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1.
Chem Biol Interact ; 330: 109219, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32846153

RESUMO

The lack of tissue selectivity of anticancer drugs generates intense collateral and adverse effects of cancer patients, making the incorporation of vitamins or micronutrients into the diet of individuals to reduce side or adverse effects of antineoplastics. The study aimed to evaluate the effects of retinol palmitate (RP) on the toxicogenic damages induced by cyclophosphamide (CPA), doxorubicin (DOX) and its association with the AC protocol (CPA + DOX), in Sarcoma 180 (S-180) tumor cell line, using the micronuclei test with a block of cytokinesis (CBMN); and in non-tumor cells derived from Mus musculus using the comet assay. The results suggest that CPA, DOX and AC protocol induced significant toxicogenic damages (P < 0.05) on the S-180 cells by induction of micronuclei, cytoplasmic bridges, nuclear buds, apoptosis, and cell necrosis, proving their antitumor effects, and significant damage (P < 0.001) to the genetic material of peripheral blood cells of healthy mice, proving the genotoxic potential of these drugs. However, RP modulated the toxicogenic effects of antineoplastic tested both in the CBMN test (P < 0.05), at the concentrations of 1, 10 and 100 IU/mL; as in the comet assay (P < 0.001) at the concentration of 100 IU/kg for the index and frequency of genotoxic damage. The accumulated results suggest that RP reduced the action of antineoplastics in non-tumor cells as well as the cytotoxic, mutagenic, and cell death in neoplastic cells.


Assuntos
Antineoplásicos/toxicidade , Diterpenos/farmacologia , Vitamina A/análogos & derivados , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Ensaio Cometa , Ciclofosfamida/efeitos adversos , Ciclofosfamida/toxicidade , Dano ao DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/efeitos adversos , Doxorrubicina/toxicidade , Interações Medicamentosas , Humanos , Camundongos , Testes para Micronúcleos , Mutagênese/efeitos dos fármacos , Vitamina A/farmacologia
2.
Life Sci ; 258: 118242, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32784056

RESUMO

AIMS: As the spermatogenesis process is targeted by cisplatin (Cis) that changes testicular morphology, alters sperm quality, and hence causes male infertility. This study investigated the possible therapeutic effects of l-carnitine (LC) on Cis impaired spermatogenesis's establishment during the prepubertal phase. MATERIALS AND METHODS: Ninety-six prepubertal Sprague Dawley male rats were divided into four groups. CONTROL GROUP: rats were injected with 0.9% saline solution intraperitoneally (i.p.). LC group: animals were injected for eight weeks, with 250 mg/kg/wk. LC (i.p.). Cis group: animals were injected with a single dose of 5 mg/kg Cis (i.p.). LC + Cis group: animals were pre-injected with LC 250 mg/kg 2 h before Cis injection. The rats were sacrificed at 37, 60, and 90 days old, and their testes were taken for biochemical, molecular, and histopathological studies. The motility, viability, morphology, and DNA fragmentation of sperm in adult rats were also measured. KEY FINDINGS: Group treated with LC and Cis showed an increase in antioxidant and hormonal activity compared to the Cis treated group in the pre and post-pubertal period. Moreover, there was an increase in sperm survival, motility, and DNA integrity. Furthermore, LC showed an increase in the anti-apoptotic and chromatin remodeling genes and a decrease in the pro-inflammatory genes. SIGNIFICANCE: LC could enhance the spermatogenesis process after exposure to Cis during the prepubertal phase by restoring the balance between reactive oxygen species and antioxidant activity, improving hormonal activity, sperm quality and DNA integrity, promoting protamination and blood-testis barrier integrity, and maintaining the testicular architecture.


Assuntos
Carnitina/farmacologia , Cisplatino/toxicidade , Infertilidade Masculina/prevenção & controle , Infertilidade Masculina/fisiopatologia , Maturidade Sexual/efeitos dos fármacos , Espermatogênese/efeitos dos fármacos , Animais , Antineoplásicos/toxicidade , Carnitina/uso terapêutico , Infertilidade Masculina/induzido quimicamente , Masculino , Ratos , Ratos Sprague-Dawley , Maturidade Sexual/fisiologia , Motilidade Espermática/efeitos dos fármacos , Motilidade Espermática/fisiologia , Espermatogênese/fisiologia
3.
PLoS One ; 15(7): e0236115, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32697811

RESUMO

BACKGROUND: Anti-GD2 therapy with dinutuximab is effective in improving the survival of high-risk neuroblastoma patients in remission and after relapse. However, allodynia is the major dose-limiting side effect, hindering its use for neuroblastoma patients at higher doses and for other GD2-expressing malignancies. As polyamines can enhance neuronal sensitization, including development of allodynia and other forms of pathological pain, we hypothesized that polyamine depletion might prove an effective strategy for relief of anti-GD2 induced allodynia. METHOD: Sprague-Dawley rats were allowed to drink water containing various concentrations of difluoromethylornithine (DFMO) for several days prior to behavioral testing. Anti-GD2 (14G2a) was injected into the tail vein of lightly sedated animals and basal mechanical hindpaw withdrawal threshold assessed by von Frey filaments. Endpoint serum DFMO and polyamines, assessed 24h after 14G2a injection, were measured by HPLC and mass spectrometry. RESULTS: An i.v. injection of 14G2a causes increased paw sensitivity to light touch in this model, a response that closely mimics patient allodynia. Animals allowed to drink water containing 1% DFMO exhibited a significant reduction of 14G2a-induced pain sensitivity (allodynia). Increasing the dosage of the immunotherapeutic increased the magnitude (intensity and duration) of the pain behavior. Administration of DFMO attenuated the enhanced sensitivity. Consistent with the known actions of DFMO on ornithine decarboxylase (ODC), serum putrescene and spermidine levels were significantly reduced by DFMO, though the decrease in endpoint polyamine levels did not directly correlate with the behavioral changes. CONCLUSIONS: Our results demonstrate that DFMO is an effective agent for reducing anti-GD2 -induced allodynia. Using DFMO in conjunction with dinutuximab may allow for dose escalation in neuroblastoma patients. The reduction in pain may be sufficient to allow new patient populations to utilize this therapy given the more acceptable side effect profile. Thus, DFMO may be an important adjunct to anti-GD2 immunotherapy in addition to a role as a potential anti-cancer therapeutic.


Assuntos
Anticorpos Monoclonais/toxicidade , Antineoplásicos/toxicidade , Eflornitina/farmacologia , Gangliosídeos/imunologia , Hiperalgesia/tratamento farmacológico , Inibidores da Ornitina Descarboxilase/farmacologia , Animais , Hiperalgesia/induzido quimicamente , Hiperalgesia/patologia , Masculino , Poliaminas/sangue , Ratos , Ratos Sprague-Dawley
4.
Environ Toxicol ; 35(11): 1225-1233, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32697429

RESUMO

Hepatocellular carcinoma is the second leading cause of cancer-related mortality worldwide. Lagerstroemia speciosa Pers. (Lythraceae) commonly known as Banaba has been used in different forms in traditional medicinal systems for treating various diseases which include diabetes and obesity. In this study, we investigated the cytotoxic potential of ethanolic Banaba leaf extract (EBLE) in HepG2 cells. The phytochemical analysis of EBLE was performed by HPTLC. HepG2 cells were treated with EBLE at 25, 50, 100, and 150 µg/mL concentrations, and cytotoxicity was evaluated by MTT assay. Oxidative stress was assessed by the evaluation of lipid peroxidation, superoxide dismutase, and reduced glutathione. Apoptosis-related morphology was investigated by acridine orange and ethidium bromide (AO/EB) dual staining. Mitochondrial membrane potential (ΔΨm) was evaluated by JC-1 staining. Apoptosis-related marker genes were evaluated by qPCR. HPTLC analysis confirmed the presence of corosolic acid (12.87 µg/mg), berberine (3.19 µg/mg), and gallic acid (2.94 µg/mg) in EBLE. EBLE treatments caused significant and concentration-dependent cytotoxicity and oxidative stress in HepG2 cells. Dual staining with AO/EB confirmed membrane distortion and nuclear chromatin condensation upon EBLE treatments. JC-I staining revealed the loss of ΔΨm. Furthermore, at a molecular level, EBLE treatments interfere with Bax/Bcl-2 homeostasis and induced the pro-apoptotic marker genes such as cytochrome c, Apaf-1, and caspases 9 and 3. EBLE treatments caused cytotoxicity in HepG2 cells, and this could be due to the induction of oxidative stress and apoptosis via the intrinsic or mitochondrial pathway.


Assuntos
Antineoplásicos/toxicidade , Extratos Vegetais/toxicidade , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Caspase 9 , Células Hep G2 , Humanos , Lagerstroemia , Neoplasias Hepáticas/patologia , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2 , Triterpenos
5.
Toxicology ; 441: 152507, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32512035

RESUMO

Vorinostat was approved as the first histone deacetylase inhibitor for the management of cutaneous T cell lymphoma. However, it's in vivo genetic and epigenetic effects on non-cancerous cells remain poorly understood. As genetic and epigenetic changes play a critical role in the pathogenesis of carcinogenesis, we investigated whether vorinostat induces genetic and epigenetic alterations in mouse bone marrow cells. Bone marrow cells were isolated 24 h following the last oral administration of vorinostat at the doses of 25, 50, or 100 mg/kg/day for five days (approximately equal to the recommended human doses). The cells were then used to assess clastogenicity and aneugenicity by the micronucleus test complemented by fluorescence in situ hybridization assay; DNA strand breaks, oxidative DNA strand breaks, and DNA methylation by the modified comet assay; apoptosis by annexin V/PI staining analysis and the occurrence of the hypodiploid DNA content; and DNA damage/repair gene expression by polymerase chain reaction (PCR) Array. The expression of the mRNA transcripts were also confirmed by real-time PCR and western blot analysis. Vorinostat caused structural chromosomal damage, numerical chromosomal abnormalities, DNA strand breaks, oxidative DNA strand breaks, DNA hypomethylation, and programed cell death in a dose-dependent manner. Furthermore, the expression of numerous genes implicated in DNA damage/repair were altered after vorinostat treatment. Accordingly, the genetic/epigenetic mechanism(s) of action of vorinostat may play a role in its carcinogenicity and support the continued study and development of new compounds with lower toxicity.


Assuntos
Antineoplásicos/toxicidade , Células da Medula Óssea/efeitos dos fármacos , Vorinostat/toxicidade , Animais , Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Aberrações Cromossômicas/induzido quimicamente , Ensaio Cometa , Metilação de DNA/efeitos dos fármacos , Reparo do DNA/efeitos dos fármacos , Relação Dose-Resposta a Droga , Regulação para Baixo , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Vorinostat/administração & dosagem
6.
Nat Commun ; 11(1): 3157, 2020 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-32572029

RESUMO

Resistance to targeted cancer drugs is thought to result from selective pressure exerted by a high drug dose. Partial inhibition of multiple components in the same oncogenic signalling pathway may add up to complete pathway inhibition, while decreasing the selective pressure on each component to acquire a resistance mutation. We report here testing of this Multiple Low Dose (MLD) therapy model in EGFR mutant NSCLC. We show that as little as 20% of the individual effective drug doses is sufficient to completely block MAPK signalling and proliferation when used in 3D (RAF + MEK + ERK) or 4D (EGFR + RAF + MEK + ERK) inhibitor combinations. Importantly, EGFR mutant NSCLC cells treated with MLD therapy do not develop resistance. Using several animal models, we find durable responses to MLD therapy without associated toxicity. Our data support the notion that MLD therapy could deliver clinical benefit, even for those having acquired resistance to third generation EGFR inhibitor therapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Receptores ErbB/genética , Inibidores de Proteínas Quinases/farmacologia , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/toxicidade , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Modelos Animais , Mutação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/toxicidade , Células Tumorais Cultivadas
7.
Toxicol Lett ; 331: 1-10, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32428544

RESUMO

Cisplatin is a well-known and commonly used chemotherapeutic agent. However, cisplatin-induced ototoxicity limits its clinical use. Previous studies have shown an important role of reactive oxygen species (ROS) accumulation in the pathogenesis of cisplatin-induced ototoxicity. In many cell types, the transcription factor, nuclear factor erythroid 2-related factor 2 (Nrf2) and antioxidant response element (ARE) protect against oxidative stress by suppressing ROS. Here our results showed that cisplatin injury reduced Nrf2 expression and inhibited Nrf2 translocation in HEI-OC1 cells and Nrf2 activator tert-butylhydroquinone (TBHQ) rescued hair cells from cisplatin induced apoptosis by suppressing the total cellular ROS accumulation. Moreover, we found that decreased ROS accumulation induced by TBHQ didn't depend on mitochondrial derived ROS production, indicating that Nrf2 activation alleviated cisplatin induced oxidative stress and apoptosis through mitochondrial-independent ROS production. Therefore, we provide a potential strategy of prevention and treatment for cisplatin-induced ototoxicity by Nrf2 activation. In conclusion, Nrf2 activation protects auditory hair cells from cisplatin-induced ototoxicity through suppressing the total cellular ROS levels which arise from sources other than mitochondria.


Assuntos
Antineoplásicos/toxicidade , Cisplatino/toxicidade , Células Ciliadas Auditivas/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Ototoxicidade/prevenção & controle , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Potenciais Evocados Auditivos do Tronco Encefálico/efeitos dos fármacos , Células Ciliadas Auditivas/metabolismo , Hidroquinonas/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Fator 2 Relacionado a NF-E2/genética , Ototoxicidade/patologia , Espécies Reativas de Oxigênio/metabolismo
8.
Am J Physiol Heart Circ Physiol ; 319(1): H133-H143, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32469636

RESUMO

In clinical studies, platelet aggregation and risk of thrombosis are increased in patients after doxorubicin treatment. However, the exact role of doxorubicin in platelet functions and thrombus formation in vivo remain unclear. The present study is to investigate the role of doxorubicin in platelet function in relation to thrombus formation and vascular toxicity, as well as the efficacy of antiplatelet therapy. Mice were treated with doxorubicin or vehicle (5 mg/kg iv, 4 wk), and the following parameters were determined: platelet count and size, platelet surface adhesive receptors by flow cytometry, density of granules by electron microscopy, platelet aggregation and degranulation at resting or agonist-stimulated state, platelet adhesion on fibrinogen or endothelial cells, and thrombus formation on collagen matrix. The efficacy of clopidogrel (15 mg·kg-1·day-1, followed by 5 mg·kg-1·day-1) on doxorubicin-induced changes in the aforementioned parameters as well as vascular injury were also determined. Whereas platelet count and size were similar between doxorubicin-treated and vehicle-treated mice, doxorubicin promoted thrombus formation evidenced by greater platelet aggregation, degranulation, and adhesion to endothelial cells evoked by agonists. Clopidogrel treatment attenuated the enhanced platelet activity and thrombus formation by doxorubicin, as well as vascular platelet infiltration and reactive oxygen species generation. Collectively, this study demonstrates that platelet functions are enhanced after long-term doxorubicin administration, which leads to thrombus formation and vascular toxicity, and that doxorubicin-induced changes in the functionality of platelets can be effectively inhibited by antiplatelet drugs.NEW & NOTEWORTHY Doxorubicin therapy in mice (antitumor dosage) markedly enhanced platelet functions measured as agonist-induced platelet aggregation, degranulation, and adhesion to endothelial cells, actions leading to thrombus formation and thrombosis-independent vascular injury. Clopidogrel treatment ameliorated thrombus formation and vascular toxicity induced by doxorubicin via inhibiting platelet activity.


Assuntos
Antineoplásicos/toxicidade , Plaquetas/efeitos dos fármacos , Doxorrubicina/toxicidade , Endotélio Vascular/efeitos dos fármacos , Trombose/etiologia , Animais , Antineoplásicos/farmacologia , Plaquetas/fisiologia , Células Cultivadas , Doxorrubicina/farmacologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Agregação Plaquetária
9.
J Med Chem ; 63(10): 5185-5200, 2020 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-32364386

RESUMO

Human carbonic anhydrase (CA; EC 4.2.1.1) isoforms II and VII are implicated in neuronal excitation, seizures, and neuropathic pain (NP). Their selective inhibition over off-target CAs is expected to produce an anti-NP action devoid of side effects due to promiscuous CA modulation. Here, a drug design strategy based on the observation of (dis)similarities between the target CA active sites was planned with benzenesulfonamide derivatives and, for the first time, a phosphorus-based linker. Potent and selective CA II/VII inhibitors were identified among the synthesized phenyl(thio)phosphon(amid)ates 3-22. X-ray crystallography depicted the binding mode of phosphonic acid 3 to both CAs II and VII. The most promising derivatives, after evaluation of their stability in acidic media, were tested in a mouse model of oxaliplatin-induced neuropathy. The most potent compound racemic mixture was subjected to HPLC enantioseparation, and the identification of the eutomer, the (S)-enantiomer, allowed to halve the dose totally relieving allodynia in mice.


Assuntos
Anidrase Carbônica II/antagonistas & inibidores , Anidrase Carbônica II/metabolismo , Inibidores da Anidrase Carbônica/uso terapêutico , Anidrases Carbônicas/metabolismo , Hiperalgesia/tratamento farmacológico , Oxaliplatina/toxicidade , Animais , Antineoplásicos/toxicidade , Inibidores da Anidrase Carbônica/química , Inibidores da Anidrase Carbônica/farmacologia , Temperatura Baixa/efeitos adversos , Cristalografia por Raios X/métodos , Modelos Animais de Doenças , Humanos , Hiperalgesia/induzido quimicamente , Hiperalgesia/enzimologia , Masculino , Camundongos , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/enzimologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
10.
Aquat Toxicol ; 223: 105495, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32371336

RESUMO

Platinum-based antineoplastic drugs (PBADs) enter the environment via hospital and municipal wastes as reactive and highly toxic molecules. Chlorella vulgaris is a freshwater microalgae and is used as an excellent aquatic model for toxicity assessment. In the present study, the toxicity of PBADs to C. vulgaris was investigated for better understanding of PBADs environmental toxicity. The algae were cultured in Bold´s Basal Medium (BBM) and exposed to different concentrations of PBADs for 48, 72 and 96 h. Then, cell proliferation, the synthesis of photosynthetic pigments, protein content, malondialdehyde (MDA) release and antioxidant potential were determined. IC50 s of cisplatin, carboplatin and oxaliplatin for 96 h of exposure were 106.2, 124.3 and 153.9 mg/L respectively. Cell proliferation, synthesis of chlorophyll a, chlorophyll b and algal protein content significantly decreased in a time and dose-dependent manner. The release of MDA to culture media significantly increased and antioxidant potential decreased. Cisplatin showed more toxic effects on C. vulgaris compared to carboplatin and oxaliplatin indicating its severe toxicity for marine organisms. PBADs induce their toxic effects in algal cells via the interaction with DNA, production of free radicals (such as reactive oxygen species), lipid peroxidation and cell wall damages. Due to these toxic effects of PBADs for various environmental organisms, there must be severe restriction on their release into the environment.


Assuntos
Antineoplásicos/toxicidade , Chlorella vulgaris/efeitos dos fármacos , Microalgas/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Antioxidantes/metabolismo , Carboplatina/toxicidade , Chlorella vulgaris/metabolismo , Clorofila/metabolismo , Clorofila A/metabolismo , Cisplatino/toxicidade , Água Doce/química , Peroxidação de Lipídeos/efeitos dos fármacos , Malondialdeído/metabolismo , Microalgas/metabolismo , Oxaliplatina/toxicidade , Fotossíntese/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo
11.
Crit Rev Oncol Hematol ; 151: 102963, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32446180

RESUMO

Treatment of testicular cancer (TC) has an exceptionally high success rate compared to other cancer types; even in case of metastasized disease, 80-90 % of TC patients can be cured. Consequently, attention has been drawn to a potential downside of this treatment success: late adverse treatment effects such as the accelerated development of otherwise age-associated features like cardiovascular disease and second malignancies. Underlying mechanisms are poorly understood. Emerging data suggest that cytotoxic treatment induces cellular senescence, resulting in secretion of inflammatory factors contributing to this early ageing phenotype. Molecular and cellular characterization of this early ageing will enhance understanding the pathogenesis of TC treatment-induced morbidity and contribute to better recognition and prevention of late effects. In this review, we describe clinical manifestations of the early ageing phenotype among TC survivors, and subsequently focus on potential underlying mechanisms. We discuss the clinical implications and describe perspectives for future research and intervention strategies.


Assuntos
Antineoplásicos/uso terapêutico , Senescência Celular/efeitos dos fármacos , Neoplasias Testiculares/tratamento farmacológico , Envelhecimento , Antineoplásicos/toxicidade , Humanos , Masculino , Sobreviventes
12.
Artigo em Inglês | MEDLINE | ID: mdl-32293934

RESUMO

The transport of electrolytes and fluid by the intestinal epithelium is critical in health to maintain appropriate levels of fluidity of the intestinal contents. The transport mechanisms that underlie this physiological process are also subject to derangement in various digestive disease states, such as diarrheal illnesses. This article summarizes the 2019 Hans Ussing Lecture of the Epithelial Transport Group of the American Physiological Society and discusses some pathways by which intestinal transport is dysregulated, particularly in the setting of infection with the diarrheal pathogen, Salmonella, and in patients treated with small-molecule inhibitors of the tyrosine kinase activity of the epidermal growth factor receptor (EGFr-TKI). The burdensome diarrhea in patients infected with Salmonella may be attributable to decreased expression of the chloride-bicarbonate exchanger downregulated in adenoma (DRA) that participates in electroneutral NaCl absorption. This outcome is possibly secondary to increased epithelial proliferation and/or decreased epithelial differentiation that occurs following infection. Conversely, the diarrheal side effects of cancer treatment with EGFr-TKI may be related to the known ability of EGFr-associated signaling to reduce calcium-dependent chloride secretion. Overall, the findings described may suggest targets for therapeutic intervention in a variety of diarrheal disease states.


Assuntos
Antiporters/metabolismo , Diarreia/metabolismo , Células Epiteliais/metabolismo , Absorção Intestinal , Mucosa Intestinal/metabolismo , Transportadores de Sulfato/metabolismo , Animais , Antineoplásicos/toxicidade , Diferenciação Celular , Proliferação de Células , Diarreia/induzido quimicamente , Diarreia/microbiologia , Diarreia/patologia , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/microbiologia , Células Epiteliais/patologia , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Camundongos , Permeabilidade , Inibidores de Proteínas Quinases/toxicidade , Salmonelose Animal/metabolismo , Salmonelose Animal/microbiologia , Salmonelose Animal/patologia
13.
Cancer Sci ; 111(6): 2146-2155, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32227405

RESUMO

Chemotherapy-induced alopecia is one of the most difficult adverse events of cancer treatment for patients. However, it is still unknown why anticancer drugs cause hair loss. We aimed to clarify the mechanism of chemotherapy-induced alopecia in mice using an in vivo imaging technique with a two-photon microscope, which enables observation of the deep reaction in the living body in real time. In this study, ICR mice were injected intraperitoneally with cyclophosphamide (120 µg/g). Changes in the hair bulb morphology, subcutaneous vessel permeability, and vessel density were evaluated by two-photon microscopy and conventional methods. In order to determine whether there is a causal relationship between vascular permeability and hair loss, we combined cyclophosphamide (50 µg/g) with subcutaneous histamine. Using two­photon microscopy and conventional examination, we confirmed that the hair bulbs became smaller, blood vessels around the hair follicle decreased, and vascular permeability increased at 24 hours after cyclophosphamide injection [corrected]. Apoptosis occurred in vascular endothelial cells around the hair follicle. Additionally, hair loss was exacerbated by temporarily enhancing vascular permeability with histamine. In conclusion, cyclophosphamide caused a decrease in vascular density and an increase in vascular permeability, therefore increased vascular permeability might be one of the causes of chemotherapy-induced alopecia.


Assuntos
Alopecia/induzido quimicamente , Antineoplásicos/toxicidade , Permeabilidade Capilar/efeitos dos fármacos , Ciclofosfamida/toxicidade , Folículo Piloso/efeitos dos fármacos , Animais , Feminino , Camundongos , Camundongos Endogâmicos ICR
14.
Toxicol Appl Pharmacol ; 396: 114996, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32278510

RESUMO

Antineoplastic drugs cause severe cytotoxicity for normal cells, especially hematopoietic stem cells (HSCs). However, bleomycin (BLM) is glycopeptide antibiotic that is effective on various cancers and has either low or no myelosuppression effects. The aim of the present study was to investigate the effect of BLM on 5-Azacitidine (5-AZA) induced cytotoxicity in bone marrow HSCs. 5-AZA reduced HSC cell viability in a time and dose-dependent manner with an IC50 value of 16 µM. However, pretreatment of the cells with BLM for 4 h induced an antagonistic cytotoxicity with an increased IC50 of 64 µM. 5-AZA decreased the colony formation ability of HSC cells in semi-solid agar culture and this effect was attenuated by BLM. 5-AZA significantly downregulated high mobility group Box1 (HMGB1) and Bcl-2 gene expression but upregulated Bax gene expression, while BLM impeded the action of 5-AZA. Pretreatment with BLM remarkably decreased HMGB1 release into culture media that was induced by 5-AZA. The cells were distribution at the sub/G1 phase. Annexin/PI staining of the cells, poly (ADP-ribose) polymerase (PARP) cleavage, and anion superoxide production indicated that BLM limited 5-AZA induced apoptotic cell death. In conclusion, BLM in combination with 5-AZA effectively reduces the adverse cytotoxic effects of 5-AZA on bone marrow hematopoietic stem cells, providing a new chemotherapeutic strategy.


Assuntos
Antineoplásicos/toxicidade , Apoptose/efeitos dos fármacos , Azacitidina/toxicidade , Bleomicina/farmacologia , Proteína HMGB1/metabolismo , Células-Tronco Hematopoéticas/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo , Animais , Azacitidina/antagonistas & inibidores , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Espécies Reativas de Oxigênio/metabolismo
15.
Am J Physiol Renal Physiol ; 318(4): F971-F978, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32150447

RESUMO

Acute kidney injury (AKI) remains a major global healthcare problem, and there is a need to develop human-based models to study AKI in vitro. Toward this goal, we have characterized induced pluripotent stem cell-derived human kidney organoids and their response to cisplatin, a chemotherapeutic drug that induces AKI and preferentially damages the proximal tubule. We found that a single treatment with 50 µM cisplatin induces hepatitis A virus cellular receptor 1 (HAVCR1) and C-X-C motif chemokine ligand 8 (CXCL8) expression, DNA damage (γH2AX), and cell death in the organoids but greatly impairs organoid viability. DNA damage was not specific to the proximal tubule but also affected the distal tubule and interstitial cell populations. This lack of specificity correlated with low expression of proximal tubule-specific SLC22A2/organic cation transporter 2 (OCT2) for cisplatin. To improve viability, we developed a repeated low-dose regimen of 4 × 5 µM cisplatin over 7 days and found this caused less toxicity while still inducing a robust injury response that included secretion of known AKI biomarkers and inflammatory cytokines. This work validates the use of human kidney organoids to model aspects of cisplatin-induced injury, with the potential to identify new AKI biomarkers and develop better therapies.


Assuntos
Lesão Renal Aguda/induzido quimicamente , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Dano ao DNA , Túbulos Renais Proximais/efeitos dos fármacos , Organoides/efeitos dos fármacos , Lesão Renal Aguda/genética , Lesão Renal Aguda/metabolismo , Lesão Renal Aguda/patologia , Antineoplásicos/metabolismo , Células Cultivadas , Cisplatino/metabolismo , Relação Dose-Resposta a Droga , Receptor Celular 1 do Vírus da Hepatite A/genética , Receptor Celular 1 do Vírus da Hepatite A/metabolismo , Histonas/metabolismo , Humanos , Interleucina-8/genética , Interleucina-8/metabolismo , Túbulos Renais Proximais/metabolismo , Túbulos Renais Proximais/patologia , Transportador 2 de Cátion Orgânico/metabolismo , Organoides/metabolismo , Organoides/patologia , Fatores de Tempo
16.
Int. arch. otorhinolaryngol. (Impr.) ; 24(1): 47-52, Jan.-Mar. 2020. graf
Artigo em Inglês | LILACS | ID: biblio-1090559

RESUMO

Abstract Introduction Cisplatin damages the auditory system and is related to the generation of free radicals. Glutathione peroxidase is an endogenous free radicals remover. Objective To investigate the mechanisms involved in otoprotection by N-acetylcys- teine through the expression of glutathione peroxidase in outer hair cells from rats treated with cisplatin. Methods Male Wistar rats were intraperitoneally injected with cisplatin (8 mg/Kg) and/or received oral administration by gavage of N-acetylcysteine (300 mg/Kg) for 3 consecutive days. On the 4th day, the animals were euthanized and beheaded. The tympanic bullae were removed and prepared for scanning electron microscopy and Results Among the groups exposed to ototoxic doses of cisplatin, there was an increase in glutathione peroxidase immunostaining in two groups, the one exposed to cisplatin alone, and the group exposed to both cisplatin and N-acetylcysteine. Conclusion The expression of glutathione peroxidase in the outer hair cells of rats exposed to cisplatin showed the synthesis of this enzyme under cellular toxicity conditions.


Assuntos
Animais , Masculino , Acetilcisteína/uso terapêutico , Depuradores de Radicais Livres/uso terapêutico , Cisplatino/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Antineoplásicos/toxicidade , Acetilcisteína/metabolismo , Acetilcisteína/farmacologia , Microscopia Eletrônica de Varredura , Potenciais Evocados Auditivos do Tronco Encefálico , Depuradores de Radicais Livres/metabolismo , Depuradores de Radicais Livres/farmacologia , Imunofluorescência , Cisplatino/uso terapêutico , Ratos Wistar , Cóclea/anatomia & histologia , Cóclea/efeitos dos fármacos , Radicais Livres , Glutationa Peroxidase/metabolismo , Perda Auditiva Neurossensorial/prevenção & controle
17.
J Med Chem ; 63(6): 2877-2893, 2020 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-32084316

RESUMO

As an FDA-approved drug, teniposide, was utilized in cancer treatment but was accompanied by a strong side effect in long-term clinical trials. This work discovered potential candidate drugs with low toxicity by modifying the molecule structure of teniposide through a structure-guided drug design approach. The IC50 value of novel 4,6-O-thenylidene-ß-d-glucopyranoside-(2″-acetamido, 3″-acetyl-di-S-5-fluorobenzothizole/5-fluorobenzoxazole)-4'-demethylepipodophyllotoxin (compounds 15 and 16) was 120.4-125.1 µM, which was significantly improved by around 10 times more than teniposide (11.5-22.3 µM) against healthy human cells (i.e., HL-7702, H8, MRC-5, and HMEC). In vivo studies demonstrated compounds 15 and 16 significantly suppressed the tumor growth in the HepG2 cell xenograft model without exhibiting obvious toxicity (LD50 values of 208.45 and 167.52 mg/kg), which was lower than that of teniposide (LD50 = 46.12 mg/kg). Compounds 15 and 16 caused mild γH2AX phosphorylation for low DNA toxicity and less inhibition of PI3K/Akt. Compounds 15 and 16 might be potential antitumor drugs with low toxicity.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Podofilotoxina/análogos & derivados , Teniposídeo/análogos & derivados , Teniposídeo/farmacologia , Animais , Antineoplásicos/toxicidade , Linhagem Celular , Dano ao DNA/efeitos dos fármacos , Células Hep G2 , Humanos , Masculino , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Neoplasias/tratamento farmacológico , Neoplasias/genética , Neoplasias/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Fosfoinositídeo-3 Quinase/química , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/toxicidade , Podofilotoxina/química , Podofilotoxina/farmacologia , Podofilotoxina/toxicidade , Teniposídeo/toxicidade
18.
Artigo em Inglês | MEDLINE | ID: mdl-32083974

RESUMO

Doxorubicin (Dox) is an effective chemotherapeutic for a variety of pediatric malignancies. Unfortunately, Dox administration often results in a cumulative dose-dependent cardiotoxicity that manifests with marked oxidative stress, leading to heart failure. Adjunct therapies are needed to mitigate Dox cardiotoxicity and enhance quality of life in pediatric patients with cancer. Angiotensin-(1-7) [Ang-(1-7)] is an endogenous hormone with cardioprotective properties. This study investigated whether adjunct Ang-(1-7) attenuates cardiotoxicity resulting from exposure to Dox in male and female juvenile rats. Dox significantly reduced body mass, and the addition of Ang-(1-7) had no effect. However, adjunct Ang-(1-7) prevented Dox-mediated diastolic dysfunction, including markers of decreased passive filling as measured by reduced early diastole mitral valve flow velocity peak (E) (P < 0.05) and early diastole mitral valve annulus peak velocity (e'; P < 0.001) and increased E/e' (P < 0.001), an echocardiographic measure of diastolic dysfunction. Since Dox treatment increases reactive oxygen species (ROS), the effect of Ang-(1-7) on oxidative by-products and enzymes that generate or reduce ROS was investigated. In hearts of male and female juvenile rats, Dox increased NADPH oxidase 4 (P < 0.05), a major cardiovascular NADPH oxidase isozyme that generates ROS, as well as 4-hydroxynonenal (P < 0.001) and malondialdehyde (P < 0.001), markers of lipid peroxidation; Ang-(1-7) prevented these effects of Dox. Cotreatment with Dox and Ang-(1-7) increased the antioxidant enzymes SOD1 (male: P < 0.05; female: P < 0.01) and catalase (P < 0.05), which likely contributed to reduced ROS. These results demonstrate that Ang-(1-7) prevents diastolic dysfunction in association with a reduction in ROS, suggesting that the heptapeptide hormone may serve as an effective adjuvant to improve Dox-induced cardiotoxicity.NEW & NOTEWORTHY Ang-(1-7) is a clinically safe peptide hormone with cardioprotective and antineoplastic properties that could be used as an adjuvant therapy to improve cancer treatment and mitigate the long-term cardiotoxicity associated with doxorubicin in pediatric patients with cancer.


Assuntos
Angiotensina I/uso terapêutico , Antineoplásicos/toxicidade , Antioxidantes/uso terapêutico , Doxorrubicina/toxicidade , Cardiopatias/tratamento farmacológico , Fragmentos de Peptídeos/uso terapêutico , Animais , Cardiotoxicidade , Catalase/metabolismo , Feminino , Cardiopatias/etiologia , Frequência Cardíaca , Masculino , Malondialdeído/metabolismo , Valva Mitral/fisiopatologia , Miocárdio/metabolismo , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo
19.
J Cardiovasc Transl Res ; 13(3): 377-389, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32078739

RESUMO

Chemotherapy-induced cardiovascular toxicity (CICT) is a well-established risk for cancer survivors and causes diseases such as heart failure, arrhythmia, vascular dysfunction, and atherosclerosis. As our knowledge of the precise cardiovascular risks of each chemotherapy agent has improved, it has become clear that genomics is one of the most influential predictors of which patients will experience cardiovascular toxicity. Most recently, GWAS-led, top-down approaches have identified novel genetic variants and their related genes that are statistically related to CICT. Importantly, the advent of human-induced pluripotent stem cell (hiPSC) models provides a system to experimentally test the effect of these genomic findings in vitro, query the underlying mechanisms, and develop novel strategies to mitigate the cardiovascular toxicity liabilities due to these mechanisms. Here we review the cardiovascular toxicities of chemotherapy drugs, discuss how these can be modeled in vitro, and suggest how these models can be used to validate genetic variants that predispose patients to these effects.


Assuntos
Antineoplásicos/toxicidade , Doenças Cardiovasculares/genética , Variação Genética , Genômica , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Animais , Cardiotoxicidade , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Células Cultivadas , Predisposição Genética para Doença , Ensaios de Triagem em Larga Escala , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Células-Tronco Pluripotentes Induzidas/patologia , Mutação , Variantes Farmacogenômicos , Fenótipo , Polimorfismo de Nucleotídeo Único , Medição de Risco , Fatores de Risco
20.
Biochem J ; 477(5): 937-951, 2020 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-32039434

RESUMO

The cisplatin-1,2-d(GpG) (Pt-GG) intrastrand cross-link is the predominant DNA lesion generated by cisplatin. Cisplatin has been shown to predominantly induce G to T mutations and Pt-GG permits significant misincorporation of dATP by human DNA polymerase ß (polß). In agreement, polß overexpression, which is frequently observed in cancer cells, is linked to cisplatin resistance and a mutator phenotype. However, the structural basis for the misincorporation of dATP opposite Pt-GG is unknown. Here, we report the first structures of a DNA polymerase inaccurately bypassing Pt-GG. We solved two structures of polß misincorporating dATP opposite the 5'-dG of Pt-GG in the presence of Mg2+ or Mn2+. The Mg2+-bound structure exhibits a sub-optimal conformation for catalysis, while the Mn2+-bound structure is in a catalytically more favorable semi-closed conformation. In both structures, dATP does not form a coplanar base pairing with Pt-GG. In the polß active site, the syn-dATP opposite Pt-GG appears to be stabilized by protein templating and pi stacking interactions, which resembles the polß-mediated dATP incorporation opposite an abasic site. Overall, our results suggest that the templating Pt-GG in the polß active site behaves like an abasic site, promoting the insertion of dATP in a non-instructional manner.


Assuntos
Antineoplásicos/química , Cisplatino/química , Dano ao DNA/fisiologia , DNA Polimerase Dirigida por DNA/química , DNA Polimerase Dirigida por DNA/genética , Mutagênese/fisiologia , Antineoplásicos/toxicidade , Cisplatino/toxicidade , Cristalografia por Raios X/métodos , Dano ao DNA/efeitos dos fármacos , Humanos , Mutagênese/efeitos dos fármacos , Estrutura Secundária de Proteína
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