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Resistance to cisplatin is the main cause of treatment failure in lung adenocarcinoma. Drug-tolerant-persister (DTP) cells are responsible for intrinsic resistance, since they survive the initial cycles of treatment, representing a reservoir for the emergence of clones that display acquired resistance. Although the molecular mechanisms of DTP cells have been described, few studies have investigated the earliest molecular alterations of DTP cells in intrinsic resistance to cisplatin. In this work, we report a gene expression signature associated with the emergence of cisplatin-DTP cells in lung adenocarcinoma cell lines. After a single exposure to cisplatin, we sequenced the transcriptome of cisplatin-DTPs to identify differentially expressed genes. Bioinformatic analysis revealed that early cisplatin-DTP cells deregulate metabolic and proliferative pathways to survive the drug insult. Interaction network analysis identified three highly connected submodules in which SOCS1 had a significant participation in controlling the proliferation of cisplatin-DTP cells. Expression of the candidate genes and their corresponding protein was validated in lung adenocarcinoma cell lines. Importantly, the expression level of SOCS1 was different between CDDP-susceptible and CDDP-resistant lung adenocarcinoma cell lines. Moreover, knockdown of SOCS1 in the CDDP-resistant cell line partially promoted its susceptibility to CDDP. Finally, the clinical relevance of the candidate genes was analyzed in silico, according to the overall survival of cisplatin-treated patients from The Cancer Genome Atlas. Survival analysis showed that downregulation or upregulation of the selected genes was associated with overall survival. The results obtained indicate that these genes could be employed as predictive biomarkers or potential targets to improve the effectiveness of CDDP treatment in lung cancer patients.
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Photodynamic therapy (PDT) may be an excellent alternative in the treatment of breast cancer, mainly for the most aggressive type with limited targeted therapies such as triple-negative breast cancer (TNBC). We recently generated conjugated polymer nanoparticles (CPNs) as efficient photosensitizers for the photo-eradication of different cancer cells. With the aim of improving the selectivity of PDT with CPNs, the nanoparticle surface conjugation with unique 2'-Fluoropyrimidines-RNA-aptamers that act as effective recognition elements for functional surface signatures of TNBC cells was proposed and designed. A coupling reaction with carbodiimide was used to covalently bind NH2-modified aptamers with CPNs synthetized with two polystyrene-based polymer donors of COOH groups for the amide reaction. The selectivity of recognition for TNBC membrane receptors and PDT efficacy were assayed in TNBC cells and compared with non-TNBC cells by flow cytometry and cell viability assays. Furthermore, in vitro PDT efficacy was assayed in different TNBC cells with significant improvement results using CL4, sTN29 and sTN58 aptamers compared to unconjugated CPNs and SCR non-specific aptamer. In a chemoresistance TNBC cell model, sTN58 was the candidate for improving labelling and PDT efficacy with CPNs. We proposed sTN58, sTN29 and CL4 aptamers as valuable tools for selective TNBC targeting, cell internalization and therapeutic improvements for CPNs in PDT protocols.
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Cancer cells require high levels of transcription to survive and maintain their cancerous phenotype. For several years, global transcription inhibitors have been used in the treatment of cancer. However, recent advances in understanding the functioning of the basal transcription machinery and the discovery of new drugs that affect the components of this machinery have generated a new boom in the use of this type of drugs to treat cancer. Inhibiting transcription at the global level in the cell generates a stress situation in which the cancer cell responds by overexpressing hundreds of genes in response to this transcriptional stress. Many of these over-transcribed genes encode factors that may be involved in the selection of cells resistant to the treatment and with a greater degree of malignancy. In this study, we reviewed various examples of substances that inhibit global transcription, as well as their targets, that have a high potential to be used against cancer. We also analysed what kinds of genes are overexpressed in the response to transcriptional stress by different substances and finally we discuss what types of studies are necessary to understand this type of stress response to have more tools to fight cancer.
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Neoplasias/genética , Neoplasias/terapia , Estresse Fisiológico/genética , Fatores de Transcrição/genética , Humanos , Transcrição GênicaRESUMO
Acute promyelocytic leukemia (APL) is associated with PML-RARα oncogene, which is treated using all-trans retinoic acid (ATRA)-based chemotherapy. However, chemoresistance is observed in 20-30% of treated patients and represents a clinical challenge, raising the importance of the development of new therapeutic options. In the present study, the effects of three synthetic cyclopenta[b]indoles on the leukemia phenotype were investigated using NB4 (ATRA-sensitive) and NB4-R2 (ATRA-resistant) cells. Among the tested synthetic cyclopenta[b]indoles, compound 2, which contains a heterocyclic nucleus, was the most active, presenting time-dependent cytotoxic activity in the µM range in APL cells, without cytotoxicity for normal leukocytes, and was selected for further characterization. Compound 2 significantly decreased clonogenicity, increased apoptosis, and caused cell cycle arrest at S and G2/M phases in a drug concentration-dependent manner. Morphological analyses indicated aberrant mitosis and diffuse tubulin staining upon compound 2 exposure, which corroborates cell cycle findings. In the molecular scenario, compound 2 reduced STMN1 expression and activity, and induced PARP1 cleavage and H2AX and CHK2 phosphorylation, and modulated CDKN1A, PMAIP1, GADD45A, and XRCC3 expressions, indicating reduction of cell proliferation, apoptosis, and DNA damage. Moreover, in the in vivo tubulin polymerization assay, NB4 and NB4-R2 cells showed a reduction in the levels of polymerized tubulin upon compound 2 exposure, which indicates tubulin as a target of the drug. Molecular docking supports this hypothesis. Taken together, these data indicated that compound 2 exhibits antileukemic effects through disrupting the microtubule dynamics, identifying a possible novel potential antineoplastic agent for the treatment of ATRA-resistant APL.
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Antineoplásicos/farmacologia , Ciclopentanos/química , Indóis/farmacologia , Leucemia Promielocítica Aguda/tratamento farmacológico , Microtúbulos/metabolismo , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Indóis/química , Microtúbulos/efeitos dos fármacos , Mitose/efeitos dos fármacos , Modelos Moleculares , Estatmina/biossíntese , Ensaio Tumoral de Célula-TroncoRESUMO
The inherent or developed resistance of many cancer cells to chemotherapy and irradiation is actually the main challenge to overcome in cancer treatment. It is well known that cancer cells are characterized by several hallmarks, and it seems that the ability to evolve ways to evade stressful conditions and killing therapies must be consider another typical characteristic displayed by all malignant cells. This overview aims to provide a concise description of the main mechanisms involved in the promotion of resistance to anticancer therapy and to describe the most frequent challenges faced in the war against cancer therapy resistance.
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Resistencia a Medicamentos Antineoplásicos/fisiologia , Neoplasias/tratamento farmacológico , Neoplasias/radioterapia , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos da radiação , Humanos , Imunoterapia/métodos , Terapia de Alvo Molecular , Neoplasias/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/efeitos da radiação , Hipóxia TumoralRESUMO
Acyl-CoA synthetase 4 (ACSL4) is an isoenzyme of the fatty acid ligase-coenzyme-A family taking part in arachidonic acid metabolism and steroidogenesis. ACSL4 is involved in the development of tumor aggressiveness in breast and prostate tumors through the regulation of various signal transduction pathways. Here, a bioinformatics analysis shows that the ACSL4 gene expression and proteomic signatures obtained using a cell model was also observed in tumor samples from breast and cancer patients. A well-validated ACSL4 inhibitor, however, has not been reported hindering the full exploration of this promising target and its therapeutic application on cancer and steroidogenesis inhibition. In this study, ACSL4 inhibitor PRGL493 was identified using a homology model for ACSL4 and docking based virtual screening. PRGL493 was then chemically characterized through nuclear magnetic resonance and mass spectroscopy. The inhibitory activity was demonstrated through the inhibition of arachidonic acid transformation into arachidonoyl-CoA using the recombinant enzyme and cellular models. The compound blocked cell proliferation and tumor growth in both breast and prostate cellular and animal models and sensitized tumor cells to chemotherapeutic and hormonal treatment. Moreover, PGRL493 inhibited de novo steroid synthesis in testis and adrenal cells, in a mouse model and in prostate tumor cells. This work provides proof of concept for the potential application of PGRL493 in clinical practice. Also, these findings may prove key to therapies aiming at the control of tumor growth and drug resistance in tumors which express ACSL4 and depend on steroid synthesis.
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Proliferação de Células/efeitos dos fármacos , Coenzima A Ligases/metabolismo , Resistencia a Medicamentos Antineoplásicos , Inibidores Enzimáticos/farmacologia , Animais , Sítios de Ligação , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Coenzima A Ligases/antagonistas & inibidores , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/uso terapêutico , Feminino , Humanos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Simulação de Acoplamento Molecular , Próstata/citologia , Próstata/metabolismo , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Esteroides/sangue , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Breast cancer (BCa) cells disseminating to the bone can remain dormant and resistant to treatments for many years until relapsing as bone metastases. The tyrosine kinase receptor TIE2 induces the dormancy of hematopoietic stem cells, and could also induce the dormancy of BCa cells. However, TIE2 is also a target for anti-angiogenic treatments in ongoing clinical trials, and its inhibition could then restart the proliferation of dormant BCa cells in bone. In this study, we used a combination of patient data, in vitro, and in vivo models to investigate the effect of TIE2 in the dormancy of bone metastases. In BCa patients, we found that a higher TIE2 expression is associated with an increased time to metastases and survival. In vitro, TIE2 decreased cell proliferation as it increased the expression of cyclin-dependent kinase inhibitors CDKN1A and CDKN1B and arrested cells in the G0/G1 phase. Expression of TIE2 also increased the resistance to the chemotherapeutic 5-Fluorouracil. In mice, TIE2 expression reduced tumor growth and the formation of osteolytic bone metastasis. Together, these results show that TIE2 is sufficient to induce dormancy in vitro and in vivo, and could be a useful prognostic marker for patients. Our data also suggest being cautious when using TIE2 inhibitors in the clinic, as they could awaken dormant disseminated tumor cells.
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Glioblastoma is one of the most common malignant brain tumors, with which patients have a mean survival of 24 months. Glypican-1 has been previously shown to be overexpressed in human glioblastoma and to be negatively correlated with patient's survival. This study aimed to investigate how glypican-1 influences the tumoral profile of human glioblastoma using in vitro cell line models. By downregulating the expression of glypican-1 in U-251 MG cells, we observed that the cellular growth and proliferation were highly reduced, in which cells were significantly shifted towards G0 as opposed to G1 phases. Cellular migration was severely affected, and glypican-1 majorly impacted the affinity towards laminin-binding of glioblastoma U-251 MG cells. This proteoglycan was highly prevalent in glioblastoma cells, being primarily localized in the cellular membrane and extracellular vesicles, occasionally with glypican-3. Glypican-1 could also be found in cell-cell junctions with syndecan-4 but was not identified in lipid rafts in this study. Glypican-1-silenced cells were much more susceptible to temozolomide than in U-251 MG itself. Therefore, we present evidence not only to support facts that glypican-1 is an elementary macromolecule in glioblastoma tumoral microenvironment but also to introduce this proteoglycan as a promising therapeutic target for this lethal tumor.
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Abstract Background: Canine transmissible venereal tumor (CTVT) is perhaps the oldest known canine neoplasia. It is spread by cell allogeneic transplantation among susceptible animals. It is globally distributed, mainly in urban areas with high populations of stray dogs. Objective: To estimate the current distribution and prevalence of CTVT in Colombia. Methods: After analyzing the literature, we obtained epidemiological information on CTVT from 152 veterinarians in five Colombian regions via an electronic form (using Google Forms). This analysis confirmed that CTVT is endemic in the inhabited regions of Colombia and is highly prevalent in the Andean region, the most populated region in the country. Results: For the reported cases of CTVT, no significant differences were found in terms of animal gender, reproductive status, or origin. An association was found between the number of CTVT cases and concomitant infectious diseases. Results also showed that vincristine is the most effective therapy for CTVT and resistance is not a serious problem in Colombia. Conclusion: Our results confirm that CTVT is endemic in the country, coinciding with global analysis of the factors that enable the continued existence of the disease, and implies that stray dogs are the reservoir. Accordingly, we recommend that canine control policies be introduced in Colombia.
Resumen Antecedentes: el tumor venéreo transmisible canino (TVTC) es quizá la neoplasia más antigua del canino. Se transmite por un transplante alogénico entre los animales susceptibles. Su distribución es mundial, principalmente en áreas urbanas con alta población de perros callejeros. Objetivo: estimar la actual distribución y prevalencia de TVTC en Colombia. Métodos: en este estudio, además de revisar la literatura, se obtuvo información epidemiológica del TVTC de 152 veterinarios en cinco regiones de Colombia, mediante formulario electrónico (usando Google Forms). Resultados: este análisis confirma que TVTC es endémico en las regiones habitadas de Colombia y es altamente prevalente en la región Andina, la región más poblada del país. Para los casos reportados, no se encontraron diferencias significativas respecto al género de los animales afectados, su estado reproductivo o su origen. Se encontró una asociación entre los casos de TVTC y las enfermedades infecciosas concomitantes. Los resultados muestran que la vincristina es la terapia más efectiva contra el TVTC y el fenómeno de resistencia no es un problema serio en Colombia. Conclusión: los resultados confirman que el TVTC es endémico en el país lo cual coincide con el análisis global de los factores que permiten que la enfermedad continúe existiendo, e implica que los perros callejeros son el reservorio de la enfermedad. En consecuencia, se recomienda que se implementen políticas de control de caninos callejeros en Colombia.
Resumo Antecedentes: o tumor venéreo transmissível canino (TVTC) é talvez a neoplasia mais antiga dos caninos. É transmitido por um transplante alogênico entre animais susceptíveis. Sua distribuição é mundial, principalmente em áreas urbanas com altas populações de cães de rua. Objetivo: estimar a atual distribuição e prevalência de CTVT colombiano. Métodos: neste estudo, além de uma revisão da literatura, informação epidemiológica de TVTC foi obtido de 152 veterinários em cinco regiões da Colômbia, por meio de um formulário eletrônico (usando o Google Forms). Resultados: esta análise confirma que TVTC é endêmica nas regiões habitadas da Colômbia é altamente prevalente na região andina, a região mais populosa. Para os casos relatados, não houve diferenças significativas em relação ao sexo dos animais afetados, o seu estado reprodutivo nem do sua origem. Uma associação entre os casos de TVTC e doenças infecciosas concomitantes foi encontrada. Os resultados amostram que a vincristina é terapia mais eficaz contra o TVTC e o fenómeno de resistência não é um problema grave na Colômbia. Conclusão: os resultados confirmam que a TVTC é endémico no país, o qual coincide com a análise global dos fatores que permitem que a doença continue existindo e implica que os cães de rua são o reservatório da doença. Consequentemente, recomenda-se que políticas de controle sejam implementadas para cães de rua na Colômbia.
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PURPOSE: To investigate whether ERK/MNK/eIF4E contributes chemoresistance in ovarian cancer. METHODS: The phosphorylated levels of Erk, Mnk, and eIF4E were systematically analyzed in ovarian cancer patients before and after chemotherapy, and ovarian cancer cells exposed to short- and long-term chemo-agent treatment. The roles of Erk/Mnk/eIF4E were investigated using pharmacological and genetic approaches. RESULTS: Increased phosphorylation levels of ERK, Mnk1, and eIF4E were observed in ovarian cancer cell exposed to chemotherapeutic agents, and paclitaxel-resistant SK-OV-3-r cells, and is a common response of ovarian cancer patients undergoing chemotherapy. MEK inhibitor U0126 inhibits basal and chemodrug-induced phosphorylation of ERK as well as Mnk1 and eIF4E, suggesting that Mnk1/eIF4E are the downstream signaling of ERK pathway and chemotherapy agents activate ERK/MNK/eIF4E in a MEK-dependent manner. eIF4E overexpression promotes ovarian cancer cell growth without affecting migration. In addition, ovarian cancer cells with eIF4E overexpression are more resistant to chemotherapeutic agents in aspect of growth inhibition and apoptosis induction compared to control cells. In contrast, eIF4E depletion augments chemotherapeutic agents' effect in ovarian cancer cells. These demonstrate that eIF4E play roles in growth and chemoresistance in ovarian cancer. MEK inhibitor U0126 also significantly enhances chemotherapeutic agents' inhibitory effects. CONCLUSIONS: Our work shows that ERK/Mnk/eIF4E activation is critically involved in ovarian cancer chemoresistance and inhibiting ERK/Mnk/eIF4E broadly sensitizes ovarian cancer response to chemotherapy.
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ATPases Transportadoras de Cobre/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Neoplasias Ovarianas/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
ST6GalNAc-I, the sialyltransferase responsible for sialyl-Tn (sTn) synthesis, has been previously reported to be positively associated with cancer aggressiveness. Here we describe a novel sTn-dependent mechanism for chemotherapeutic resistance. We show that sTn protects cancer cells against chemotherapeutic-induced cell death by decreasing the interaction of cell surface glycan receptors with galectin-3 and increasing its intracellular accumulation. Moreover, exogenously added galectin-3 potentiated the chemotherapeutics-induced cytotoxicity in sTn non-expressing cells, while sTn overexpressing cells were protected. We also found that the expression of sTn was associated with a reduction in galectin-3-binding sites in human gastric samples tumors. ST6GalNAc-I knockdown restored galectin-3-binding sites on the cell surface and chemotherapeutics sensibility. Our results clearly demonstrate that an interruption of O-glycans extension caused by ST6GalNAc-I enzymatic activity leads to tumor cells resistance to chemotherapeutic drugs, highlighting the need for the development of novel strategies to target galectin-3 and/or ST6GalNAc-I.
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Antineoplásicos/farmacologia , Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos , Galectina 3/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Animais , Antígenos Glicosídicos Associados a Tumores/genética , Antígenos Glicosídicos Associados a Tumores/metabolismo , Proteínas Sanguíneas , Linhagem Celular Tumoral , Proliferação de Células , Relação Dose-Resposta a Droga , Galectinas , Glicosilação , Humanos , Camundongos Endogâmicos BALB C , Camundongos Nus , Processamento de Proteína Pós-Traducional , Transporte Proteico , Interferência de RNA , Sialiltransferases/genética , Sialiltransferases/metabolismo , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia , Fatores de Tempo , Transfecção , Carga TumoralRESUMO
Thymidylate synthase (TYMS) is an important enzyme for 5-fluorouracil (5-FU) metabolism in metastatic colorectal cancer (mCRC) patients. The search for this enzyme in circulating tumor cells (CTCs) can be a powerful tool to follow-up cancer patients. mCRC patients were enrolled before the beginning of 5-FU-based chemotherapy. The blood was filtered on Isolation by Size of Epithelial Tumor Cells (ISET), and the analysis of TYMS expression in CTCs was made by immunocytochemistry. Additionally, we verified TYMS staining in primary tumors and metastases from the same patients. There were included 54 mCRC patients and 47 of them received 5-FU-based chemotherapy. The median CTCs number was 2 per mL. We were not able to analyze immunocytochemistry in 13 samples (9 patients with absence of CTCs and 4 samples due to technical reasons). Therefore, TYMS expression on CTCs was analyzed in 34 samples and was found positive in 9 (26.5%). Six of these patients had tumor progression after treatment with 5-FU. We found an association between CTC TYMS staining and disease progression (DP), although without statistical significance (P = 0.07). TYMS staining in primary tumors and metastases tissues did not have any correlation with disease progression (P = 0.67 and P = 0.42 respectively). Patients who had CTC count above the median (2 CTCs/mL) showed more TYMS expression (P = 0.02) correlating with worse prognosis. Our results searching for TYMS staining in CTCs, primary tumors and metastases suggest that the analysis of TYMS can be useful tool as a 5-FU resistance predictor biomarker if analyzed in CTCs from mCRC patients.
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Antimetabólitos Antineoplásicos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/fisiologia , Fluoruracila/uso terapêutico , Metástase Neoplásica/tratamento farmacológico , Células Neoplásicas Circulantes/metabolismo , Timidilato Sintase/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica/diagnóstico , PrognósticoRESUMO
Reversible phosphorylation of proteins, performed by kinases and phosphatases, is the major post translational protein modification in eukaryotic cells. This intracellular event represents a critical regulatory mechanism of several signaling pathways and can be related to a vast array of diseases, including cancer. Cancer research has produced increasing evidence that kinase and phosphatase activity can be compromised by mutations and also by miRNA silencing, performed by small non-coding and endogenously produced RNA molecules that lead to translational repression. miRNAs are believed to target about one-third of human mRNAs while a single miRNA may target about 200 transcripts simultaneously. Regulation of the phosphorylation balance by miRNAs has been a topic of intense research over the last years, spanning topics going as far as cancer aggressiveness and chemotherapy resistance. By addressing recent studies that have shown miRNA expression patterns as phenotypic signatures of cancers and how miRNA influence cellular processes such as apoptosis, cell cycle control, angiogenesis, inflammation and DNA repair, we discuss how kinases, phosphatases and miRNAs cooperatively act in cancer biology.
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MicroRNAs , Neoplasias/enzimologia , Neoplasias/genética , Monoéster Fosfórico Hidrolases/metabolismo , Proteínas Quinases/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Monoéster Fosfórico Hidrolases/genética , Proteínas Quinases/genética , Processamento de Proteína Pós-Traducional , Estabilidade de RNARESUMO
Research investigating biomarkers for early detection, prognosis and the prediction of treatment responses in breast cancer is rapidly expanding. However, no validated biomarker currently exists for use in routine clinical practice, and breast cancer detection and management remains dependent on invasive procedures. Histological examination remains the standard for diagnosis, whereas immunohistochemical and genetic tests are utilized for treatment decisions and prognosis determinations. Therefore, we conducted a comprehensive review of literature published in PubMed on breast cancer biomarkers between 2009 and 2013. The keywords that were used together were breast cancer, biomarkers, diagnosis, prognosis and drug response. The cited references of the manuscripts included in this review were also screened. We have comprehensively summarized the performance of several biomarkers for diagnosis, prognosis and predicted drug responses of breast cancer. Finally, we have identified 15 biomarkers that have demonstrated promise in initial studies and several miRNAs. At this point, such biomarkers must be rigorously validated in the clinical setting to be translated into clinically useful tests for the diagnosis, prognosis and prediction of drug responses of breast cancer.
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Apoptotic protease activating factor 1 (APAF-1) has a critical role in the regulation of apoptosis. In the present study, the mRNA expression analysis of different APAF-1 transcripts (APAF-1S, APAF-1LC, APAF-1LN, and APAF-1XL) was analyzed in bone marrow samples from 37 patients with acute myeloid leukemia (newly diagnosed, with no previous treatment). APAF-1XL and APAF-1LN transcripts (with and without an extra WD-40 repeat region, respectively) were detected in all samples, although the major form expressed was APAF-1XL in 65 percent of the samples (group 1), while 35 percent of the samples expressed primarily APAF-1LN (group 2). Only 46 percent of the patients presented complete remission in response to remission induction therapy (represented by less than 5 percent marrow blasts and hematological recovery), all but 2 cases being from group 1, 21.6 percent did not attain complete remission (only 1 case from group 1), and 32.4 percent of the patients died early. Lower expression of APAF-1XL (APAF-1XL/APAF-1LN ratio <1.2) was associated with a poor response to therapy (P = 0.0005, Fisher exact test). Both groups showed similar characteristics regarding white blood cell counts, cytogenetic data or presence of gene rearrangements associated with good prognosis as AML1-ETO, CBFB-MYH11 and PML/RARA. Since it has been shown that only the isoforms with the extra WD-40 repeat region activate procaspase-9, we suggest that low procaspase-9 activation may also be involved in the deregulation of apoptosis and chemotherapy resistance in acute myeloid leukemia.