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1.
Phytomedicine ; 70: 153215, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32388040

RESUMO

BACKGROUND: Recalcitrant cancers appear as a major obstacle to chemotherapy, prompting scientists to intensify the search for novel drugs to tackle the cell lines expressing multi-drug resistant (MDR) phenotypes. PURPOSE: The purpose of this study was to evaluate the antiproliferative potential of a ferrulic acid derivative, 8,8-bis-(dihydroconiferyl)-diferulate (DHCF2) on a panel of 18 cancer cell lines, including various sensitive and drug-resistant phenotypes, belonging to human and animals. The mode of induction of cell death by this compound was further studied. METHODS: The antiproliferative activity, autophagy, ferroptotic and necroptotic cell death were evaluated by the resazurin reduction assay (RRA). CCRF-CEM leukemia cells were used for all mechanistic studies. A caspase-Glo assay was applied to evaluate the activity of caspases. Cell cycle analysis (PI staining), apoptosis (annexin V/PI staining), mitochondrial membrane potential (MMP) (JC-1) and reactive oxygen species (ROS) (H2DCFH-DA) were assessed by flow cytometry. RESULTS: DHCF2 demonstrated impressive cytotoxic effects towards the 18 cancer cell lines tested, with IC50 values all below 6.5 µM. The obtained IC50 values were in the range of 1.17 µM (towards CCRF-CEM leukemia cells) to 6.34 µM (towards drug-resistant HCT116 p53-/- human colon adenocarcinoma cells) for DHCF2 and from 0.02 µM (against CCRF-CEM cells) to 122.96 µM (against multidrug-resistant CEM/ADR5000 leukemia cells) for the reference drug, doxorubicin. DHCF2 had IC50 values lower than those of doxorubicin, against CEM/ADR5000 cells and on some melanoma cell lines, such as MaMel-80a cells, Mel-2a cells, MV3 cells and SKMel-505 cells. DHCF2 induced autophagy as well as apoptosis in CCRF-CEM cells though caspases activation, MMP alteration and increase of ROS production. CONCLUSION: The studied diferulic acid, DHCF2, is a promising antiproliferative compound. It deserves further indepth investigations with the ultimate aim to develop a novel drug to fight cancer drug resistance.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/toxicidade , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral/efeitos dos fármacos , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Leucemia/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Doxorrubicina/uso terapêutico , Doxorrubicina/toxicidade , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Humanos , Camundongos , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Extratos Vegetais/toxicidade
2.
Int J Nanomedicine ; 15: 553-571, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32158208

RESUMO

Background: Breast cancer is the leading cause of cancer death in women. Chemotherapy to inhibit the proliferation of cancer cells is considered to be the most important therapeutic strategy. The development of long-circulating PEG and targeting liposomes is a major advance in drug delivery. However, the techniques used in liposome preparation mainly involve conventional liposomes, which have a short half-life, high concentrations in the liver and spleen reticuloendothelial system, and no active targeting. Methods: Four kinds of paclitaxel liposomes were prepared and characterized by various analytical techniques. The long-term targeting effect of liposomes was verified by fluorescence detection methods in vivo and in vitro. Pharmacokinetic and acute toxicity tests were conducted in ICR mice to evaluate the safety of different paclitaxel preparations. The antitumor activity of ES-SSL-PTX was investigated in detail using in vitro and in vivo human breast cancer MCF-7 cell models. Results: ER-targeting liposomes had a particle size of 137.93±1.22 nm and an acceptable encapsulation efficiency of 88.07±1.25%. The liposome preparation is best stored at 4°C, and is stable for up to 48 hrs. Cytotoxicity test on MCF-7 cells demonstrated the stronger cytotoxic activity of liposomes in comparison to free paclitaxel. We used the near-infrared fluorescence imaging technique to confirm that ES-SSL-PTX was effectively targeted and could quickly and specifically identify the tumor site. Pharmacokinetics and acute toxicity in vivo experiments were carried out. The results showed that ES-SSL-PTX could significantly prolong the half-life of the drug, increase its circulation time in vivo, improve its bioavailability and reduce its toxicity and side effects. ES-SSL-PTX can significantly improve the pharmacokinetic properties of paclitaxel, avoid allergic reaction of the original solvent, increase antitumor efficacy and reduce drug toxicity and side effects. Conclusion: ES-SSL-PTX has great potential for improving the treatment of breast cancer, thereby improving patient prognosis and quality of life.


Assuntos
Antineoplásicos Fitogênicos/farmacocinética , Sistemas de Liberação de Medicamentos/métodos , Lipossomos/farmacocinética , Paclitaxel/farmacocinética , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/toxicidade , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Meia-Vida , Humanos , Lipossomos/química , Lipossomos/toxicidade , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos ICR , Paclitaxel/administração & dosagem , Paclitaxel/toxicidade , Testes de Toxicidade Aguda , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Toxicon ; 176: 15-20, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31965969

RESUMO

Podophyllotoxin (PPT) is a lignan extracted from podophyllum genera and it shows potent antitumor activity since it could effectively inhibit the assembly of microtubule in tumor cells. However, the effects of podophyllotoxin exposure on porcine oocyte quality is still unclear. In present study we tried to examine whether podophyllotoxin exposure was toxic to porcine oocyte maturation. Our results showed that podophyllotoxin exposure inhibited porcine oocyte maturation, showing with the failure of polar body extrusion, and the inhibitory effects of podophyllotoxin on porcine oocytes was dose-depended. Moreover, the meiotic spindle formation was disturbed and the chromosomes were misaligned in the podophyllotoxin-treated porcine oocytes. However, there was no different expression for p-MAPK and ace-tubulin between the control and podophyllotoxin treatment group. In addition, after 0.01 µM podophyllotoxin treatment, the intracellular reactive oxygen species (ROS) levels and the Annexin-V signal at MI stage significantly increased compared to the control group, indicating the occurrence of oxidative stress and early apoptosis. Taken together, our results suggested that the toxic effects of podophyllotoxin exposure on porcine oocyte maturation might be through its effects on spindle formation and the induction of oxidative stress-mediated early apoptosis.


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Oócitos/efeitos dos fármacos , Estresse Oxidativo/fisiologia , Podofilotoxina/toxicidade , Animais , Apoptose , Ciclo Celular , Espécies Reativas de Oxigênio , Suínos
4.
Nutrients ; 12(1)2020 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-31963833

RESUMO

Uncontrolled growth and migration and invasion abilities are common for cancer cells in malignant tumors with low therapeutic effectiveness and high mortality and morbidity. Estrogen receptor ß (ERß), as a member of the nuclear receptor superfamily, shows potent tumor suppressive activities in many cancers. Phytoestrogens' structural resemblance to 17 ß-estradiol allows their binding to ERß isoform predominantly, and therefore, expression of genes connected with elevated proliferation, motility and invasiveness of cancer cells may be downregulated. Among polyphenolic compounds with phytoestrogenic activity, there are isoflavones from Trifolium pratense L. (red clover) sprouts, containing high amounts of formononetin and biochanin A and their glycosides. To determine the source of the most biologically active isoflavones, we obtained four extracts from sprouts before and after their lactic fermentation and/or ß-glucosidase treatment. Our previous results of ITC (isothermal titration calorimetry) modelling and a docking simulation showed clover isoflavones' affinity to ERß binding, which may downregulate cancer cell proliferation and migration. Thus, the biological activity of T. pratense sprouts' extracts was checked under in vitro conditions against highly invasive human breast cancer cell line MDA-MB-231 and non-invasive human breast cancer cell line MCF-7 cells. To compare extracts' activities acquired for cancer cells with those activities against normal cells, as a third model we choose human umbilical vein endothelial cells (HUVEC), which, due to their migration abilities, are involved in blood vessel formation. Extracts obtained from fermented sprouts at IC0 dosages were able to inhibit migration of breast cancer cells through their influence on intracellular ROS generation; membrane stiffening; adhesion; regulation of MMP-9, N-cadherin and E-cadherin at transcriptional level; or VEGF secretion. Simultaneously, isolated phenolics revealed no toxicity against normal HUVEC cells. In the manuscript, we proposed a preliminary mechanism accounting for the in vitro activity of Trifolium pratense L. isoflavones. In this manner, T. pratense sprouts, especially after their lactic fermentation, can be considered a potent source of biological active phytoestrogens and a dietary supplement with anti-cancer and anti-invasion properties.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Neoplasias da Mama/dietoterapia , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Trifolium , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/toxicidade , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Células MCF-7 , Invasividade Neoplásica , Fenóis/isolamento & purificação , Fenóis/toxicidade , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/toxicidade , Transdução de Sinais , Trifolium/química
5.
Planta Med ; 86(2): 104-112, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31777055

RESUMO

Cholangiocarcinoma (CCA) remains a significant public health problem in Thailand. New effective and safe drugs are urgently needed. Zingiber officinale Roscoe (ZO) is a widely used medicinal plant for the treatment of several ailments, and the animal study suggests a potential anti-CCA activity. The present study aimed to develop the oral formulation of standardized extract of ZO and investigate toxicological profiles (acute, repeated dose, and chronic toxicity), including anti-CCA activity of the ZO formulation. The oral pharmaceutical formulation of the standardized ZO extract was successfully developed with an acceptable level of contamination and physicochemical and pharmaceutical properties. Acute, subacute, and chronic toxicity tests were conducted in healthy Sprague Dawley rats according to the OECD guidelines. The results showed no evidence of toxicity and death in the acute and subacute toxicity testing with the maximum tolerated dose (MTD) of 5000 and 2000 mg/kg body weight, respectively. Chronic toxicity revealed MTD and No-Observed-Adverse-Effect level (NOAEL) of 1000 mg/kg body weight. The anti-CCA activity was evaluated in CCA-xenografted mouse model. The formulated ZO powder was fed to animals daily for 30 days. Significant anti-CCA activity on tumor growth inhibition and prolongation of survival time were demonstrated at the high (2000 mg/kg body weight) and moderate (1000 mg/kg body weight) dose levels. Further investigation to elucidate molecular targets of action of ZO against CCA cells is encouraged.


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Gengibre/química , Extratos Vegetais/toxicidade , Administração Oral , Animais , Antineoplásicos Fitogênicos/uso terapêutico , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Extratos Vegetais/uso terapêutico , Ratos , Ratos Sprague-Dawley , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Life Sci ; 244: 117095, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31816326

RESUMO

AIMS: Investigate Melatonin administration along with Vincristine (VCR) owing to two reasons: First, Melatonin's sciatic nerve protective effect against Chemotherapy Induced Peripheral Neuropathy (CIPN). Second, Vincristine's anticancer work potentiation that may lead to a decrease in its dose and its side effects accordingly. MAIN METHODS: In vivo and in vitro experiments were conducted in the study. The in vivo experiment included developing a CIPN Wistar Albino rat model. They were injected with VCR sulfate to induce CIPN, while Melatonin and Pregabalin (neuroleptic) were co-administered with the aim of investigating the degeneration/protection of the sciatic nerve. Tail Immersion Test and histopathological analyses were done to validate the experimental model (induction of rat peripheral neurodegeneration) and examine the possible Melatonin and Pregabalin protective/analgesic effects respectively. Liver and kidney function tests, catalase activity and malondialdehyde (MDA) level were measured. Concerning the in vitro experiment, cell viability assays in addition to ELISA (for caspases 3&9) were conducted using HCT-116 colon cancer cell line treated with VCR, Melatonin and their combination. KEY FINDINGS: VCR caused an elevated level of oxidation (MDA level increment) in the sciatic nerve, while Melatonin could prove its antioxidant effect through increasing catalase activity (antioxidant enzyme) with no significant toxic effect on body's functions. HCT-116 in vitro test proved the strong cytotoxic effect of VCR in addition to the synergistic effect of combining Melatonin to VCR on the cellular apoptotic level (caspases 3&9 increased activity levels) and inhibitory concentration 50%. SIGNIFICANCE: Melatonin possesses an antioxidant property that can protect the sciatic nerve from CIPN-induced degeneration and potentiate VCR's anticancer effect at the same time.


Assuntos
Sinergismo Farmacológico , Melatonina/uso terapêutico , Doenças do Sistema Nervoso Periférico/prevenção & controle , Pregabalina/uso terapêutico , Vincristina/toxicidade , Animais , Anticonvulsivantes/uso terapêutico , Antineoplásicos Fitogênicos/toxicidade , Antioxidantes/uso terapêutico , Masculino , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Ratos , Ratos Wistar
7.
J Biochem Mol Toxicol ; 34(1): e22415, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31682045

RESUMO

The aim of this study was to assess the therapeutic potential of oxytocin and liraglutide (LIR), a GLP-1 analogue, in a rat model of vincristine-induced neuropathy. Rats were injected with vincristine (VCR) at a dose of 4 mg/kg twice a week for 5 weeks. The VCR-administered rats were divided into three groups and received saline, oxytocin, or liraglutide simultaneously with VCR. After the treatment period, electrophysiological, biochemical, histological, and immunohistochemical investigations were performed. Electromyography (EMG) recordings demonstrated significant alterations in the VCR + saline group (p < .001). Also, motor performance was decreased in the VCR + saline group (p < .05). Histologically, the axonal diameter was decreased in all groups. VCR + saline group showed significantly increased lipid peroxidation and decreased nerve growth factor (NGF) expression. However, the administration of oxytocin and liraglutide significantly prevented the EMG alterations, lipid peroxidation, and reduction in neuronal NGF expression. On the basis of these findings, oxytocin and liraglutide may be considered as potential agents for the prevention of VCR-induced neuropathy.


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Liraglutida/uso terapêutico , Doenças do Sistema Nervoso/tratamento farmacológico , Ocitocina/uso terapêutico , Vincristina/toxicidade , Animais , Liraglutida/administração & dosagem , Masculino , Doenças do Sistema Nervoso/induzido quimicamente , Ocitocina/administração & dosagem , Ratos , Ratos Sprague-Dawley
8.
J Neuroinflammation ; 16(1): 209, 2019 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-31707979

RESUMO

BACKGROUND: Paclitaxel is a widely used and potent chemotherapeutic agent for the treatment of cancer. However, patients receiving paclitaxel often develop an acute pain syndrome for which there are few treatment options. Astrocytes play an important role in the pathogenesis of pain in multiple preclinical models, as well as in paclitaxel-treated rodents. However, it is still unclear what the exact contribution of astrocytes may be in paclitaxel-associated acute pain syndrome (P-APS). METHODS: P-APS was modeled by a single systemic or intrathecal injection of paclitaxel and astrocyte contribution tested by immunohistochemical, pharmacological, and behavioral approaches. Cell cultures were also prepared to assess whether paclitaxel treatment directly activates astrocytes and whether intrathecal injection of paclitaxel-treated astrocytes produces pain that is reminiscent of P-APS. RESULTS: Systemic injection of paclitaxel resulted in increased expression of glial fibrillary acidic protein (a common marker of astrocytic activation), as well as both systemic or intrathecal injection of paclitaxel induced pain hypersensitivity indicated by the development of mechanical allodynia, which was significantly reversed by the astrocytic inhibitor L-α-AA. Cultured astrocytes were activated by paclitaxel with significant increases in protein levels for tumor necrosis factor-α (TNF-α) and stromal-derived cell factor 1 (SDF-1). Importantly, intrathecal injection of paclitaxel-activated astrocytes produced mechanical allodynia that was reversed by TNF-α and SDF-1 neutralizing antibodies. CONCLUSION: Our results suggest for the first time that paclitaxel can directly activate astrocytes, which are sufficient to produce acute pain by releasing TNF-α and SDF-1. Targeting astrocytes and these cytokines may offer new treatments for P-APS.


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Astrócitos/metabolismo , Quimiocina CXCL12/metabolismo , Hiperalgesia/metabolismo , Paclitaxel/toxicidade , Fator de Necrose Tumoral alfa/metabolismo , Animais , Astrócitos/efeitos dos fármacos , Feminino , Hiperalgesia/induzido quimicamente , Masculino , Camundongos
9.
Int J Mol Sci ; 20(23)2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31775332

RESUMO

Paclitaxel-induced peripheral neuropathy is a common adverse effect during paclitaxel treatment resulting in sensory abnormalities and neuropathic pain during chemotherapy and in cancer survivors. Conventional therapies are usually ineffective and possess adverse effects. Here, we examined the effects of electroacupuncture (EA) on a rat model of paclitaxel-induced neuropathic pain and related mechanisms. EA robustly and persistently alleviated paclitaxel-induced pain hypersensitivities. Mechanistically, TLR4 (Toll-Like Receptor 4) and downstream signaling MyD88 (Myeloid Differentiation Primary Response 88) and TRPV1 (Transient Receptor Potential Vallinoid 1) were upregulated in dorsal root ganglion (DRGs) of paclitaxel-treated rats, whereas EA reduced their overexpression. Ca2+ imaging further indicated that TRPV1 channel activity was enhanced in DRG neurons of paclitaxel-treated rats whereas EA suppressed the enhanced TRPV1 channel activity. Pharmacological blocking of TRPV1 mimics the analgesic effects of EA on the pain hypersensitivities, whereas capsaicin reversed EA's effect. Spinal astrocytes and microglia were activated in paclitaxel-treated rats, whereas EA reduced the activation. These results demonstrated that EA alleviates paclitaxel-induced peripheral neuropathic pain via mechanisms possibly involving suppressing TLR4 signaling and TRPV1 upregulation in DRG neurons, which further result in reduced spinal glia activation. Our work supports EA as a potential alternative therapy for paclitaxel-induced neuropathic pain.


Assuntos
Eletroacupuntura/métodos , Neuralgia/prevenção & controle , Paclitaxel/toxicidade , Doenças do Sistema Nervoso Periférico/prevenção & controle , Células Receptoras Sensoriais/metabolismo , Canais de Cátion TRPV/antagonistas & inibidores , Receptor 4 Toll-Like/antagonistas & inibidores , Animais , Antineoplásicos Fitogênicos/toxicidade , Regulação da Expressão Gênica , Masculino , Fator 88 de Diferenciação Mieloide/antagonistas & inibidores , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Neuralgia/induzido quimicamente , Neuralgia/metabolismo , Neuralgia/patologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/metabolismo , Doenças do Sistema Nervoso Periférico/patologia , Ratos , Ratos Sprague-Dawley , Células Receptoras Sensoriais/efeitos dos fármacos , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
10.
Pak J Pharm Sci ; 32(3 (Supplementary)): 1145-1154, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31303583

RESUMO

Survivin (IAP proteins) is considered as a significant target for anticancer drug research owing to its upregulation in tumor cells to mediate resistance to apoptotic stimulus. The current study aimed to investigate phytochemicals as inhibitors of survivin with caspases to reactivate the functioning of caspases through molecular docking. The compounds namely 2(R), 4(R)-dihydroxypyrrolidine, 4-hydroxy-2-(4-methoxyphenyl)-1,1-dioxo-3,4-dihydrothieno[3,2-e]thiazine-6-sulfonamide, 2,3-Diketo-L-gulonic acid, (3-hydroxy-2-octadeca-9,12-dienoyloxypropyl) octadecanoate, 2-[[4-[[4-[(4-formamido-1-methylimidazole-2-carbonyl)amino]-1-methylimidazole-2-carbonyl]amino]-1-methylimidazole-2-carbonyl]amino]ethyl-dimethylazanium, Picolinic acid and (2-Hydroxy-5-nitrophenyl) dihydrogen phosphate successfully bind inside the pocket of survivin. ADMETsar was used to evaluate the anticancer potential of selected compounds. These compounds can be proposed as effective inhibitors, disrupting the survivin-caspases interaction and reactivating the caspases function of apoptosis. The study might facilitate the development of cost-effective and natural drugs against cancer. However, further validation is essential for confirmation of its drug efficacy and bio-compatibility.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais/métodos , Compostos Fitoquímicos/farmacologia , Survivina/antagonistas & inibidores , Survivina/química , Antineoplásicos Fitogênicos/farmacocinética , Antineoplásicos Fitogênicos/toxicidade , Caspases/metabolismo , Simulação por Computador , Humanos , Simulação de Acoplamento Molecular , Terapia de Alvo Molecular , Compostos Fitoquímicos/farmacocinética , Compostos Fitoquímicos/toxicidade , Conformação Proteica , Survivina/metabolismo , Distribuição Tecidual
11.
Toxicology ; 424: 152231, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31170432

RESUMO

Many drugs exert serious cytotoxic effects on pulmonary tissues. Although several reports have shown an association of epithelial-mesenchymal transition (EMT) with anticancer drug-induced lung injury, mechanisms of these effects are poorly understood. In the present study, we evaluated mechanisms of anticancer drug-induced EMT, with a focus on involvement of cell cycle arrest. We found that methotrexate (MTX) altered mRNA expression levels of many genes as determined by microarray analysis. Gene set enrichment analysis revealed that cell cycle arrest pathways may be associated with MTX-induced EMT. In addition, thymidine (THY) and nocodazole (NOC), which induce cell cycle arrest at S-phase and G2/M-phase, increased mRNA expression levels of α-smooth muscle actin (SMA), an EMT marker. Furthermore, α-SMA protein expression in cells arrested at S- and G2/M-phases by MTX and paclitaxel (PTX) was significantly higher than that in cells at G1. Notably, co-treatment of cells with THY or NOC and EMT-inducing anticancer drugs did not result in additional upregulation of α-SMA mRNA expression. These findings suggested that cell cycle arrest may be closely associated with anticancer drug-induced EMT in alveolar epithelial cells.


Assuntos
Células Epiteliais Alveolares/efeitos dos fármacos , Antineoplásicos/toxicidade , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Células A549 , Actinas/biossíntese , Antimetabólitos Antineoplásicos/toxicidade , Antineoplásicos Fitogênicos/toxicidade , Linhagem Celular Tumoral , Humanos , Metotrexato/toxicidade , Nocodazol/farmacologia , Paclitaxel/toxicidade , Timidina/farmacologia
12.
Chin J Nat Med ; 17(5): 381-386, 2019 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-31171273

RESUMO

Three new prenylated stilbenes, named as cajanusins A-C (1-3), and one new natural product cajanusin D (4), along with six known derivatives (5-10) were isolated from the leaves of Cajanus cajan. Their structures were fully elucidated by means of extensive spectroscopic methods and comparison with data in the reported literatures. The new compounds of 1 and 2 were evaluated for in vitro cytotoxic activities against a panel of human cancer cell lines.


Assuntos
Antineoplásicos Fitogênicos/química , Cajanus/química , Flavonoides/química , Estilbenos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/toxicidade , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Flavonoides/isolamento & purificação , Humanos , Estrutura Molecular , Extratos Vegetais/química , Folhas de Planta/química , Estilbenos/isolamento & purificação , Estilbenos/toxicidade
13.
Neurobiol Dis ; 130: 104492, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31176721

RESUMO

BACKGROUND: Vincristine, a widely used antineoplastic agent, is known to be neurotoxic and to lead to chemotherapy-induced peripheral neuropathy (CIPN), which is characterized by nerve damage. Growing evidence suggests that disruption of intracellular calcium homeostasis in peripheral neurons contributes largely to the pathological conditions of CIPN. Our previous study showed that forced expression of a peripheral nerve injury-induced small heat shock protein (Hsp), Hsp27, accelerates axon regeneration and functional recovery. In the current study, we examined whether neuronal expression of human Hsp27 (hHsp27) can prevent the inhibitory effects of vincristine in two mouse models of peripheral nerve injury, namely, sciatic nerve crush and CIPN. METHODS: The protective effects of hHsp27 against vincristine were examined in mouse models of both sciatic nerve crush and CIPN using multiple approaches, including animal behavioral tests, histology, electrophysiology, transmission electron microscopy and calcium imaging. RESULTS: Vincristine delayed functional recovery in littermate mice; however, hHsp27 Tg mice were unaffected after vincristine treatment and sciatic nerve crush. In CIPN mice, hHsp27 protected against vincristine-induced mechanical and cold allodynia by preventing axonal degeneration, demyelination, mitochondrial dysfunction, and apoptosis. Strikingly, vincristine-induced calcium influx was markedly attenuated in sensory neurons of hHsp27 Tg mice. CONCLUSIONS: Our findings suggest that preserving myelin and mitochondrial integrity as well as maintaining intracellular calcium homeostasis is beneficial for preventing CIPN, and these findings shed new light on the development of anti-CIPN drugs.


Assuntos
Cálcio/metabolismo , Proteínas de Choque Térmico HSP27/metabolismo , Mitocôndrias/metabolismo , Síndromes Neurotóxicas/metabolismo , Doenças do Sistema Nervoso Periférico/metabolismo , Animais , Antineoplásicos Fitogênicos/toxicidade , Homeostase/fisiologia , Humanos , Camundongos , Camundongos Transgênicos , Síndromes Neurotóxicas/patologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/patologia , Vincristina/toxicidade
14.
J Ethnopharmacol ; 241: 112004, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31152784

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Extracts, essential oils and molecules from Casearia sylvestris have popularly shown pharmacological actions against chronic diseases, as anxiety, inflammation, cancer and dyslipidemia. In the context of antitumoral therapy, we investigated in vitro, ex vivo and in vivo toxicological changes induced by a Fraction with Casearins (FC) and its component Casearin X isolated from C. sylvestris on animal and vegetal cells, and upon invertebrates and mammals. MATERIAL AND METHODS: Cytotoxicity was carried out using normal lines and absorbance and flow cytometry techniques, Artemia salina nauplii, Danio rerio embryos and meristematic cells from Allium cepa roots. Acute and 30 days-mice analysis were done by behavioral, hematological and histological investigations and DNA/chromosomal damages detected by alkaline Cometa and micronucleus assays. RESULTS: FC was cytotoxic against lung and fibroblasts cells and caused DNA breaks, loss of integrity and mitochondrial depolarization on ex vivo human leukocytes. It revealed 24 h-LC50 values of 48.8 and 36.7 µg/mL on A. salina nauplii and D. rerio embryos, reduced mitotic index of A. cepa roots, leading to cell cycle arrest at metaphase and anaphase and micronuclei. FC showed i.p. and oral LD50 values of 80.9 and 267.1 mg/kg body weight. Subacute i.p. injections induced loss of weight, swelling of hepatocytes and tubules, tubular and glomerular hemorrhage, microvesicular steatosis, lung inflammatory infiltration, augment of GPT, decrease of albumin, alkaline phosphatase, glucose, erythrocytes, and lymphocytes, and neutrophilia (p > 0.05). FC-treated animals at 10 mg/kg/day i.p. caused micronuclei in bone marrow and DNA strand breaks in peripheral leukocytes. CONCLUSIONS: This research postulated suggestive side effects after use of FC-related drugs, demonstrating FC as antiproliferative and genotoxic on mammal and meristematic cells, including human leukocytes, teratogenicity upon zebrafish embryos, myelosuppression, clastogenicity, and morphological and biochemical markers indicating liver as main target for FC-induced systemic toxicity.


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Casearia , Diterpenos Clerodânicos/toxicidade , Animais , Brasil , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cricetulus , Embrião não Mamífero/efeitos dos fármacos , Feminino , Fibroblastos/efeitos dos fármacos , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Medicina Tradicional , Meristema/citologia , Camundongos , Cebolas , Testes de Toxicidade , Peixe-Zebra
15.
DNA Cell Biol ; 38(7): 651-659, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31140859

RESUMO

Breast cancer is the leading cause of death in women. Although numerous clinical regimens are used to treat breast cancer and manifest satisfied efficacy, drug resistance is emerging as the major obstacle to their long-term use. It is critically necessary to decipher the molecular mechanism underlying this process to obtain improved and long-term use of each regimen. In the present study, we showed the negative relationship between EZH2 and chemoresistance to taxol in breast cancer cells. EZH2 interference was capable of decreasing while overexpression increasing apoptosis of breast cancer cells challenged with taxol. Meanwhile, p21, the inhibitor of cell cycle entry, interference upregulated, while overexpression downregulated apoptosis induced by taxol. Mechanistically, EZH2 was recruited to the promoter of p21 accompanied with H3K27me3 enrichment and transcription silencing. Collectively, EZH2 attenuates chemoresistance of breast cancer cells to taxol by dampening p21 epigenetically.


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Neoplasias da Mama/genética , Inibidor de Quinase Dependente de Ciclina p21/genética , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Epigênese Genética , Paclitaxel/toxicidade , Apoptose/efeitos dos fármacos , Neoplasias da Mama/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Resistencia a Medicamentos Antineoplásicos , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Feminino , Humanos , Células MCF-7
16.
Fitoterapia ; 136: 104161, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31048010

RESUMO

Ailanthone (AIL) has many biological activities including antimalarial, antiviral and anticancer. Our previous study also found that AIL targets p23 against castration-resistant prostate cancer. In this report, the preclinical safety of AIL was evaluated by acute toxicity, subacute toxicity and toxicokinetics in mice. In the acute toxicity study, the LD50 of AIL was 27.3 mg/kg, and severe pathological damages were mainly found in the liver and gastrointestinal tract. In the subacute toxicity study, mice were orally administered at doses of 2.5, 5 and 10 mg/kg for 28 days. The results showed the body weight of male mice in the 10 mg/kg dose group decreased, but that of female mice increased. Biochemical and histopathological analysis showed that AIL could cause steatohepatitis, splenomegaly, gastrointestinal mucosal damage and reproductive system abnormalities. In addition, AIL presented the reversible hematotoxicity. To determine the relationship between AIL toxicity and dose/exposure in vivo, toxicokinetics of AIL were carried out after a single oral dose of 15 mg/kg. The stomach was identified as the main target organ, followed by the intestine and kidney. On the basis of this study, the dose of 2.5 mg/kg had no adverse effect on mice. To sum up, this study is the first time to evaluate the systemic toxicity of AIL, which is useful for the further development of AIL.


Assuntos
Antineoplásicos Fitogênicos/toxicidade , Fígado/efeitos dos fármacos , Neoplasias de Próstata Resistentes à Castração , Quassinas/toxicidade , Animais , Antineoplásicos Fitogênicos/farmacologia , Feminino , Masculino , Camundongos , Quassinas/farmacologia , Testes de Toxicidade Aguda , Testes de Toxicidade Subaguda , Toxicocinética
17.
Chin J Nat Med ; 17(4): 291-297, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31076132

RESUMO

Eight new annonaceous acetogenins, squamotin A-D (1-4), annosquatin IV-V (5 and 6), muricin O (7) and squamosten B (8), together with four known ones (9-12) were isolated from the seeds of Annona squamosa. Their structures were elucidated by chemical methods and spectral data. The inhibitory activities of compound 1-9 against three multidrug resistance cell lines were evaluated. All tested compounds showed strong cytotoxicity.


Assuntos
Acetogeninas/toxicidade , Annona/química , Sobrevivência Celular/efeitos dos fármacos , Sementes/química , Acetogeninas/química , Acetogeninas/isolamento & purificação , Acetogeninas/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/toxicidade , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Extratos Vegetais/toxicidade
18.
Neuron ; 102(5): 944-959.e3, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31030955

RESUMO

Hyperexcitability of the anterior cingulate cortex (ACC) is thought to drive aversion associated with chronic neuropathic pain. Here, we studied the contribution of input from the mediodorsal thalamus (MD) to ACC, using sciatic nerve injury and chemotherapy-induced mouse models of neuropathic pain. Activating MD inputs elicited pain-related aversion in both models. Unexpectedly, excitatory responses of layer V ACC neurons to MD inputs were significantly weaker in pain models compared to controls. This caused the ratio between excitation and feedforward inhibition elicited by MD input to shift toward inhibition, specifically for subcortically projecting (SC) layer V neurons. Furthermore, direct inhibition of SC neurons reproduced the pain-related aversion elicited by activating MD inputs. Finally, both the ability to elicit pain-related aversion and the decrease in excitation were specific to MD inputs; activating basolateral amygdala inputs produced opposite effects. Thus, chronic pain-related aversion may reflect activity changes in specific pathways, rather than generalized ACC hyperactivity.


Assuntos
Aprendizagem da Esquiva/fisiologia , Complexo Nuclear Basolateral da Amígdala/fisiopatologia , Dor Crônica/fisiopatologia , Giro do Cíngulo/fisiopatologia , Núcleo Mediodorsal do Tálamo/fisiopatologia , Neuralgia/fisiopatologia , Animais , Antineoplásicos Fitogênicos/toxicidade , Dor Crônica/induzido quimicamente , Dor Crônica/etiologia , Potenciais Pós-Sinápticos Excitadores , Masculino , Camundongos , Vias Neurais/fisiopatologia , Neuralgia/induzido quimicamente , Neuralgia/etiologia , Paclitaxel/toxicidade , Técnicas de Patch-Clamp , Nervo Isquiático/lesões
19.
Phytomedicine ; 60: 152832, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31031043

RESUMO

BACKGROUND: Successful cancer chemotherapy is hampered by resistance of cancer cells to established anticancer drugs. Numerous natural products reveal cytotoxicity towards tumor cells. PURPOSE: The present study was aimed to determine the cytotoxicity of a betaine-type alkaloid, ungeremine, towards 9 cancer cell lines including various sensitive and drug-resistant phenotypes. The mode of action of this compound was further investigated. METHODS: The cytotoxicity, ferroptotic and necroptotic cell death were determined by the resazurin reduction assay. Caspase activation was evaluated using the caspase-Glo assay. Flow cytometry was applied for the analysis of cell cycle analysis (PI staining), apoptosis (annexin V/PI staining), mitochondrial membrane potential (MMP) (JC-1) and reactive oxygen species (ROS) (H2DCFH-DA). Apoptotic, necroptotic and autophagic markers were determined by Western blotting. CCRF-CEM leukemia cells were used for all mechanistic studies. RESULTS: Ungeremine displayed cytotoxic activity towards the 9 cancer cell lines tested, including drug-sensitive and MDR phenotypes. The IC50values obtained varied from 3.67 µM (in MDA-MB-231-BCRP breast carcinoma cells) to 75.24 µM (against in CEM/ADR5000 leukemia cells) for ungeremine and from 0.02 µM (against CCRF-CEM cells) to 122.96 µM (against CEM/ADR5000 cells) for doxorubicin (control drug). Ungeremine induced ferroptosis, necroptosis, autophagy as well as apoptosis mediated by caspase activation, MMP alteration and increase ROS production. CONCLUSION: The present investigation showed that ungeremine is a promising cytotoxic compoundthat could be further explored in the future to develop new anticancer drugs to fight sensitive and resistant phenotypes.


Assuntos
Alcaloides/toxicidade , Alcaloides de Amaryllidaceae/toxicidade , Antineoplásicos Fitogênicos/toxicidade , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Indolizinas/toxicidade , Extratos Vegetais/toxicidade , Alcaloides de Amaryllidaceae/química , Antineoplásicos Fitogênicos/química , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Indolizinas/química , Extratos Vegetais/química , Espécies Reativas de Oxigênio/metabolismo
20.
Theriogenology ; 132: 201-211, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31029850

RESUMO

Cancer is a major public health problem, young cancer patients therefore undergo chemotherapy, and most of them may lose their fertility. DNA damage level provides important clues about the quality and reproductive potential of spermatozoa. In this study, we evaluated the levels of both DNA fragmentation and abnormal DNA integrity in the epididymal sperms of New Zealand rabbit (Oryctolagus cuniculus) after cryopreservation using the terminal deoxyribonucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) assay and the toluidine blue (TB) staining methods and assessed the effects of paclitaxel, resveratrol, l-glutamine (LG), and basal medium eagle (BME) solution on DNA damage. Paclitaxel induced the levels of both DNA damages in the sperms, but resveratrol ameliorated this effect. LG and BME supplementation to the extender prevented the sperm samples from DNA fragmentation after cryopreservation. Chemotherapy drugs containing paclitaxel can cause the sperm DNA to be damaged, and hence adversely affect the fertility of male cancer patients of reproductive age. The administration of resveratrol together with paclitaxel may ameliorate the DNA damage inducing effect of paclitaxel. Sperm banking and cryopreservation with the appropriate cryoprotectants such as LG and BME prior to cancer treatment can also be suggested to all male cancer patients of reproductive age facing cancer treatment for fertility preservation.


Assuntos
Dano ao DNA/efeitos dos fármacos , Epididimo/fisiologia , Paclitaxel/toxicidade , Resveratrol/farmacologia , Espermatozoides/efeitos dos fármacos , Animais , Antineoplásicos Fitogênicos/toxicidade , Glutamina/farmacologia , Humanos , Marcação In Situ das Extremidades Cortadas , Masculino , Coelhos
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