxidative Stress/genetics , Molecular Docking Simulation , Cell Proliferation/drug effects , Cell Survival/drug effects , Cyclic AMP-Dependent Protein Kinases/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/toxicityABSTRACT
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.
Subject(s)
Acute Kidney Injury , Biomarkers , Cisplatin , Metabolomics , Animals , Acute Kidney Injury/chemically induced , Acute Kidney Injury/blood , Rats , Biomarkers/blood , Metabolomics/methods , Male , Disease Models, Animal , Rats, Sprague-Dawley , Antineoplastic Agents/adverse effects , Antineoplastic Agents/toxicity , Tandem Mass Spectrometry , Chromatography, High Pressure Liquid , Creatinine/bloodABSTRACT
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.
Subject(s)
Cisplatin , Limosilactobacillus reuteri , Ovary , Primary Ovarian Insufficiency , Female , Animals , Cisplatin/adverse effects , Cisplatin/toxicity , Mice , Primary Ovarian Insufficiency/chemically induced , Primary Ovarian Insufficiency/pathology , Ovary/drug effects , Ovary/pathology , Ovary/metabolism , Gastrointestinal Microbiome/drug effects , Apoptosis/drug effects , Fecal Microbiota Transplantation , Oocytes/drug effects , Oocytes/metabolism , Mice, Inbred C57BL , Antineoplastic Agents/toxicity , Antineoplastic Agents/adverse effects , Granulosa Cells/drug effects , Granulosa Cells/metabolism , Disease Models, Animal , InfertilityABSTRACT
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.
Subject(s)
Cyclophosphamide , Epirubicin , Fetal Blood , Placenta , Humans , Fetal Blood/cytology , Fetal Blood/metabolism , Female , Pregnancy , Cyclophosphamide/toxicity , Cyclophosphamide/adverse effects , Epirubicin/adverse effects , Placenta/drug effects , Placenta/metabolism , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/metabolism , Trophoblasts/drug effects , Trophoblasts/metabolism , Reactive Oxygen Species/metabolism , DNA Damage/drug effects , Apoptosis/drug effects , Infant, Newborn , Antineoplastic Agents/toxicity , Antineoplastic Agents/pharmacology , Antineoplastic Agents/adverse effects , Cells, CulturedABSTRACT
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.
Subject(s)
Apoptosis , Caenorhabditis elegans , Cisplatin , Mitophagy , Cisplatin/adverse effects , Cisplatin/toxicity , Animals , Humans , Mitophagy/drug effects , Caenorhabditis elegans/drug effects , Caenorhabditis elegans/metabolism , Apoptosis/drug effects , Cell Line , Plant Extracts/pharmacology , Kidney Tubules/drug effects , Kidney Tubules/metabolism , Kidney Tubules/pathology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/toxicity , Antineoplastic Agents/adverse effects , Kidney Tubules, Proximal/drug effects , Kidney Tubules, Proximal/metabolism , Kidney Tubules, Proximal/pathologyABSTRACT
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.
Subject(s)
Cell Survival , Cisplatin , Cochlea , DNA Damage , Iridoid Glucosides , Ototoxicity , Cisplatin/toxicity , Iridoid Glucosides/pharmacology , DNA Damage/drug effects , Animals , Cochlea/drug effects , Cochlea/metabolism , Cochlea/pathology , Cell Survival/drug effects , Ototoxicity/prevention & control , Mice , Iridoids/pharmacology , Antineoplastic Agents/toxicity , Antioxidants/pharmacology , Humans , Cell Line , Gene Expression/drug effectsABSTRACT
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.
Subject(s)
Bufanolides , Zebrafish , Animals , Bufanolides/pharmacology , Bufanolides/toxicity , Humans , Antineoplastic Agents/pharmacology , Antineoplastic Agents/toxicity , Hep G2 Cells , Chromatography, High Pressure Liquid/methods , Cardiotoxicity , Biomarkers/metabolism , Metabolomics , Amphibian Venoms/pharmacology , Amphibian Venoms/chemistry , MultiomicsABSTRACT
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.
Subject(s)
Caspase Inhibitors , Cisplatin , Neomycin , Cisplatin/adverse effects , Cisplatin/toxicity , Cisplatin/pharmacology , Animals , Neomycin/pharmacology , Neomycin/toxicity , Caspase Inhibitors/pharmacology , Mice , Apoptosis/drug effects , Cochlea/drug effects , Cochlea/cytology , Cell Survival/drug effects , Hair Cells, Auditory/drug effects , Spiral Ganglion/drug effects , Ototoxicity/etiology , Ototoxicity/prevention & control , Antineoplastic Agents/pharmacology , Antineoplastic Agents/toxicity , Cell Line , Cells, CulturedABSTRACT
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.
Subject(s)
Breast Neoplasms , Colonoscopy , Diarrhea , Quinolines , Rats, Wistar , Receptor, ErbB-2 , Animals , Female , Diarrhea/chemically induced , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Quinolines/pharmacology , Quinolines/therapeutic use , Rats , Pilot Projects , Receptor, ErbB-2/metabolism , Receptor, ErbB-2/genetics , Humans , Middle Aged , Colon/pathology , Colon/drug effects , Colon/metabolism , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Agents/toxicityABSTRACT
PURPOSE: The present study investigated the nephron-testicular protective effects of sesamin against cisplatin (CP)-induced acute renal and testicular injuries. METHODS: Thirty-two male Wistar rats were allocated to receive carboxymethylcellulose (0.5%, as sesamin vehicle), CP (a single i.p. 5 mg/kg dose), CP plus sesamin at 10 or 20 mg/kg orally for 10 days. RESULTS: Data analysis showed significant increases in serum urea, creatinine, interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α), as well as renal and testicular tissue malondialdehyde and nitric-oxide concentrations in CP-intoxicated rats in comparison to control animals. On the contrary, rats treated with CP only exhibited significantly lower (p < .05) serum testosterone, tissue glutathione, and activities of endogenous antioxidant enzymes compared to control rats. Histopathologically examining CP-intoxicated rats' tissues using H&E and PAS stains showed atrophied glomeruli, interstitial inflammatory cells, atypic tubular epithelium with focal apoptosis, and reduced mucopolysaccharide content. Further, immunohistochemical staining of the same group revealed an increase in p53 and cyclooxygenase-II (Cox-II) expression in renal and testicular tissues. Treatment with sesamin alleviated almost all the changes mentioned above in a dose-dependent manner, with the 20 mg/kg dose restoring several parameters' concentrations to normal ranges. CONCLUSIONS: In brief, sesamin could protect the kidneys and testes against CP toxicity through its antioxidant, anti-inflammatory, and anti-apoptotic effects.
Subject(s)
Anti-Inflammatory Agents , Antioxidants , Apoptosis , Cisplatin , Dioxoles , Kidney , Lignans , Rats, Wistar , Testis , Animals , Male , Lignans/pharmacology , Lignans/therapeutic use , Cisplatin/toxicity , Cisplatin/adverse effects , Rats , Dioxoles/pharmacology , Antioxidants/pharmacology , Testis/drug effects , Testis/pathology , Testis/metabolism , Apoptosis/drug effects , Kidney/drug effects , Kidney/pathology , Kidney/metabolism , Anti-Inflammatory Agents/pharmacology , Oxidative Stress/drug effects , Acute Kidney Injury/chemically induced , Acute Kidney Injury/prevention & control , Acute Kidney Injury/pathology , Acute Kidney Injury/metabolism , Antineoplastic Agents/toxicityABSTRACT
Although the presence of nitro groups in chemicals can be recognized as structural alerts for mutagenicity and carcinogenicity, nitroaromatic compounds have attracted considerable interest as a class of agents that can serve as source of potential new anticancer agents. In the present study, the in vitro cytotoxicity, genotoxicity, and mutagenicity of three synthetic ortho-nitrobenzyl derivatives (named ON-1, ON-2 and ON-3) were evaluated by employing human breast and ovarian cancer cell lines. A series of biological assays was carried out with and without metabolic activation. Complementarily, computational predictions of the pharmacokinetic properties and druglikeness of the compounds were performed in the Swiss ADME platform. The MTT assay showed that the compounds selectively affected selectively the cell viability of cancer cells in comparison with a nontumoral cell line. Additionally, the metabolic activation enhanced cytotoxicity, and the compounds affected cell survival, as demonstrated by the clonogenic assay. The comet assay, the cytokinesis-block micronucleus assay, and the immunofluorescence of the γ-H2AX foci formation assay have that the compounds caused chromosomal damage to the cancer cells, with and without metabolic activation. The results obtained in the present study showed that the compounds assessed were genotoxic and mutagenic, inducing double-strand breaks in the DNA structure. The high selectivity indices observed for the compounds ON-2 and ON-3, especially after metabolic activation with the S9 fraction, must be highlighted. These experimental biological results, as well as the theoretical properties predicted for the compounds have shown that they are promising anticancer candidates to be exploited in additional studies.
Subject(s)
Activation, Metabolic , Antineoplastic Agents , Cell Survival , DNA Damage , Humans , Cell Survival/drug effects , Antineoplastic Agents/toxicity , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , DNA Damage/drug effects , Cell Line, Tumor , Micronucleus Tests , Mutagens/toxicity , Comet Assay , Mutagenicity Tests , Female , Nitrobenzenes/toxicity , Nitrobenzenes/chemistry , Breast Neoplasms/pathology , Breast Neoplasms/drug therapy , Ovarian Neoplasms/pathology , Ovarian Neoplasms/drug therapy , Dose-Response Relationship, DrugABSTRACT
Cisplatin is a widely used chemotherapy drug for the treatment of various cancers. However, although cisplatin is effective in targeting cancer cells, it has severe side effects including skeletal muscle atrophy. In this study, we aimed to characterize the role of Dihydromyricetin in cisplatin-induced muscle atrophy in mice. 5-week-old male C57BL/6 mice were treated with Dihydromyricetin for 14 days orally followed by in intraperitoneally cisplatin administration for 6 days. Gastrocnemius muscles were isolated for the following experiments. Antioxidative stress were determined by peroxidative product malondialdehyde (MDA) and antioxidants superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. Quadriceps muscle mass and grip strength were significantly restored by Dihydromyricetin in a dose-dependent manner. Moreover, muscle fibers were improved in Dihydromyricetin treated group. Excessive skeletal muscle E3 ubiquitin-protein ligases in cisplatin group were significantly repressed by Dihydromyricetin treatment. Dihydromyricetin significantly reduced oxidative stress induced by cisplatin by decreasing MDA level and restored SOD and GPx activities. In addition, ferroptosis was significantly reduced by Dihydromyricetin characterized by reduced iron level and ferritin heavy chain 1 and improved Gpx4 level. The present study demonstrated that Dihydromyricetin attenuated cisplatin-induced muscle atrophy by reducing skeletal muscle E3 ubiquitin-protein ligases, oxidative stress, and ferroptosis.
Subject(s)
Cisplatin , Ferroptosis , Flavonols , Mice, Inbred C57BL , Muscular Atrophy , Oxidative Stress , Animals , Male , Flavonols/pharmacology , Flavonols/therapeutic use , Muscular Atrophy/chemically induced , Muscular Atrophy/pathology , Muscular Atrophy/metabolism , Muscular Atrophy/prevention & control , Muscular Atrophy/drug therapy , Ferroptosis/drug effects , Cisplatin/toxicity , Mice , Oxidative Stress/drug effects , Muscle, Skeletal/drug effects , Muscle, Skeletal/pathology , Muscle, Skeletal/metabolism , Antineoplastic Agents/toxicity , Antioxidants/pharmacologyABSTRACT
OBJECTIVE: Cisplatin, a widely used anticancer agent, induces hepatotoxicity alongside organ damage. Understanding Cisplatin's toxicity mechanism and developing preventive measures are crucial. Our study explores Myricetin, a flavonoid, for its protective effects against Cisplatin-induced hepatotoxicity. METHODS: In our study, a total of 32 Wistar albino male rats were utilized, which were categorized into four distinct groups: Control, Myricetin, Cisplatin, and Myricetin+Cisplatin. For the histological assessment of hepatic tissues, hematoxylin-eosin and periodic acid Schiff staining were employed, alongside immunohistochemical measurements of TNF-α, interleukin-17, and interleukin-6 immunoreactivity. Additionally, aspartate transaminase and alanine transaminase values were examined by biochemical analysis. RESULTS: In the histological evaluation of the tissues, a normal healthy cell structure and a strong periodic acid Schiff (+) reaction were observed in the hepatocyte cells in the tissues of the Control and Myricetin groups, while intense eosinophilia, minimal vacuolization, congestion, and sinusoidal expansions were observed in the hematoxylin-eosin stainings, and a decrease in the positive reaction in the periodic acid Schiff staining was observed in the Cisplatin group. Consistent with these histological findings, an increase in TNF-α, interleukin-17, and interleukin-6 expressions (p<0.0001) and a concomitant increase in aspartate transaminase and alanine transaminase values were observed in the Cisplatin group. In the group protected by Myricetin, a significant improvement was observed in all these histological and biochemical values. CONCLUSION: Cisplatin induces notable histopathological alterations in the liver. In this context, Myricetin exhibits the potential to alleviate Cisplatin-induced damage by modulating histological parameters and biochemical processes.
Subject(s)
Alanine Transaminase , Antineoplastic Agents , Aspartate Aminotransferases , Chemical and Drug Induced Liver Injury , Cisplatin , Flavonoids , Interleukin-6 , Rats, Wistar , Tumor Necrosis Factor-alpha , Animals , Flavonoids/pharmacology , Flavonoids/therapeutic use , Cisplatin/toxicity , Male , Chemical and Drug Induced Liver Injury/prevention & control , Chemical and Drug Induced Liver Injury/pathology , Alanine Transaminase/blood , Aspartate Aminotransferases/blood , Antineoplastic Agents/adverse effects , Antineoplastic Agents/toxicity , Interleukin-6/analysis , Interleukin-6/metabolism , Liver/drug effects , Liver/pathology , Rats , Interleukin-17/metabolism , ImmunohistochemistryABSTRACT
Background: Cisplatin (CIS) is a broad-spectrum anticancer drug, with cytotoxic effects on either malignant or normal cells. We aimed to evaluate the hepatotoxicity in rats caused by CIS and its amelioration by the co-administration of either curcumin or resveratrol. Materials and Methods: Forty adult male rats divided into four equal groups: (control group): rats were given a saline solution (0.9%) once intraperitoneally, daily for the next 28 days; (cisplatin group): rats were given a daily oral dose of saline solution (0.9%) for 28 days after receiving a single dose of cisplatin (3.3 mg/kg) intraperitoneally for three successive days; (CIS plus curcumin/resveratrol groups): rats received the same previous dose of cisplatin (3.3 mg/kg) daily for three successive days followed by oral administration of either curcumin/resveratrol solution at a dose of (20 mg/kg) or (10 mg/kg) consequently daily for 28 days. Different laboratory tests (ALT, AST, ALP, bilirubin, oxidative stress markers) and light microscopic investigations were done. Results: Administration of CIS resulted in hepatotoxicity in the form of increased liver enzymes, oxidative stress markers; degenerative and apoptotic changes, the co-administration of CIS with either curcumin or resveratrol improved hepatotoxicity through improved microscopic structural changes, reduction in liver enzymes activity, decreased oxidative stress markers, improved degenerative, and apoptotic changes in liver tissues. Conclusion: Co-administration of either curcumin or resveratrol with cisplatin treatment could ameliorate hepatotoxicity caused by cisplatin in rats via anti-inflammatory and oxidative stress-apoptotic pathways.
Subject(s)
Apoptosis , Chemical and Drug Induced Liver Injury , Cisplatin , Curcumin , Oxidative Stress , Resveratrol , Animals , Resveratrol/pharmacology , Resveratrol/administration & dosage , Cisplatin/toxicity , Cisplatin/administration & dosage , Curcumin/pharmacology , Curcumin/administration & dosage , Oxidative Stress/drug effects , Male , Rats , Apoptosis/drug effects , Chemical and Drug Induced Liver Injury/pathology , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/prevention & control , Chemical and Drug Induced Liver Injury/etiology , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/toxicity , Liver/drug effects , Liver/metabolism , Liver/pathology , Antioxidants/pharmacology , Antioxidants/administration & dosage , Stilbenes/administration & dosage , Stilbenes/pharmacology , Stilbenes/therapeutic use , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/administration & dosage , Rats, WistarABSTRACT
BACKGROUND: and Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) constitutes a significant health problem due to the increasing prevalence and lack of therapies for treatment and prevention. While pivotal for routine cancer treatment, paclitaxel and vincristine frequently cause CIPN and impact the quality of life among cancer patients and survivors. Here, we investigate molecular mechanisms and drug transport in CIPN. EXPERIMENTAL APPROACH: Human sensory neurons were derived from induced pluripotent stem cells (iPSC-SNs), which were characterized using flow cytometry and immunolabeling. These iPSC-SNs were exposed to different concentrations of the two microtubule-targeting agents, paclitaxel and vincristine, with and without pre-exposure to inhibitors and inducers of efflux transporters. Neuronal networks were quantified via fluorescent staining against sensory neuron markers. Transcriptional effects of the chemotherapeutics were examined using quantitative polymerase chain reactions (qPCR). KEY RESULTS: Paclitaxel exposure resulted in axonal retraction and thickening, while vincristine caused fragmentation and abolishment of axons. Both agents increased the mRNA expression of the pain receptor, transient receptor potential vanilloid (TRPV1), and highly induced neuronal damage, as measured by activating transcription factor 3 (ATF3) mRNA. iPSC-SNs express the efflux transporters, P-glycoprotein (P-gp, encoded by ABCB1) and multidrug resistance-associated protein 1 (MPR1, encoded by ABCC1). Modulation of efflux transporters indicate that P-gp and MRP1 play a role in modulating neuronal accumulation and neurotoxicity in preliminary experiments. CONCLUSION: and Implications: iPSC-SNs are a valuable and robust model to study the role of efflux transporters and other mechanistic targets in CIPN. Efflux transporters may play a role in CIPN pathogenesis as they regulate the disposition of chemotherapy to the peripheral nervous system, and they may present potential therapeutic targets for CIPN.
Subject(s)
Induced Pluripotent Stem Cells , Multidrug Resistance-Associated Proteins , Paclitaxel , Peripheral Nervous System Diseases , Sensory Receptor Cells , Vincristine , Induced Pluripotent Stem Cells/drug effects , Induced Pluripotent Stem Cells/metabolism , Humans , Paclitaxel/toxicity , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/metabolism , Sensory Receptor Cells/drug effects , Sensory Receptor Cells/metabolism , Multidrug Resistance-Associated Proteins/metabolism , Multidrug Resistance-Associated Proteins/genetics , Antineoplastic Agents/adverse effects , Antineoplastic Agents/toxicity , TRPV Cation Channels/metabolism , ATP Binding Cassette Transporter, Subfamily B/metabolism , ATP Binding Cassette Transporter, Subfamily B/genetics , Cells, CulturedABSTRACT
Cisplatin is a widely used anticancer drug with notable side effects including ototoxicity and nephrotoxicity. Macrophages, the major resident immune cells in the cochlea and kidney, are important drivers of both inflammatory and tissue repair responses. To investigate the roles of macrophages in cisplatin-induced toxicities, we used PLX3397, a U.S. Food and Drug Administration-approved inhibitor of the colony-stimulating factor 1 receptor, to eliminate tissue-resident macrophages. Mice treated with cisplatin alone had considerable hearing loss (ototoxicity) and kidney injury (nephrotoxicity). Macrophage ablation resulted in significantly reduced hearing loss and had greater outer hair cell survival. Macrophage ablation also protected against cisplatin-induced nephrotoxicity, as evidenced by markedly reduced tubular injury and fibrosis. Mechanistically, our data suggest that the protective effect of macrophage ablation against cisplatin-induced ototoxicity and nephrotoxicity is mediated by reduced platinum accumulation in both the inner ear and the kidney. Together, our data indicate that ablation of tissue-resident macrophages represents an important strategy for mitigating cisplatin-induced ototoxicity and nephrotoxicity.
Subject(s)
Cisplatin , Macrophages , Ototoxicity , Cisplatin/adverse effects , Cisplatin/toxicity , Animals , Macrophages/drug effects , Macrophages/metabolism , Ototoxicity/etiology , Ototoxicity/prevention & control , Mice , Kidney/drug effects , Kidney/metabolism , Kidney/pathology , Hearing Loss/chemically induced , Hearing Loss/prevention & control , Antineoplastic Agents/adverse effects , Antineoplastic Agents/toxicity , Kidney Diseases/chemically induced , Kidney Diseases/prevention & control , Kidney Diseases/pathology , Cochlea/drug effects , Cochlea/metabolism , Cochlea/pathology , Mice, Inbred C57BL , Aminopyridines , PyrrolesABSTRACT
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.
Subject(s)
Cisplatin , Cyclophosphamide , Epirubicin , Ovary , Female , Animals , Cyclophosphamide/toxicity , Cyclophosphamide/adverse effects , Pregnancy , Ovary/drug effects , Cisplatin/adverse effects , Cisplatin/toxicity , Epirubicin/adverse effects , Epirubicin/toxicity , Paclitaxel/adverse effects , Paclitaxel/toxicity , Mice , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Mice, Inbred BALB C , Antineoplastic Agents/adverse effects , Antineoplastic Agents/toxicityABSTRACT
Calcitriol as a biologically active form of vitamin D3 has beneficial effects on all body systems. This vitamin has a potent neuroprotective effect via several independent mechanisms against brain insults induced by anticancer drugs. The present study was designed to examine the neuroprotective effects of calcitriol against neurotoxicity induced by cisplatin. Induction of neurotoxicity was done with cisplatin administration (5 mg/kg/week) for 5 successive weeks in male Wistar rats. The neuroprotective influence of calcitriol supplementation (100ng/kg/day for 5 weeks) was assessed through behavioral, electrophysiological, and molecular experiments. Cisplatin administration impaired spatial learning and memory and decreased prefrontal brain-derived neurotrophic factor (BDNF). Peripheral sensory neuropathy was induced through cisplatin administration. Cisplatin also reduced the amplitudes of the compound action potential of sensory nerves in electrophysiological studies. Cisplatin treatment elevated MDA levels and reduced anti-oxidant (SOD and GPx) enzymes. Pro-inflammatory cytokines (IL-1ß and TNF-α) and metalloproteinase-2 and 9 (MMP-2/9) were augmented through treatment with cisplatin. Learning and memory impairments along with BDNF changes caused by cisplatin were amended with calcitriol supplementation. Reduced sensory nerve conduction velocity in the cisplatin-treated group was improved by calcitriol. Calcitriol partially improved redox imbalance and diminished the pro-inflammatory cytokines and MMP-2/9 levels. Our findings showed that calcitriol supplementation can relieve cisplatin-induced peripheral neurotoxicity. Calcitriol can be regarded as a promising new neuroprotective agent.
Subject(s)
Calcitriol , Cisplatin , Matrix Metalloproteinase 2 , Matrix Metalloproteinase 9 , Neuroprotective Agents , Oxidative Stress , Rats, Wistar , Animals , Cisplatin/toxicity , Male , Oxidative Stress/drug effects , Rats , Matrix Metalloproteinase 2/metabolism , Neuroprotective Agents/pharmacology , Neuroprotective Agents/therapeutic use , Matrix Metalloproteinase 9/metabolism , Calcitriol/pharmacology , Calcitriol/therapeutic use , Antineoplastic Agents/toxicity , Brain-Derived Neurotrophic Factor/metabolism , Neurotoxicity Syndromes/drug therapy , Neurotoxicity Syndromes/metabolismABSTRACT
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.