RESUMO
The expression and function of many ion channels and transporters in cancer cells display major differences in comparison to those from healthy cells. These differences provide the cancer cells with advantages for tumor development. Accordingly, targeting ion channels and transporters have beneficial anticancer effects including inhibition of cancer cell proliferation, migration, invasion, metastasis, tumor vascularization, and chemotherapy resistance, as well as promoting apoptosis. Some of the molecular mechanisms associating ion channels and transporters with cancer include the participation of oxidative stress, immune response, metabolic pathways, drug synergism, as well as noncanonical functions of ion channels. This diversity of mechanisms offers an exciting possibility to suggest novel and more effective therapeutic approaches to fight cancer. Here, we review and discuss most of the current knowledge suggesting novel therapeutic approaches for cancer therapy targeting ion channels and transporters. The role and regulation of ion channels and transporters in cancer provide a plethora of exceptional opportunities in drug design, as well as novel and promising therapeutic approaches that may be used for the benefit of cancer patients.
Assuntos
Neoplasias , Apoptose , Proliferação de Células , Humanos , Canais Iônicos , Neoplasias/patologia , Neovascularização PatológicaRESUMO
BACKGROUND: The nuclear envelope (NE), which is composed of the outer and inner nuclear membranes, the nuclear pore complex and the nuclear lamina, regulates a plethora of cellular processes, including those that restrict cancer development (genomic stability, cell cycle regulation, and cell migration). Thus, impaired NE is functionally related to tumorigenesis, and monitoring of NE alterations is used to diagnose cancer. However, the chronology of NE changes occurring during cancer evolution and the connection between them remained to be precisely defined, due to the lack of appropriate cell models. METHODS: The expression and subcellular localization of NE proteins (lamins A/C and B1 and the inner nuclear membrane proteins emerin and ß-dystroglycan [ß-DG]) during prostate cancer progression were analyzed, using confocal microscopy and western blot assays, and a prostate cancer cell system comprising RWPE-1 epithelial prostate cells and several prostate cancer cell lines with different invasiveness. RESULTS: Deformed nuclei and the mislocalization and low expression of lamin A/C, lamin B1, and emerin became more prominent as the invasiveness of the prostate cancer lines increased. Suppression of lamin A/C expression was an early event during prostate cancer evolution, while a more extensive deregulation of NE proteins, including ß-DG, occurred in metastatic prostate cells. CONCLUSIONS: The RWPE-1 cell line-based system was found to be suitable for the correlation of NE impairment with prostate cancer invasiveness and determination of the chronology of NE alterations during prostate carcinogenesis. Further study of this cell system would help to identify biomarkers for prostate cancer prognosis and diagnosis.
Assuntos
Lamina Tipo A , Lamina Tipo B , Proteínas de Membrana , Membrana Nuclear , Proteínas Nucleares , Neoplasias da Próstata , Masculino , Humanos , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Neoplasias da Próstata/genética , Membrana Nuclear/metabolismo , Linhagem Celular Tumoral , Proteínas de Membrana/metabolismo , Lamina Tipo B/metabolismo , Lamina Tipo A/metabolismo , Lamina Tipo A/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Distroglicanas/metabolismo , Regulação Neoplásica da Expressão Gênica , Núcleo Celular/metabolismoRESUMO
Cervical cancer is the fourth most common cancer among women worldwide. The main factor associated with the onset and progression of this neoplasia is the human papillomavirus (HPV) infection. The HPV-oncogenes E6 and E7 are critical drivers of cellular transformation, promoting the expression of oncogenes such as KCNH1. The phytochemical α-mangostin (AM) is a potent antineoplastic and antiviral compound. However, its effects on HPV oncogenes and KCNH1 gene expression remain unknown. This study evaluated the effects of AM on cell proliferation, cell cycle distribution and gene expression, including its effects on tumor growth in xenografted mice. AM inhibited cell proliferation in a concentration-dependent manner, being the most sensitive cell lines those with the highest number of HPV16 copies. In addition, AM promoted G1-cell cycle arrest in CaSki cells, while led to cell death in SiHa and HeLa cells. Of interest was the finding of an AM-dependent decreased gene expression of E6, E7 and KCNH1 both in vitro and in vivo, as well as the modulation of cytokine expression, Ki-67, and tumor growth inhibition. On these bases, we suggest that AM represents a good option as an adjuvant for the treatment and prevention of cervical cancer.
Assuntos
Proteínas Oncogênicas Virais , Infecções por Papillomavirus , Neoplasias do Colo do Útero , Humanos , Feminino , Animais , Camundongos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/metabolismo , Células HeLa , Proteínas E7 de Papillomavirus/genética , Proteínas E7 de Papillomavirus/metabolismo , Proteínas Repressoras/genética , Oncogenes , Proliferação de Células , Expressão Gênica , Canais de Potássio Éter-A-Go-Go/genéticaRESUMO
BACKGROUND: The aim of the study was to analyze the clinical manifestations and outcome of the oldest old (people aged ≥85 years) who were admitted to the hospital with a confirmed influenza A virus infection in comparison with younger patients and to assess the role of inflammation in the outcome of influenza infection in this population. METHODS: This is an observational prospective study including all adult patients with influenza A virus infection hospitalized in a tertiary teaching hospital in Madrid, in 2 consecutive influenza seasons (2016-17 and 2017-18). RESULTS: Five hundred nine hospitalized patients with influenza A infection were included, of whom 117 (23%) were older than 85 years (median age: 89.3 ± 3.2). We compared the clinical characteristics and outcome with those of the rest of the population (median age: 72.8 ± 15.7). Overall, mortality was higher in older patients (10% vs. 4%; p = 0.03) with no differences in clinical presentation. Patients older than 85 years who ultimately died (12 out of 117) showed increased systemic inflammation expressed by higher levels of C-reactive protein (CRP) and ferritin compared to survivors who were discharged (odds ratio [OR] of CRP >20 mg/dL: 5.16, 95% confidence interval [CI]: 1.29-20.57, and OR of ferritin >500 mg: 4.3, 95% CI: 1.04-17.35). CONCLUSIONS: Patients aged 85 and older with influenza A virus infection presented a higher in-hospital mortality than younger subjects. CRP and ferritin levels were higher in the oldest old who died, suggesting that inflammation could play a key role in the outcome of this subset of patients.
Assuntos
Influenza Humana , Idoso , Idoso de 80 Anos ou mais , Proteína C-Reativa/análise , Ferritinas , Mortalidade Hospitalar , Hospitalização , Humanos , Inflamação , Influenza Humana/complicações , Influenza Humana/epidemiologia , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos RetrospectivosRESUMO
The Hispanic population, compared with other ethnic groups, presents a more aggressive gastric cancer phenotype with higher frequency of diffuse-type gastric adenocarcinoma (GA); this could be related to the mutational landscape of GA in these patients. Using whole-exome sequencing, we sought to present the mutational landscape of GA from 50 Mexican patients who were treated at The Instituto Nacional de Cancerología from 2019 to 2020. We performed a comprehensive statistical analysis to explore the relationship of the genomic variants and clinical data such as tumor histology and presence of signet-ring cell, H. pylori, and EBV. We describe a potentially different mutational landscape between diffuse and intestinal GA in Mexican patients. Patients with intestinal-type GA tended to present a higher frequency of NOTCH1 mutations, copy number gains in cytobands 13.14, 10q23.33, and 12q25.1, and copy number losses in cytobands 7p12, 14q24.2, and 11q13.1; whereas patients with diffuse-type GA tended to present a high frequency of CDH1 mutations and CNV gains in cytobands 20q13.33 and 22q11.21. This is the first description of a mutational landscape of GA in Mexican patients to better understand tumorigenesis in Hispanic patients and lay the groundwork for discovering potential biomarkers and therapeutic targets.
Assuntos
Adenocarcinoma , Helicobacter pylori , Neoplasias Gástricas , Adenocarcinoma/genética , Antígenos CD/genética , Caderinas/genética , Helicobacter pylori/genética , Humanos , Mutação , Neoplasias Gástricas/patologia , Sequenciamento do ExomaRESUMO
The clinical significance of molecular detection of respiratory viruses in bronchoalveolar lavage (BAL) samples is poorly defined. We performed an observational retrospective study including all patients who underwent a BAL procedure in our institution, regardless of the reason for bronchoscopy, from January 2015 to December 2018. Respiratory viruses were detected by real-time polymerase chain reaction with a commercial multiplex panel, and a cell culture was performed to detect cytomegalovirus and herpes simplex virus. Positive results were correlated with clinical symptoms and patients' characteristics. Of 540 BAL samples analyzed, 113 (20.9%) were positive for any respiratory virus. Viral detection was significantly associated with respiratory symptoms (83.2% vs. 68.9%, p = .004) and radiological infiltrates (67.3% vs. 52.2%, p = .006). The most frequent viruses detected were rhinovirus (42/113, 37.2%), influenza virus (20/113, 17.7%), and parainfluenza virus (PIV) (16/113, 14.2%). Respiratory pathogens codetections were found in 51/113 (45.1%) BAL samples, including more than one virus (16/51, 31.4%), fungi (8/51, 15.7%), and bacteria (9/51, 17.6%). Viral detection was significantly higher in immunocompromised patients (26.5% vs. 16.9%; p = .022). PIV and human metapneumovirus were mostly observed in lung (50.0%, 8/16) and hemopoietic transplant recipients (25%, 2/8), respectively, with clinical repercussions. Our data underline that molecular diagnosis allows identification of viral agents as the etiology of respiratory infections; however, the high frequency of codetections hinders identification of the agent responsible for the current respiratory symptomatology. Immunocompromised patients are the target population in whom to investigate the presence of respiratory viruses in their BAL samples.
Assuntos
Líquido da Lavagem Broncoalveolar/virologia , Infecções Respiratórias/epidemiologia , Infecções Respiratórias/virologia , Vírus/genética , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Genoma Viral , Humanos , Hospedeiro Imunocomprometido , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Espanha/epidemiologia , Vírus/classificação , Vírus/isolamento & purificação , Adulto JovemRESUMO
INTRODUCTION AND AIM: Stevia has exhibited antioxidant, antihyperglycemic, antihypertensive and anti-inflammatory properties in several in vivo and in vitro models. The objective of this study was to investigate the ability of an aqueous extract of stevia (AES) to prevent experimental cirrhosis in rats and to explore its mechanism of action. MATERIALS AND METHODS: Liver cirrhosis was induced by administering carbon tetrachloride (CCl4) (400mg/kg by i.p. injection 3 times a week for 12 weeks); AES was administered (100mg/kg by gavage daily) during the CCl4 treatment. Fibrosis was evaluated with histological, biochemical and molecular approaches, and liver damage was assessed with standardized procedures. The profibrotic pathways were analyzed by western blotting, qRT-PCR and immunohistochemistry. RESULTS AND CONCLUSIONS: Chronic CCl4 administration increased nuclear factor kappa B (NF-κB) and proinflammatory cytokine production as well as oxidative parameters such as lipid peroxidation and 4-hydroxynonenal levels, whereas GSH and nuclear factor-E2-related factor 2 (Nrf2) levels were decreased. CCl4 induced profibrogenic mediator expression, hepatic stellate cell (HSC) activation and, consequently, extracellular matrix production. AES exhibited antioxidant, anti-inflammatory and antifibrotic properties, probably because of its capacity to induce Nrf2 expression, reduce NF-κB expression and block several profibrogenic signaling pathways, subsequently inhibiting HSC activation and preventing fibrosis induced by chronic CCl4 administration.
Assuntos
Cirrose Hepática Experimental/prevenção & controle , Fígado/patologia , Estresse Oxidativo , Extratos Vegetais/farmacologia , Stevia , Animais , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Cirrose Hepática Experimental/metabolismo , Cirrose Hepática Experimental/patologia , Masculino , Ratos , Ratos Wistar , Edulcorantes/farmacologiaRESUMO
Stevia has been shown to prevent oxidative stress and inflammation in carbon tetrachlorideinduced cirrhosis models. This study aimed to investigate the ability of an aqueous extract of stevia (AES) to prevent thioacetamide (TAA)induced cirrhosis in rats and to explore its mechanism of action. Liver cirrhosis was established by administering TAA (200 mg/kg by i.p. injections three times a week for 10 weeks); AES was administered (100 mg/kg by gavage daily) during the TAA treatment. Liver damage and fibrosis were evaluated, and the profibrotic pathways were analyzed by western blotting and immunohistochemistry. TAA increased nuclear factor kappa B (NFκB) and proinflammatory cytokine production, as well as the malondialdehyde and 4hydroxynonenal levels, whereas the glutathione/glutathione disulfide and nuclear factorE2related factor 2 (Nrf2) levels were decreased. Moreover, TAA increased collagen production, hepatic stellate cell (HSC) activation, and expression of profibrogenic mediators. TAAtreated rats that had been exposed to Mn2+ exhibited altered striatal dopamine turnover, indicating hepatic encephalopathy. AES partially or completely prevented all of these effects. AES showed antioxidant, antiinflammatory, and antifibrotic properties, probably because of its capacity to induce Nrf2 expression, reduce NFκB expression, and block several profibrogenic signaling pathways, subsequently inhibiting HSC activation and preventing fibrosis and dopamine turnover.
Assuntos
Células Estreladas do Fígado/efeitos dos fármacos , Cirrose Hepática Experimental/prevenção & controle , Fator 2 Relacionado a NF-E2/fisiologia , NF-kappa B/fisiologia , Extratos Vegetais/uso terapêutico , Proteína Smad7/fisiologia , Stevia , Fator de Crescimento Transformador beta/fisiologia , Animais , Células Estreladas do Fígado/fisiologia , Cirrose Hepática Experimental/induzido quimicamente , Masculino , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , TioacetamidaRESUMO
BACKGROUND: miRNAs exert their effect through a negative regulatory mechanism silencing expression upon hybridizing to their target mRNA, and have a prominent position in the control of many cellular processes including carcinogenesis. Previous miRNA studies on retinoblastoma (Rb) have been limited to specific miRNAs reported in other tumors or to medium density arrays. Here we report expression analysis of the whole miRNome on 12 retinoblastoma tumor samples using a high throughput microarray platform including 2578 mature miRNAs. METHODS: Twelve retinoblastoma tumor samples were analyzed using an Affymetrix platform including 2578 mature miRNAs. We applied RMA analysis to normalize raw data, obtained categorical data from detection call values, and also used signal intensity derived expression data. We used Diana-Tools-microT-CDS to find miRNA targets and ChromDraw to map miRNAs in chromosomes. RESULTS: We discovered a core-cluster of 30 miRNAs that were highly expressed in all the cases and a cluster of 993 miRNAs that were uniformly absent in all cases. Another 1022 miRNA were variably present in the samples reflecting heterogeneity between tumors. We explored mRNA targets, pathways and biological processes affected by some of these miRNAs. We propose that the core-cluster of 30 miRs represent miRNA machinery common to all Rb, and affecting most pathways considered hallmarks of cancer. In this core, we identified miR-3613 as a potential and critical down regulatory hub, because it is highly expressed in all the samples and its potential mRNA targets include at least 36 tumor suppressor genes, including RB1. In the variably expressed miRNA, 36 were differentially expressed between males and females. Some of the potential pathways targeted by these 36 miRNAs were associated with hormonal production. CONCLUSION: These findings indicate that Rb tumor samples share a common miRNA expression profile regardless of tumor heterogeneity, and shed light on potential novel therapeutic targets such as mir-3613 This is the first work to delineate the miRNA landscape in retinoblastoma tumor samples using an unbiased approach.
Assuntos
MicroRNAs/genética , Retinoblastoma/genética , Transcriptoma , Adolescente , Adulto , Criança , Análise por Conglomerados , Biologia Computacional/métodos , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Análise de Sequência com Séries de Oligonucleotídeos , Reprodutibilidade dos Testes , Retinoblastoma/patologia , Fatores Sexuais , Adulto JovemRESUMO
Prostate cancer (PC) is the main cause of cancer mortality in men worldwide. Therefore, novel treatments for PC are needed. Ether à-go-go-1 (Eag1) potassium channels display oncogenic properties, and have been suggested as early tumor markers and therapeutic targets for different cancers. These channels are overexpressed in many human tumors including PC. Astemizole targets several molecules involved in cancer including Eag1 channels, histamine receptors and ABC transporters. Here we studied Eag1 mRNA expression and protein levels in the non-tumorigenic and non-invasive human prostate RWPE-1 cell line, and in the tumorigenic and highly invasive human prostate WPE1-NB26 cell lines. The effect of astemizole on cell proliferation and apoptosis was also studied. The human prostate cell lines RWPE-1 and WPE1-NB26 were cultured following the provider´s instructions. Eag1 mRNA expression and protein levels were studied by real time RT-PCR and immunocytochemistry, respectively. Cell proliferation and apoptosis were studied by a fluorescence AlamarBlue® assay and flow cytometry, respectively. No difference in Eag1 mRNA expression was observed between the cell lines. However, high Eag1 protein levels were observed in the invasive WPE1-NB26 cells, in contrast to the weak protein expression in RWPE-1 cells. Accordingly, astemizole decreased cell proliferation at nanomolar concentrations only in the invasive WPE1-NB26 cells. Our results suggest that astemizole may have clinical relevance for prostate cancer treatment in patients with high Eag1 protein levels.
Assuntos
Astemizol/farmacologia , Proliferação de Células/efeitos dos fármacos , Canais de Potássio Éter-A-Go-Go/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Canais de Potássio Éter-A-Go-Go/genética , Humanos , Imuno-Histoquímica , Masculino , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Hepatocellular carcinoma (HCC) has very poor prognosis. Astemizole has gained great interest as a potential anticancer drug because it targets several proteins involved in cancer including the Eag1 (ether à-go-go-1) potassium channel that is overexpressed in human HCC. Eag1 channels are regulated by cancer etiological factors and have been proposed as early tumor markers. Here, we found that HepG2 and HuH-7 HCC cells displayed Eag1 messenger RNA (mRNA) and protein expression, determined by real-time RT-PCR and immunochemistry, respectively. Astemizole inhibited human HCC cell proliferation (assessed by metabolic activity assay) and induced apoptosis (studied with flow cytometry) in both cell lines. The subcellular Eag1 protein localization was modified by astemizole in the HepG2 cells. The treatment with astemizole prevented diethylnitrosamine (DEN)-induced rat HCC development in vivo (followed by studying γ-glutamyl transpeptidase (GGT) activity). The Eag1 mRNA and protein levels were increased in most DEN-treated groups but decreased after astemizole treatment. GGT activity was decreased by astemizole. The Eag1 protein was detected in cirrhotic and dysplastic rat livers. Astemizole might have clinical utility for HCC prevention and treatment, and Eag1 channels may be potential early HCC biomarkers. These data provide significant basis to include astemizole in HCC clinical trials.
Assuntos
Astemizol/administração & dosagem , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Canais de Potássio Éter-A-Go-Go/biossíntese , Neoplasias Hepáticas/genética , Animais , Apoptose/efeitos dos fármacos , Biomarcadores Tumorais/biossíntese , Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/patologia , Proliferação de Células/efeitos dos fármacos , Dietilnitrosamina/administração & dosagem , Canais de Potássio Éter-A-Go-Go/genética , Regulação Neoplásica da Expressão Gênica , Células Hep G2 , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/patologia , Estadiamento de Neoplasias , Prognóstico , Ratos , gama-Glutamiltransferase/biossínteseRESUMO
BACKGROUND: Ion channels and transporters are potential markers and therapeutic targets for several cancers. However, their expression during hepatocellular carcinoma (HCC) development remains unclear. AIM: To investigate the mRNA expression of Na(+), K(+) and Ca(2+) channels and ABC transporters during rat HCC development, as well as Abcc3 protein in human liver biopsies. METHODS: Wistar rats were treated with diethylnitrosamine (DEN) and developed both cirrhosis (12 weeks of treatment) and either pre-neoplastic lesions (16 weeks of treatment) or multinodular HCC (16 weeks of treatment plus 2 weeks DEN-free). The mRNA expression of 12 ion channels and two ABC transporters was studied using real-time RT-PCR. Tumor-containing or tumor-free liver sections were isolated by laser-capture microdissection. Abcc3 protein expression was studied by immunohistochemistry in healthy, cirrhotic and HCC human biopsies. RESULTS: We observed expression changes in seven genes. Kcna3, Kcnn4, Kcnrg and Kcnj11 potassium channel mRNA expression reached peak values at the end of DEN treatment, while Scn2a1 sodium channel, Trpc6 calcium channel and Abcc3 transporter mRNA expression reached their highest levels in the presence of HCC (18 weeks). Whereas Kcnn4 and Scn2a1 channel expression was similar in non-tumor and tumor tissue, the Abcc3 transporter and Kcna3 potassium channels were preferentially overexpressed in the tumor sections. We observed differential Abcc3 protein subcellular localization and expression in human samples. CONCLUSIONS: The ion channel/transporter expression profile observed suggests that these genes are potential early markers or therapeutic targets of HCC. The differential localization of Abcc3 may be useful in the diagnosis of cirrhosis and HCC.
Assuntos
Carcinoma Hepatocelular/metabolismo , Canais Iônicos/metabolismo , Neoplasias Hepáticas/metabolismo , Animais , Canais de Cálcio/metabolismo , Carcinoma Hepatocelular/induzido quimicamente , Humanos , Imuno-Histoquímica , Microdissecção e Captura a Laser , Neoplasias Hepáticas/induzido quimicamente , Masculino , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Canais de Potássio/metabolismo , Ratos Wistar , Reação em Cadeia da Polimerase em Tempo Real , Canais de Sódio/metabolismoRESUMO
BACKGROUND: The oncogenic ether-à-go-go-1 potassium channel (EAG1) activity and expression are necessary for cell cycle progression and tumorigenesis. The active vitamin D metabolite, calcitriol, and astemizole, a promising antineoplastic drug, target EAG1 by inhibiting its expression and blocking ion currents, respectively. We have previously shown a synergistic antiproliferative effect of calcitriol and astemizole in breast cancer cells in vitro, but the effect of this dual therapy in vivo has not been studied. METHODS: In the present study, we explored the combined antineoplastic effect of both drugs in vivo using mice xenografted with the human breast cancer cell line T-47D and a primary breast cancer-derived cell culture (MBCDF). Tumor-bearing athymic female mice were treated with oral astemizole (50 mg/kg/day) and/or intraperitoneal injections of calcitriol (0.03 µg/g body weight twice a week) during 3 weeks. Tumor sizes were measured thrice weekly. For mechanistic insights, we studied EAG1 expression by qPCR and Western blot. The expression of Ki-67 and the relative tumor volume were used as indicators of therapeutic efficacy. RESULTS: Compared to untreated controls, astemizole and calcitriol significantly reduced, while the coadministration of both drugs further suppressed, tumor growth (P < 0.05). In addition, the combined therapy significantly downregulated tumoral EAG1 and Ki-67 expression. CONCLUSIONS: The concomitant administration of calcitriol and astemizole inhibited tumor growth more efficiently than each drug alone, which may be explained by the blocking of EAG1. These results provide the bases for further studies aimed at testing EAG1-dual targeting in breast cancer tumors expressing both EAG1 and the vitamin D receptor.
Assuntos
Antineoplásicos/administração & dosagem , Astemizol/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Calcitriol/administração & dosagem , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Animais , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Astemizol/uso terapêutico , Calcitriol/uso terapêutico , Linhagem Celular Tumoral , Sinergismo Farmacológico , Canais de Potássio Éter-A-Go-Go/genética , Canais de Potássio Éter-A-Go-Go/metabolismo , Feminino , Humanos , Camundongos , Camundongos Nus , Transplante de NeoplasiasRESUMO
BACKGROUND: Approximately 30% of breast tumors do not express the estrogen receptor (ER) α, which is necessary for endocrine therapy approaches. Studies are ongoing in order to restore ERα expression in ERα-negative breast cancer. The aim of the present study was to determine if calcitriol induces ERα expression in ER-negative breast cancer cells, thus restoring antiestrogen responses. METHODS: Cultured cells derived from ERα-negative breast tumors and an ERα-negative breast cancer cell line (SUM-229PE) were treated with calcitriol and ERα expression was assessed by real time PCR and western blots. The ERα functionality was evaluated by prolactin gene expression analysis. In addition, the effects of antiestrogens were assessed by growth assay using the XTT method. Gene expression of cyclin D1 (CCND1), and Ether-à-go-go 1 (EAG1) was also evaluated in cells treated with calcitriol alone or in combination with estradiol or ICI-182,780. Statistical analyses were determined by one-way ANOVA. RESULTS: Calcitriol was able to induce the expression of a functional ERα in ER-negative breast cancer cells. This effect was mediated through the vitamin D receptor (VDR), since it was abrogated by a VDR antagonist. Interestingly, the calcitriol-induced ERα restored the response to antiestrogens by inhibiting cell proliferation. In addition, calcitriol-treated cells in the presence of ICI-182,780 resulted in a significant reduction of two important cell proliferation regulators CCND1 and EAG1. CONCLUSIONS: Calcitriol induced the expression of ERα and restored the response to antiestrogens in ERα-negative breast cancer cells. The combined treatment with calcitriol and antiestrogens could represent a new therapeutic strategy in ERα-negative breast cancer patients.
Assuntos
Neoplasias da Mama/patologia , Calcitriol/farmacologia , Moduladores de Receptor Estrogênico/farmacologia , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Neoplasias da Mama/tratamento farmacológico , Calcitriol/análogos & derivados , Linhagem Celular Tumoral , Ciclina D1/metabolismo , Estradiol/análogos & derivados , Estradiol/farmacologia , Feminino , Fulvestranto , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Receptores de Calcitriol/metabolismoRESUMO
OBJECTIVE: Cervical cancer is a major cause of mortality among women in developing countries. Thus, it is necessary to offer novel therapies to treat this malignancy. Astemizole has been suggested as a novel and interesting anticancer agent because it targets several proteins involved in cancer including Eag1 (ether à-go-go-1) potassium channels. Eag1 has been proposed as a tumor marker for different types of cancer. Actually, we previously suggested Eag1 channels as cervical cancer and dysplasia markers. Besides, Eag1 has been proposed as a therapeutic target for different malignancies. However, the effect of astemizole in cervical cancer cells is unknown. Therefore, we investigated the effect of astemizole on the proliferation and apoptosis of cervical cancer cells. METHODS: Five cervical cancer cell lines (HeLa, SiHa, CaSki, INBL, and C-33A) were cultured according to manufacturer's instructions. Eag1 protein expression was studied by immunocytochemistry. Cell proliferation was assayed with the MTT method, and apoptosis was investigated by flow cytometry. RESULTS: Eag1 protein expression was observed in different cell lines. Astemizole decreased cell proliferation in up to 40% and increased apoptosis severalfold in all the cell lines studied. CONCLUSIONS: Our results suggest astemizole as a potential therapy for cervical cancer.
Assuntos
Antialérgicos/farmacologia , Apoptose/efeitos dos fármacos , Astemizol/farmacologia , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/patologia , Biomarcadores Tumorais/metabolismo , Western Blotting , Canais de Potássio Éter-A-Go-Go/metabolismo , Feminino , Citometria de Fluxo , Humanos , Técnicas Imunoenzimáticas , Células Tumorais Cultivadas , Neoplasias do Colo do Útero/metabolismoRESUMO
BACKGROUND/AIM: Liver cancer is one of the malignancies with the highest mortality-to-incidence ratio worldwide. Therefore, novel therapeutic approaches are urgently needed. Combination therapy and drug repurposing can improve the response of the patients to therapy in several cancers. The aim of the present study was to merge these two strategies and evaluate whether the two-drug- or three-drug- combination of sorafenib, raloxifene, and loratadine improves the antineoplastic effect on human liver cancer cells in comparison to the single-drug effect. MATERIALS AND METHODS: The human liver cancer cell lines HepG2 and HuH7 were studied. The effect of sorafenib, raloxifene, and loratadine on the metabolic activity was determined using the MTT assay. The inhibitory concentrations (IC20 and IC50) were calculated from these results and used in the drug-combination experiments. Apoptosis and cell survival were studied by flow cytometry and using the colony formation assay, respectively. RESULTS: In both cell lines, sorafenib, raloxifene, and loratadine in two-drug and three-drug combinations significantly reduced metabolic activity and significantly increased the percentage of apoptotic cells compared to the single-drug effect. In addition, all the combinations significantly reduced the colony-forming capacity in the HepG2 cell line. Surprisingly, the effect of raloxifene on apoptosis was similar to that observed using the combinations. CONCLUSION: The triple combination sorafenib-raloxifene-loratadine may be a novel promising approach in the treatment of liver cancer patients.
Assuntos
Antineoplásicos , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Sorafenibe/farmacologia , Loratadina/farmacologia , Loratadina/uso terapêutico , Cloridrato de Raloxifeno/farmacologia , Carcinoma Hepatocelular/patologia , Proliferação de Células , Neoplasias Hepáticas/patologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose , Linhagem Celular TumoralRESUMO
Targeted therapy against cancer plays a key role in delivering safer and more efficient treatments. In the last decades, ion channels have been studied for their participation in oncogenic processes because their aberrant expression and/or function have been associated with different types of malignancies, including ovarian, cervical, and endometrial cancer. The altered expression or function of several ion channels have been associated with tumor aggressiveness, increased proliferation, migration, invasion, and metastasis of cancer cells and with poor prognosis in gynecological cancer patients. Most ion channels are integral membrane proteins easily accessible by drugs. Interestingly, a plethora of ion channel blockers have demonstrated anticancer activity. Consequently, some ion channels have been proposed as oncogenes, cancer, and prognostic biomarkers, as well as therapeutic targets in gynecological cancers. Here, we review the association of ion channels with the properties of cancer cells in these tumors, which makes them very promising candidates to be exploited in personalized medicine. The detailed analysis of the expression pattern and function of ion channels could help to improve the clinical outcomes in gynecological cancer patients.
RESUMO
Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumours worldwide. The mortality-to-incidence ratio is up to 91.6% in many countries, representing the third leading cause of cancer-related deaths. Systemic drugs, including the multikinase inhibitors sorafenib and lenvatinib, are first-line drugs used in HCC treatment. Unfortunately, these therapies are ineffective in most cases due to late diagnosis and the development of tumour resistance. Thus, novel pharmacological alternatives are urgently needed. For instance, immune checkpoint inhibitors have provided new approaches targeting cells of the immune system. Furthermore, monoclonal antibodies against programmed cell death-1 have shown benefits in HCC patients. In addition, drug combinations, including first-line treatment and immunotherapy, as well as drug repurposing, are promising novel therapeutic alternatives. Here, we review the current and novel pharmacological approaches to fight HCC. Preclinical studies, as well as approved and ongoing clinical trials for liver cancer treatment, are discussed. The pharmacological opportunities analysed here should lead to significant improvement in HCC therapy.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/patologia , Sorafenibe/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Terapia de Alvo Molecular , ImunoterapiaRESUMO
The human papilloma virus (HPV) group comprises approximately 200 genetic types that have a special affinity for epithelial tissues and can vary from producing benign symptoms to developing into complicated pathologies, such as cancer. The HPV replicative cycle affects various cellular and molecular processes, including DNA insertions and methylation and relevant pathways related to pRb and p53, as well as ion channel expression or function. Ion channels are responsible for the flow of ions across cell membranes and play very important roles in human physiology, including the regulation of ion homeostasis, electrical excitability, and cell signaling. However, when ion channel function or expression is altered, the channels can trigger a wide range of channelopathies, including cancer. In consequence, the up- or down-regulation of ion channels in cancer makes them attractive molecular markers for the diagnosis, prognosis, and treatment of the disease. Interestingly, the activity or expression of several ion channels is dysregulated in HPV-associated cancers. Here, we review the status of ion channels and their regulation in HPV-associated cancers and discuss the potential molecular mechanisms involved. Understanding the dynamics of ion channels in these cancers should help to improve early diagnosis, prognosis, and treatment in the benefit of HPV-associated cancer patients.
Assuntos
Neoplasias , Infecções por Papillomavirus , Humanos , Papillomavirus Humano , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/diagnóstico , Neoplasias/diagnóstico , Neoplasias/terapia , Neoplasias/metabolismo , Canais Iônicos/metabolismo , Íons/metabolismoRESUMO
Breast cancer is the most prevalent neoplasia among women worldwide. For the estrogen receptor-positive (ER+) phenotype, tamoxifen is the standard hormonal therapy; however, it carries the risk of promoting endometrial carcinoma. Hence, we aimed to evaluate the antiproliferative effect of the phytochemical α-mangostin (AM) as a co-adjuvant alongside tamoxifen on breast cancer cells to improve its efficacy while reducing its adverse effects on endometrium. For this, ER+ breast cancer cells (MCF-7 and T-47D) and endometrial cells (N30) were treated with AM, 4-hydroxytamoxifen (4-OH-TMX), and their combination. Cell proliferation was evaluated using sulforhodamine B assay, and the pharmacological interaction was determined through the combination index and the dose reduction index calculation. The genes KCNH1, CCDN1, MKI67, and BIRC5 were amplified by real-time PCR as indicators of oncogenesis, cell cycle progression, cell proliferation, and apoptosis, respectively. Additionally, genes involved in ER signaling were analyzed. In breast cancer cells, the combination of AM with 4-OH-TMX showed a synergistic antiproliferative effect and favorable dose reduction. AM and 4-OH-TMX decreased KCNH1, CCND1, and BIRC5 gene expression. In endometrial cells, AM decreased MKI-67 gene expression, while it reverted the 4-OH-TMX-dependent CCND1 upregulation. This study establishes the benefits of incorporating AM as a co-adjuvant for first-line ER+ breast cancer therapy.