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INTRODUCTION: As a vital mechanism of survival, lymphopoiesis requires the collaboration of different signaling molecules to orchestrate each step of cell development and maturation. The PI3K pathway is considerably involved in the maturation of lymphatic cells and therefore, its dysregulation can immensely affect human well-being and cause some of the most prevalent malignancies. As a result, studies that investigate this pathway could pave the way for a better understanding of the lymphopoiesis mechanisms, the undesired changes that lead to cancer progression, and how to design drugs to solve this issue. AREAS COVERED: The present review addresses the aforementioned aspects of the PI3K pathway and helps pave the way for future therapeutic approaches. In order to access the articles, databases such as Medicine Medline/PubMed, Scopus, Google Scholar, and Science Direct were utilized. The search formula was established by identifying main keywords including PI3K/Akt/mTOR pathway, Lymphopoiesis, Lymphoid malignancies, and inhibitors. EXPERT OPINION: The PI3K pathway is crucial for lymphocyte development and differentiation, making it a potential target for therapeutic intervention in lymphoid cancers. Studies are focused on developing PI3K inhibitors to impede the progression of hematologic malignancies, highlighting the pathway's significance in lymphoma and lymphoid leukemia.
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Desenvolvimento de Medicamentos , Linfoma , Linfopoese , Fosfatidilinositol 3-Quinases , Inibidores de Fosfoinositídeo-3 Quinase , Transdução de Sinais , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Animais , Inibidores de Fosfoinositídeo-3 Quinase/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase/administração & dosagem , Linfoma/patologia , Linfoma/tratamento farmacológico , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Progressão da Doença , Terapia de Alvo Molecular , Desenho de Fármacos , Diferenciação CelularRESUMO
Objective: Propolis is a viscous resinous honeybee-produced substance with numerous medicinal functions; its composition and texture varies according to the geographic location. It is considered to be a promising natural source for the management and prevention of various pathological conditions. Although several studies have exhibited the anti-cancer activity of different types of propolis, the tumor-suppressing potential of Kermanian propolis against leukemia cell lines has remained poorly understood. Therefore, the current experiment was aimed to reveal the anti-tumor activity of this bioactive compound both as monotherapy and combined therapy with cytarabine against an acute myeloid leukemia (AML) cell line, NB4. Materials and Methods: Following the treatment of NB4 cells with either Kermanian propolis (5, 10, 20, 40, 80, 160, and 320 µg/mL), cytarabine (0.1, 0.25, 0.5, 0.75, 1, and 2 mM), or their combination (40 and 80 µg/mL of Kermanian propolis along with 0.1, 0.25, and 0.5 mM of cytarabine), colorimetric 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was employed to measure the viability (%) of the cells. Next, to examine the apoptotic rate and the pattern of corresponding gene expression (Bcl-2, Bax, p53, and p21), Annexin-V/PI staining by flow cytometry and quantitative Real-Time polymerase chain reaction assays were performed, respectively. Results: We perceived significant apoptosis induction in a dose-dependent manner following the treatment with Kermanian propolis, cytarabine, and also their combination in the NB4 cell line. In addition, the combined treatment was associated with lower expression of the anti-apoptotic gene (Bcl-2) and higher expression of the pro-apoptotic genes (p53, Bax, and p21) in comparison to mono treatments. Conclusion: The synergistic anti-tumor activity induced by the combination of Kermanian propolis and cytarabine presents a novel and encouraging option for AML treatment.
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Leucemia Mieloide Aguda , Própole , Abelhas , Humanos , Animais , Regulação para Cima , Própole/farmacologia , Proteína X Associada a bcl-2/genética , Proteína Supressora de Tumor p53/genética , Leucemia Mieloide Aguda/tratamento farmacológico , Apoptose , Linhagem Celular , CitarabinaRESUMO
BACKGROUND: Anaplastic thyroid cancer (ATC) is an aggressive subtype of thyroid cancer, accounting for 1 to 2% of all cases. Deregulations of cell cycle regulatory genes including cyclins, cyclin-dependent kinases (CDKs), and endogenous inhibitors of CDKs (CKIs) are hallmarks of cancer cells and hence, studies indicate the inhibition of CDK4/6 kinases and cell cycle progression as potent therapeutic strategies. In this study, we investigated the anti-tumor activity of Abemaciclib, a CDK4 and CDK6 inhibitor, in ATC cell lines. METHODS AND RESULTS: The ATC cell lines C643 and SW1736 were selected to study the antiproliferative effects of Abemaciclib using a cell proliferation assay and crystal violet staining assay. Annexin V/PI staining and cell cycle analysis by flow cytometry were also performed to examine the effects on apoptosis induction and cell cycle arrest. Wound healing assay and zymography analysis examined the effects of the drug on invasive abilities of ATC cells and Western blot analyses were applied to further study the anti-tumor mechanism of Abemaciclib, in addition to combination treatment with alpelisib. Our data demonstrated that Abemaciclib significantly inhibited cell proliferation and increased cellular apoptosis and cell cycle arrest in ATC cell lines, while considerably reducing cell migration and colony formation. The mechanism seemed to involve the PI3K pathway. CONCLUSION: Our preclinical data highlight CDK4/6 as interesting therapeutic targets in ATC and suggest CDK4/6-blockade therapies as promising strategies in this malignancy.
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Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/genética , Fosfatidilinositol 3-Quinases , Linhagem Celular Tumoral , Neoplasias da Glândula Tireoide/genética , Ciclo Celular , Apoptose , Proliferação de CélulasRESUMO
PURPOSE: Therapy resistance is the principal obstacle to achieving cures in cancer patients and its successful tackling requires a deep understanding of the resistance mediators. Increasing evidence indicates that tumor phosphatases are novel and druggable targets in translational oncology and their modulation may hinder tumor growth and motility and potentiate therapeutic sensitivity in various neoplasms via regulation of various signal transduction pathways. Dual-specificity phosphatases (DUSPs) are key players of cell growth, survival and death and have essential roles in tumor initiation, malignant progression and therapy resistance through regulation of the MAPK signaling pathway. In this review, different aspects of DUSPs are discussed. METHODS: A comprehensive literature review was performed using various websites including PubMed. RESULTS: We provide mechanistic insights into the roles of well-known DUSPs in resistance to a wide range of cancer therapeutic approaches including chemotherapy, radiation and molecular targeted therapy in human malignancies. Moreover, we discuss the development of DUSP modulators, with a focus on DUSP1 and 6 inhibitors. Ultimately, the preclinical investigations of small molecule inhibitors of DUSP1 and 6 are outlined. CONCLUSION: Emerging evidence indicates that the DUSP family is aberrantly expressed in human malignancies and plays critical roles in determining sensitivity to a wide range of cancer therapeutic strategies through regulation of the MAPK signaling pathways. Consequently, targeting DUSPs and their downstream molecules can pave the way for more effective cancer therapies.
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Antineoplásicos/farmacologia , Fosfatase 1 de Especificidade Dupla/antagonistas & inibidores , Fosfatase 6 de Especificidade Dupla/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Benzofuranos/farmacologia , Carcinogênese/patologia , Resistencia a Medicamentos Antineoplásicos/genética , Fosfatase 1 de Especificidade Dupla/biossíntese , Fosfatase 1 de Especificidade Dupla/genética , Fosfatase 6 de Especificidade Dupla/biossíntese , Fosfatase 6 de Especificidade Dupla/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Imidazóis/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Terapia de Alvo Molecular/métodos , Neoplasias/patologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Despite remarkable advances in different types of cancer therapies, an effective therapeutic strategy is still a major and significant challenge. One of the most promising approaches in this regard is immunotherapy, which takes advantage of the patients' immune system; however, the many mechanisms that cancerous cells harbor to extend their survival make it impossible to gain perfect eradication of tumors. The response rate to cancer immunotherapies, especially checkpoint inhibitors and adoptive T cell therapy, substantially differs in various cancer types with the highest rates in advanced melanoma and non-small cell lung cancer. Indeed, the lack of response in many tumors indicates primary resistance that can originate from either tumor cells (intrinsic) or tumor microenvironment (extrinsic). On the other hand, some tumors show an initial response to immunotherapy followed by relapse in few months (acquired resistance). Understanding the underlying molecular mechanisms of immunotherapy resistance makes it possible to develop effective strategies to overcome this hurdle and boost therapy outcomes. In this review, we take a look at immunotherapy strategies and go through a number of primary and acquired resistance mechanisms. Also, we present various ongoing methods to overcoming resistance and introduce some promising fields to improve the outcome of immunotherapy in patients affected with cancer.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Neoplasias , Humanos , Imunoterapia , Recidiva Local de Neoplasia , Neoplasias/patologia , Microambiente TumoralRESUMO
AIMS: Glioblastoma (GB) is the most aggressive type of brain tumor. Rapid progression, active angiogenesis, and therapy resistance are major reasons for its high mortality. Elevated expression of members of the vascular endothelial growth factor (VEGF) family suggests that anti-VEGF therapies may be potent anti-glioma therapeutic approaches. Here, we evaluated the anti-tumor activity of cediranib, a pan inhibitor of the VEGF receptors, on GB cells. MATERIALS AND METHODS: Anti-proliferative effects of cediranib were determined using MTT, crystal-violet staining, clonogenic and anoikis resistance assays. Apoptosis induction was assessed by Annexin V/PI staining and Western blot analysis and aggressive abilities of GB cells were investigated using cell migration/invasion assays and zymography. Small-interfering RNA (siRNA)-mediated Knockdown was used to study resistance mechanisms. The anti-proliferative and apoptotic effects of cediranib in combination with radiotherapy, temozolomide, bevacizumab were also evaluated using MTT, Annexin V/PI staining and Western blot analysis for cleaved PARP-1. KEY FINDINGS: Cediranib reduced GB cell proliferation, induced apoptotic cell death and inhibited the aggressive abilities of GB cells. Cediranib synergistically increased the anti-proliferative and apoptotic effects of radiotherapy and bevacizumab and augmented the sensitivity of GB cells to temozolomide chemotherapy. In addition, knockdown of MET and AKT potentiated cediranib sensitivity in cediranib-resistant GB cells. SIGNIFICANCE: These findings suggest that cediranib, alone or in combination with other therapeutics, is a promising strategy for the treatment of GB and provide a rationale for further investigation of the therapeutic potential of cediranib for the treatment of this fatal malignancy.
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Antineoplásicos/farmacologia , Neoplasias Encefálicas/metabolismo , Proliferação de Células/efeitos dos fármacos , Glioblastoma/metabolismo , Quinazolinas/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/metabolismo , Antineoplásicos/uso terapêutico , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células/fisiologia , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Inibidores do Crescimento/farmacologia , Inibidores do Crescimento/uso terapêutico , Humanos , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidoresRESUMO
Along with evolution, a considerable number of signaling cascades have evolved within cells to meet their multifaceted needs. Among transmitting molecules, phosphoinositide 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR) have teamed up to build a signaling axis that effectively regulates various cellular processes including cell proliferation and migration. Given the extensive output of the PI3K/Akt/mTOR signaling axis, its aberrancy could subsequently lead to the formation of a wide range of human cancers spanning from hematologic malignancies to different types of solid tumors. Despite the high frequency of the PI3K pathway over-activation in most malignancies, mutations in the DNA sequence are not equally common. Such incompatibility sheds light on the possible effects of post-translational modification mechanisms that may take control of this pathway, some of the most important ones of which are through microRNAs (miRNAs or miRs). The present review is designed to take off the veil from the regulatory role of these small non-coding RNAs on the PI3K/Akt/mTOR signaling axis in carcinogenesis.
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MicroRNAs/genética , Neoplasias/genética , Transdução de Sinais/fisiologia , Carcinogênese/genética , Carcinogênese/patologia , Movimento Celular/genética , Proliferação de Células/genética , Humanos , MicroRNAs/metabolismo , Neoplasias/metabolismo , Fosfatidilinositol 3-Quinase/genética , Fosfatidilinositol 3-Quinase/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Processamento de Proteína Pós-Traducional/genética , Processamento de Proteína Pós-Traducional/fisiologia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
OBJECTIVES AND BACKGROUND: In December 2019, the first case of COVID-19 was reported in Wuhan, China. Its causative virus, is a novel strain of RNA viruses with high mortality rate. There is no definitive treatment, but among available approaches the use of recovered patients' plasma containing specific antibodies can enhance the immune response against coronavirus. However, the dearth of eligible donors and also ABO incompatibility in plasma transfusion, have limited this therapeutic method. Therefore, it is highly desirable to introduce a simple procedure that allows efficient reduction or even removal of natural ABO antibodies. Accordingly, we aimed to evaluate a RBC-mediated adsorption technique that reduces the titer of the mentioned antibodies in plasma. METHODS/MATERIALS: This experimental study was conducted in Kerman University of Medical Sciences, Kerman, Iran. The pre- and post-incubation antibody titers of 168 plasma samples were determined. For incubation, each plasma sample was exposed (60 min) to different percentages of RBCs at room temperature or 4 °C. RESULTS: The results evidenced that both the concentration of RBCs and temperature had significant decreasing effects on antibody titer (P < 0.001) and all concentrations significantly reduced titer. Compared to RT, 4 °C further reduced the antibody titer. Overall, the best incubation condition for reducing antibody titer in all blood groups was 4 °C and 2% RBCs concentration. CONCLUSION: The presented adsorption procedure is able to produce universal plasma (we call it Ubiquitous Convalescent Plasma) with a non-immunogenic level of ABO mismatch antibodies which can be used for COVID-19 patients with any type of blood group with desirable simplicity, feasibility, and efficacy.
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COVID-19/terapia , Técnicas de Imunoadsorção , Isoanticorpos/sangue , Plasma , SARS-CoV-2 , Sistema ABO de Grupos Sanguíneos/imunologia , Adsorção , Antígenos de Grupos Sanguíneos , COVID-19/sangue , Temperatura Baixa , Convalescença , Contagem de Eritrócitos , Eritrócitos/imunologia , Humanos , Imunização Passiva/métodos , Isoanticorpos/imunologia , Soroterapia para COVID-19RESUMO
The toll-like receptor (TLR) family consists of vital receptors responsible for pattern recognition in innate immunity, making them the core proteins involved in pathogen detection and eliciting immune responses. The most studied member of this family, TLR4, has been the center of attention regarding its contributory role in many inflammatory diseases including sepsis shock and asthma. Notably, mounting pieces of evidence have proved that this receptor is aberrantly expressed on the tumor cells and the tumor microenvironment in a wide range of cancer types and it is highly associated with the initiation of tumorigenesis as well as tumor progression and drug resistance. Cancer therapy using TLR4 inhibitors has recently drawn scientists' attention, and the promising results of such studies may pave the way for more investigation in the foreseeable future. This review will introduce the key proteins of the TLR4 pathway and how they interact with major growth factors in the tumor microenvironment. Moreover, we will discuss the many aspects of tumor progression affected by the activation of this receptor and provide an overview of the recent therapeutic approaches using various TLR4 antagonists.
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Neoplasias/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Antineoplásicos/uso terapêutico , Progressão da Doença , Humanos , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Neoplasias/patologia , Receptor Cross-Talk , Receptores de Fatores de Crescimento/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/antagonistas & inibidores , Microambiente TumoralRESUMO
PURPOSE: Acute myeloid leukemia (AML) is one of the most severe blood cancers. Many studies have revealed that inflammation has an essential role in the progression of hematopoietic malignancies. Since the toll-like receptor 4 (TLR4) pathway, an important pathway involved in inflammation induction, has previously been associated with solid tumors, we hypothesized that it would be correlated with the pathophysiological characteristics of AML patients and could be considered as an anticancer target. METHOD: We evaluated the mRNA expression of TLR4, MyD88, RelB, and NF-кB using qRT-PCR in bone-marrow samples of 40 AML patients categorized into four groups according to prognosis, cell type, age, and drug response. Next, we explored the expression of these genes in three AML cell lines (NB4, U937, and KG-1) and used TAK-242, a specific inhibitor of TLR4, to investigate whether this inhibition could suppress AML cell proliferation using cell-cycle analysis. The effect of TAK-242 on arsenic trioxide (ATO) cytotoxicity was also assessed. RESULT: The results of qRT-PCR showed that most genes had higher expression in patients with poor prognosis or drug-resistant statues. They were also overexpressed in patients with less-differentiated cells. Moreover, TAK-242 inhibited cell proliferation of all the cell lines and altered their cell cycle distribution. It could also intensify the cytotoxicity of ATO in combination therapy. CONCLUSION: In sum, the TLR4 pathway was related to pathophysiological characteristics of AML and its inhibition using TAK-242 could be considered as a promising treatment strategy in the TLR4 expressing AML cells, individually or in combination with ATO.
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Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Leucemia Mieloide Aguda/tratamento farmacológico , Sulfonamidas/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Trióxido de Arsênio/farmacologia , Ciclo Celular/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Masculino , Pessoa de Meia-Idade , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Células U937 , Adulto JovemRESUMO
AIMS: Despite the remarkable anti-proliferative effects of Arsenic trioxide (ATO) in breast cancer cells, the requirement of high, toxic concentrations to induce apoptosis may cause serious side effects in patients. In the present study, we aimed to use BIBR1532, an hTERT inhibitor, in combination with ATO to sensitize MCF7 and MDA-231 cells to lower concentrations of ATO. MAIN METHODS: Breast cancer cell lines MCF7 and MDA-231 were cultured and treated with different doses of ATO and BIBR1532 for 48 h and its effects on cell survival and proliferation were analyzed by MTT, crystal violet staining, colony formation assay, cell cycle, AnnexinV/PI and Real-time PCR tests. KEY FINDINGS: ATO and BIBR1532 synergistically inhibited proliferation and colony-forming ability of breast cancer cells. Besides, BIBR1532 augmented ATO-induced cytotoxic effects via triggering G1 cell cycle arrest and induction of apoptosis coupled with the down-regulation of NF-κB target genes that were involved in cell cycle progression (e.g. CCND1 and CDK6) and prevention of apoptosis such as Bcl-2, Bcl-xl, c-IAP2, and Survivin Respectively. Moreover, ATO-BIBR1532 significantly reduced the mRNA expression level of RELA, NFKB1, and several validated target genes of the NF-κB signaling pathway including NFKBIA, VEGFC, c-Myc, and hTERT. SIGNIFICANCE: The combination of ATO and BIBR1532 synergistically induced its anti-proliferative effect in breast cancer cells by targeting the two key cancer-related pathways, hTERT and NF-κB, and disrupting their feed-forward loop at the same time which result in the reduction of NF-κB transcriptional activity and subsequent down-regulation of its target genes.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Proliferação de Células/efeitos dos fármacos , Aminobenzoatos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Trióxido de Arsênio/administração & dosagem , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Humanos , Células MCF-7 , NF-kappa B/metabolismo , Naftalenos/administração & dosagem , Transdução de Sinais/efeitos dos fármacosRESUMO
Prostate Cancer is the second cause of cancer-related death in men and development of metastatic castration-resistant prostate cancer (mCRPC) is the major reason for its high mortality rate. Despite various treatments, all patients succumb to resistant disease, suggesting that there is a pressing need for novel and more efficacious treatments. Members of the vascular endothelial growth factor (VEGF) family play key roles in the tumorigenesis of mCRPC, indicating that VEGF-targeted therapies may have potential anti-tumor efficacy in this malignancy. However, due to compensatory activation of other family members, clinical trials with single-targeted VEGF inhibitors were discouraging. Here, we determined the anti-neoplastic activity of Cediranib, a pan-VEGF receptor inhibitor, in the mCRPC cell lines. Anti-growth effects of Cediranib were studied by MTT and BrdU cell proliferation assays and crystal violet staining. Annexin V/PI, radiation therapy and cell motility assays were carried out to examine the effects of Cediranib on apoptosis, radio-sensitivity and cell motility. Quantitative reverse transcription-PCR (qRT-PCR) and Western blot analyses were conducted to determine the molecular mechanisms underlying the anti-tumor activity of Cediranib. Cediranib decreased cell viability and induced apoptosis via inhibition of the anti-apoptotic proteins. Combination with Cediranib synergistically increased Docetaxel sensitivity and potentiated the effects of radiation therapy. Furthermore, Cediranib impaired cell motility via decrease in the expression of the epithelial-to-mesenchymal transition markers. These findings suggest that Cediranib may have anti-tumor activity in mCRPC cells and warrant further investigation on the therapeutic activity of this pan-VEGF receptor inhibitor in mCRPC.
Assuntos
Adenocarcinoma , Antineoplásicos/farmacologia , Neoplasias da Próstata , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/radioterapia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Movimento Celular/efeitos da radiação , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/efeitos da radiação , Terapia Combinada , Docetaxel/farmacologia , Raios gama , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Tolerância a Radiação/efeitos dos fármacos , Receptores de Fatores de Crescimento do Endotélio Vascular/genéticaRESUMO
BACKGROUND: Despite all advances in the treatment of ovarian cancer (OC), it remains the most lethal gynecological malignancy worldwide. There are growing amounts of evidence indicating the role of inflammation in initiating chemoresistance. Therefore, Toll-like receptor 4 (TLR4), a mediator of inflammation in cancer cells, may be a proper anticancer target. METHODS: The effects of TLR4 activation by LPS was studied using MTT, colony formation, staining, scratch, and qRT-PCR assays as the first step. Then the same assays, in addition to anoikis resistance, cell cycle and annexin V/PI apoptosis tests, were used to investigate whether the inhibition of TLR4 using a small molecule inhibitor, TAK-242, could suppress the proliferation of various OC cell lines: A2780CP, 2008C13, SKOV3, and A2780S. RESULTS: The activation of TLR4 using LPS showed enhanced proliferation and invasion in the TLR4-expressing cell line (SKOV3). Next, treatment with the inhibitor revealed that TAK-242 suppressed the inflammatory condition of ovarian cancer cells, as evident by the down-regulation of IL-6 gene expression. We also found that TAK-242 halted cancer cell proliferation by inducing cell cycle arrest and apoptosis through the modulation of genes involved in these processes. Given the fact that the overexpression of TLR4 contributes to drug resistance, it was tempting to investigate the effect of TAK-242 in a combined-modality strategy. Interestingly, we found enhanced cytotoxicity when TAK-242 was used in combination with doxorubicin. CONCLUSION: TAK-242 serves as an appealing therapeutic strategy in the TLR4-expressing OC cells, either in the context of monotherapy or in combination with a chemotherapeutic drug.
Assuntos
Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias Ovarianas/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/farmacologia , Sulfonamidas/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Anoikis/efeitos dos fármacos , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Doxorrubicina/farmacologia , Sinergismo Farmacológico , Feminino , Humanos , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Transdução de Sinais , Células Tumorais CultivadasRESUMO
Increasing pieces of evidence indicate that inflammatory processes facilitate tumorigenesis; tumor cells simulate the mechanisms by which innate immune cells produce pro-inflammatory cytokines to exploit them for their own survival and proliferation. Toll-like receptor 4 (TLR4), which serves as one of the most well-known receptors on the surface of the immune cells, is often expressed ectopically in the tumor cells resulting in tumor progression, invasion, and chemoresistance. In this study, we examined the anticancer effects of TAK-242, a small molecule inhibitor of TLR4, on different breast cancer cell lines: MCF7, SKBR3, MDA-MB-231, and BT-474. Our results showed that the TLR4 inhibition, as revealed by the downregulation of TLR4 downstream genes, exerted desirable cytotoxicity on the TLR4-expressing cells, at least partly, through the downregulation of EGFR and c-Myc genes. TAK-242 also inhibited the proliferation of anoikis-resistant cells and suppressed the clonal growth of the indicated cells. The results of this study propose a mechanistic pathway by which the inhibition of TLR4 using TAK-242 could augment apoptotic cell death through the alteration of both nuclear factor-кB- and p53-related apoptosis genes in breast cancer cells, especially cells with overexpression of TLR4. Taken together, this study supports the idea that the activation of inflammatory pathways may have a crucial role in breast cancer progression and the inhibition of TLR4 using TAK-242, either as a single agent or in combination, seems to be a novel promising strategy that could be clinically available in foreseeable future.
Assuntos
Antineoplásicos/farmacologia , Neoplasias da Mama/tratamento farmacológico , Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Sulfonamidas/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Apoptose , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclo Celular , Movimento Celular , Proliferação de Células , Quimioterapia Combinada , Feminino , Humanos , Células Tumorais CultivadasRESUMO
Gastric adenocarcinoma (GAC), the most common malignancy of the stomach, is the fourth most common and the second cause of cancer-related death worldwide. Although HER family plays a cardinal role in tumorigenesis of GAC, trastuzumab is the only approved anti-HER drug for this malignancy and development of resistance to trastuzumab is inevitable. Additionally, single-targeted HER inhibitors have demonstrated limited activity in GAC. Hence, there is a pressing need to devise more efficacious anti-HER therapeutic strategies. Here, we examined the anti-tumor activity of neratinb, a pan-HER inhibitor, on GAC cells. Anti-proliferative effects of neratinib were determined using a cell proliferation assay and crystal violet staining. Annexin V/PI staining, radiation therapy and anoikis resistance and wound healing assays were carried out to examine the effects of neratinib on apoptosis, radio-sensitivity and cell motility, respectively. Quantitative reverse transcription-PCR (qRT-PCR) analyses were applied to further investigate the anti-tumor activity of neratinib. We found that neratinib sensitized GAC cells to 5FU, carboplatin and oxaliplatin. Moreover, we found that neratinib was synergistic with trametinib (an approved MEK inhibitor) and foretinib (a c-MET inhibitor) and potentiated radio-sensitivity of GAC cells. Furthermore, we found that neratinib diminished GAC cell proliferation along with downregulation of FOXM1 and its targets. Additionally, neratinib induced apoptosis along with upregulation of pro-apoptotic and downregulation of anti-apoptotic genes. Treatment with neratinib attenuated invasive ability of GAC cells as shown by reduced anoikis resistance, downregulation of EMT markers, and reduced width in scratch assay. Our findings indicate that neratinib provides the therapeutic potential in the treatment of GAC.
Assuntos
Adenocarcinoma/patologia , Antineoplásicos/farmacologia , Receptores ErbB/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Quinolinas/farmacologia , Neoplasias Gástricas/patologia , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Humanos , Invasividade NeoplásicaRESUMO
Numerous links exist between inflammation and tumor development. Toll-like receptor 4 (TLR4) expression by tumor cells can be a contributing factor that promotes tumor cell proliferation, survival, migration, and metastasis. In this study, we explored the impact of TLR4 inhibition using TAK-242, a specific inhibitor of TLR4, on the invasion properties of ovarian (A2780CP, 2008C13, SKOV3, and A2780S) and breast (MCF7, SKBR3, MDA-MB-231, and BT-474) cancer cell lines. Six out of eight cell lines expressed TLR4 and its downstream mediators (MyD88, NF-ĸB1, and RELB), indicating that these cell lines could be proper candidates for the TLR4 inhibition. TAK-242 induced a cytotoxic effect on all tested cell lines; however, a different cell sensitivity pattern was noticeable. Interestingly, in the TLR4-expressing cell lines, there was a significant correlation between the TLR4/MyD88 expressions and the cancer cell response to TAK-242: the higher the expression, the higher the IC50. To the best of our knowledge, no study has addressed the effects of TAK-242 on invasive abilities of cancer cells and our study suggests for the first time that TAK-242 could considerably decrease invasion properties of ovarian and breast cancer cell lines. We found that not only did TAK-242 reduce the enzymatic activity of MMP2 and MMP9, but also down-regulated gene expressions of epithelial-mesenchymal transition (EMT)-related genes. In sum, it seems that targeting TLR4 using TAK-242 possesses novel promising potential in cancer treatment strategies and may prevent invasion in patients suffering from ovarian and breast cancers, especially in those with over-expression of TLR4.
Assuntos
Neoplasias da Mama/patologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Neoplasias Ovarianas/patologia , Sulfonamidas/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Matriz Extracelular/metabolismo , Feminino , Humanos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Invasividade Neoplásica , Receptor 4 Toll-Like/metabolismoRESUMO
BACKGROUND: Nutrigenomic has revolutionized our understanding of nutrition. As plants make up a noticeable part of our diet, in the present study we chose microRNAs of edible plants and investigated if they can perfectly match human genes, indicating potential regulatory functionalities. METHODS: miRNAs were obtained using the PNRD database. Edible plants were separated and microRNAs in common in at least four of them entered our analysis. Using vmatchPattern, these 64 miRNAs went through four steps of refinement to improve target prediction: Alignment with the whole genome (2581 results), filtered for those in gene regions (1371 results), filtered for exon regions (66 results) and finally alignment with the human CDS (41 results). The identified genes were further analyzed in-silico to find their functions and relations to human diseases. RESULTS: Four common plant miRNAs were identified to match perfectly with 22 human transcripts. The identified target genes were involved in a broad range of body functions, from muscle contraction to tumor suppression. We could also indicate some connections between these findings and folk herbology and botanical medicine. CONCLUSIONS: The food that we regularly eat has a great potential in affecting our genome and altering body functions. Plant miRNAs can provide means of designing drugs for a vast range of health problems including obesity and cancer, since they target genes involved in cell cycle (CCNC), digestion (GIPR) and muscular contractions (MYLK). They can also target regions of CDS for which we still have no sufficient information, to help boost our knowledge of the human genome.
Assuntos
Simulação por Computador , Bases de Dados de Ácidos Nucleicos , Alimentos , Genoma Humano , Nutrigenômica , RNA de Plantas , Análise de Sequência de RNA , Humanos , RNA de Plantas/genética , RNA de Plantas/metabolismoRESUMO
It is believed that pathways of the immune system are responsible for eradicating cancer cells; however, their over-activation and also their ectopic expression in tumor cells and microenvironment are major contributors to tumor growth and chemoresistance. Toll-like receptor 4 (TLR4) pathway is an innate immune-related pathway which is usually overexpressed in tumor cells that leads to excessive pro-inflammatory cytokines and eventually results in tumor survival, drug resistance, and metastasis. In this study, we investigated whether TLR4 expression is affected upon the treatment of breast and ovarian cancer cells with common chemotherapeutics (paclitaxel, cisplatin, doxorubicin, and arsenic trioxide) and if TLR4 inhibition using its specific inhibitor TAK-242 could enhance cancer cells' response to the drugs. Both breast (MCF7) and ovarian (2008C13) cancer cells experienced an elevated expression of TLR4 after treatment with the drugs. The expression of this receptor was also upregulated in cisplatin-resistant 2008C13 cells; however, it was significantly higher upon short-term treatment with cisplatin. More importantly, the combination treatment of the drugs with TAK-242 intensified the chemosensitivity of six different breast and ovarian cancer cells to chemotherapeutic drugs. It was also identified that co-treatment of paclitaxel and TAK-242 not only led to enhanced G2/M arrest and apoptosis but also satisfactorily decreased the expression of TLR4 and different interleukins in these cells. Taken together, the results of the present study emphasize that chemotherapy may lead to chemoresistance through inducing TLR4 expression, and therefore inhibiting this receptor using TAK-242 could be a promising approach to improve the outcome of chemotherapy in foreseeable future.