RESUMO
Transcription factors (TFs) are essential in controlling gene regulatory networks that determine cellular fate during embryogenesis and tumor development. TFs are the major players in promoting cancer stemness by regulating the function of cancer stem cells (CSCs). Understanding how TFs interact with their downstream targets for determining cell fate during embryogenesis and tumor development is a critical area of research. CSCs are increasingly recognized for their significance in tumorigenesis and patient prognosis, as they play a significant role in cancer initiation, progression, metastasis, and treatment resistance. However, traditional therapies have limited effectiveness in eliminating this subset of cells, allowing CSCs to persist and potentially form secondary tumors. Recent studies have revealed that cancer cells and tumors with CSC-like features also exhibit genes related to the epithelial-to-mesenchymal transition (EMT). EMT-associated transcription factors (EMT-TFs) like TWIST and Snail/Slug can upregulate EMT-related genes and reprogram cancer cells into a stem-like phenotype. Importantly, the regulation of EMT-TFs, particularly through post-translational modifications (PTMs), plays a significant role in cancer metastasis and the acquisition of stem cell-like features. PTMs, including phosphorylation, ubiquitination, and SUMOylation, can alter the stability, localization, and activity of EMT-TFs, thereby modulating their ability to drive EMT and stemness properties in cancer cells. Although targeting EMT-TFs holds potential in tackling CSCs, current pharmacological approaches to do so directly are unavailable. Therefore, this review aims to explore the role of EMT- and CSC-TFs, their connection and impact in cellular development and cancer, emphasizing the potential of TF networks as targets for therapeutic intervention.
Assuntos
Neoplasias , Fatores de Transcrição , Humanos , Fatores de Transcrição/genética , Neoplasias/genética , Neoplasias/terapia , Transição Epitelial-Mesenquimal/genética , Diferenciação Celular , Células-Tronco Neoplásicas/patologia , Linhagem Celular TumoralRESUMO
Cancer progression is a multifaceted process that entails several stages and demands the persistent expression or activation of transcription factors (TFs) to facilitate growth and survival. TFs are a cluster of proteins with DNA-binding domains that attach to promoter or enhancer DNA strands to start the transcription of genes by collaborating with RNA polymerase and other supporting proteins. They are generally acknowledged as the major regulatory molecules that coordinate biological homeostasis and the appropriate functioning of cellular components, subsequently contributing to human physiology. TFs proteins are crucial for controlling transcription during the embryonic stage and development, and the stability of different cell types depends on how they function in different cell types. The development and progression of cancer cells and tumors might be triggered by any anomaly in transcription factor function. It has long been acknowledged that cancer development is accompanied by the dysregulated activity of TF alterations which might result in faulty gene expression. Recent studies have suggested that dysregulated transcription factors play a major role in developing various human malignancies by altering and rewiring metabolic processes, modifying the immune response, and triggering oncogenic signaling cascades. This review emphasizes the interplay between TFs involved in metabolic and epigenetic reprogramming, evading immune attacks, cellular senescence, and the maintenance of cancer stemness in cancerous cells. The insights presented herein will facilitate the development of innovative therapeutic modalities to tackle the dysregulated transcription factors underlying cancer.
Assuntos
Neoplasias , Fatores de Transcrição , Humanos , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Neoplasias/genética , Neoplasias/patologia , Regulação da Expressão Gênica , Regiões Promotoras Genéticas , DNARESUMO
PURPOSE OF REVIEW: Cytokine-mediated signaling pathways, including JAK/STAT, PI3K/AKT, and Ras/MAPK pathways, play an important role in the process of erythropoiesis. These pathways are involved in the survival, proliferation, and differentiation function of erythropoiesis. RECENT FINDINGS: The JAK/STAT pathway controls erythroid progenitor differentiation, proliferation, and survival. The PI3K/AKT signaling cascade facilitates erythroid progenitor survival, proliferation, and final differentiation. During erythroid maturation, MAPK, triggered by EPO, suppresses myeloid genes, while PI3K is essential for differentiation. Pro-inflammatory cytokines activate signaling pathways that can alter erythropoiesis like EPOR-triggered signaling, including survival, differentiation, and proliferation. SUMMARY: A comprehensive understanding of signaling networks is crucial for the formulation of treatment approaches for hematologic disorders. Further investigation is required to fully understand the mechanisms and interactions of these signaling pathways in erythropoiesis.
Assuntos
Eritropoese , Transdução de Sinais , Humanos , Transdução de Sinais/fisiologia , Eritropoese/fisiologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Janus Quinases , Fosfatidilinositol 3-Quinases/metabolismo , Fatores de Transcrição STAT/metabolismo , Diferenciação CelularRESUMO
Cutaneous T cell lymphomas (CTCLs) are a heterogeneous group of lymphoproliferative neoplasms that exhibit a wide spectrum of immune-phenotypical, clinical, and histopathological features. The biology of CTCL is complex and remains elusive. In recent years, the application of next-generation sequencing (NGS) has evolved our understanding of the pathogenetic mechanisms, including genetic aberrations and epigenetic abnormalities that shape the mutational landscape of CTCL and represent one of the important pro-tumorigenic principles in CTCL initiation and progression. Still, identification of the major pathophysiological pathways including genetic and epigenetic components that mediate malignant clonal T cell expansion has not been achieved. This is of prime importance given the role of malignant T cell clones in fostering T helper 2 (Th2)-bias tumor microenvironment and fueling progressive immune dysregulation and tumor cell growth in CTCL patients, manifested by the secretion of Th2-associated cytokines and chemokines. Alterations in malignant cytokine and chemokine expression patterns orchestrate the inflammatory milieu and influence the migration dynamics of malignant clonal T cells. Here, we highlight recent insights about the molecular mechanisms of CTCL pathogenesis, emphasizing the role of cytokines, chemokines, and associated downstream signaling networks in driving immune defects, malignant transformation, and disease progression. In-depth characterization of the CTCL immunophenotype and tumoral microenvironment offers a facile opportunity to expand the therapeutic armamentarium of CTCL, an intractable malignant skin disease with poor prognosis and in dire need of curative treatment approaches.
Assuntos
Linfoma Cutâneo de Células T , Neoplasias Cutâneas , Humanos , Citocinas , Quimiocinas , Linfoma Cutâneo de Células T/genética , Transdução de Sinais , Neoplasias Cutâneas/genética , Microambiente Tumoral/genéticaRESUMO
Signaling involving chemokine receptor CXCR4 and its ligand SDF-1/CXL12 has been investigated for many years for its possible role in cancer progression and pathogenesis. Evidence emerging from clinical studies in recent years has further established diagnostic as well as prognostic importance of CXCR4 signaling. CXCR4 and SDF-1 are routinely reported to be elevated in tumors, distant metastases, which correlates with poor survival of patients. These findings have kindled interest in the mechanisms that regulate CXCR4/SDF-1 expression. Of note, there is a particular interest in the epigenetic regulation of CXCR4 signaling that may be responsible for upregulated CXCR4 in primary as well as metastatic cancers. This review first lists the clinical evidence supporting CXCR4 signaling as putative cancer diagnostic and/or prognostic biomarker, followed by a discussion on reported epigenetic mechanisms that affect CXCR4 expression. These mechanisms include regulation by non-coding RNAs, such as, microRNAs, long non-coding RNAs and circular RNAs. Additionally, we also discuss the regulation of CXCR4 expression through methylation and acetylation. Better understanding and appreciation of epigenetic regulation of CXCR4 signaling can invariably lead to identification of novel therapeutic targets as well as therapies to regulate this oncogenic signaling.
Assuntos
MicroRNAs , Neoplasias , Humanos , Epigênese Genética , Quimiocina CXCL12/genética , Receptores CXCR4/genética , Neoplasias/genética , Transdução de Sinais/genética , Prognóstico , MicroRNAs/genéticaRESUMO
The global burden of breast cancer (BC) is increasing significantly. This trend is caused by several factors such as late diagnosis, limited treatment options for certain BC subtypes, drug resistance which all lead to poor clinical outcomes. Recent research has reported the role of epigenetic alterations in the mechanism of BC pathogenesis and its hallmarks include drug resistance and stemness features. The understanding of these modifications and their significance in the management of BC carcinogenesis is challenging and requires further attention. Nevertheless, it promises to provide novel insight needed for utilizing these alterations as potential diagnostic, prognostic markers, predict treatment efficacy, as well as therapeutic agents. This highlights the importance of continuing research development to further advance the existing knowledge on epigenetics and BC carcinogenesis to overcome the current challenges. Hence, this review aims to shed light and discuss the current state of epigenetics research in the diagnosis and management of BC.
Assuntos
Neoplasias da Mama , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Carcinogênese , Metilação de DNA , Epigênese Genética , Epigenômica , Feminino , HumanosRESUMO
Skin, the largest organ of human body, is vital for the existence and survival of human beings. Further, developmental and physiological mechanisms associated with cutaneous biology are vital for homeostasis as their deregulations converge towards pathogenesis of a number of skin diseases, including cancer. It has now been well accepted that most of the transcribed human genome lacks protein translational potential and has been termed as non-coding RNAs (nc-RNAs), which includes circular RNA (circRNA), small nuclear RNA (snRNA), small nucleolar RNA (snoRNA), micro RNA (miRNA), long noncoding RNA (lncRNA), and piwi-interacting RNA (piRNAs). These nc-RNAs have gained great attention in both preclinical and clinical research as they are critical in most of the regulatory mechanisms of biological homeostasis and disease development by controlling the gene expression at transcriptional, post-transcriptional and epigenetic level. In this review we have illustrated how nc-RNAs are critical in the development and maintenance of cutaneous homeostasis and functioning and also, most importantly, how the dysregulated expression and functioning of nc-RNAs play critical role in the pathogenesis of cutaneous diseases including cancer and the autoimmune skin diseases. Considering the vital role of nc-RNAs in cancer resistance, metastasis and autoimmune diseases, we have also highlighted their role as promising prognostic and therapeutic targets for the cutaneous diseases.
Assuntos
Doenças Autoimunes , MicroRNAs , RNA Longo não Codificante , Neoplasias Cutâneas , Doenças Autoimunes/genética , Humanos , RNA Longo não Codificante/genética , RNA Nucleolar Pequeno/genética , RNA não Traduzido/genética , Neoplasias Cutâneas/genéticaRESUMO
Abnormally activated RAS proteins are the main oncogenic driver that governs the functioning of major signaling pathways involved in the initiation and development of human malignancies. Mutations in RAS genes and or its regulators, most frequent in human cancers, are the main force for incessant RAS activation and associated pathological conditions including cancer. In general, RAS is the main upstream regulator of the highly conserved signaling mechanisms associated with a plethora of important cellular activities vital for normal homeostasis. Mutated or the oncogenic RAS aberrantly activates a web of interconnected signaling pathways including RAF-MEK (mitogen-activated protein kinase kinase)-ERK (extracellular signal-regulated kinase), phosphoinositide-3 kinase (PI3K)/AKT (protein kinase B), protein kinase C (PKC) and ral guanine nucleotide dissociation stimulator (RALGDS), etc., leading to uncontrolled transcriptional expression and reprogramming in the functioning of a range of nuclear and cytosolic effectors critically associated with the hallmarks of carcinogenesis. This review highlights the recent literature on how oncogenic RAS negatively use its signaling web in deregulating the expression and functioning of various effector molecules in the pathogenesis of human malignancies.
Assuntos
Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Transdução de Sinais , Proteínas ras/genética , Proteínas ras/metabolismo , Animais , Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica , Frequência do Gene , Humanos , Imunomodulação/genética , Inflamação/genética , Inflamação/metabolismo , Terapia de Alvo Molecular , Mutação , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia , Oncogenes , Proteínas Quinases Associadas a Fase S/genética , Proteínas Quinases Associadas a Fase S/metabolismo , Relação Estrutura-Atividade , Fatores de Transcrição/metabolismo , Proteínas ras/químicaRESUMO
Early-stage detection of leukemia is a critical determinant for successful treatment of the disease and can increase the survival rate of leukemia patients. The factors limiting the current screening approaches to leukemia include low sensitivity and specificity, high costs, and a low participation rate. An approach based on novel and innovative biomarkers with high accuracy from peripheral blood offers a comfortable and appealing alternative to patients, potentially leading to a higher participation rate.Recently, non-coding RNAs due to their involvement in vital oncogenic processes such as differentiation, proliferation, migration, angiogenesis and apoptosis have attracted much attention as potential diagnostic and prognostic biomarkers in leukemia. Emerging lines of evidence have shown that the mutational spectrum and dysregulated expression of non-coding RNA genes are closely associated with the development and progression of various cancers, including leukemia. In this review, we highlight the expression and functional roles of different types of non-coding RNAs in leukemia and discuss their potential clinical applications as diagnostic or prognostic biomarkers and therapeutic targets.
Assuntos
Biomarcadores Tumorais/genética , Resistencia a Medicamentos Antineoplásicos/genética , Regulação Neoplásica da Expressão Gênica , Leucemia/patologia , RNA Longo não Codificante/genética , Animais , Progressão da Doença , Humanos , Leucemia/tratamento farmacológico , Leucemia/genética , Metástase NeoplásicaRESUMO
Skin is the largest human organ and is continuously exposed to various exogenous and endogenous trigger factors affecting body homeostasis. A number of mechanisms, including genetic, inflammatory and autoimmune ones, have been implicated in the pathogenesis of cutaneous diseases. Recently, there has been considerable interest in the role that extracellular vesicles, particularly exosomes, play in human diseases, through their modulation of multiple signaling pathways. Exosomes are nano-sized vesicles secreted by all cell types. They function as cargo carriers shuttling proteins, nucleic acids, lipids etc., thus impacting the cell-cell communications and transfer of vital information/moieties critical for skin homeostasis and disease pathogenesis. This review summarizes the available knowledge on how exosomes affect pathogenesis of cutaneous diseases, and highlights their potential as future targets for the therapy of various skin diseases.
Assuntos
Biomarcadores , Exossomos/metabolismo , Dermatopatias/metabolismo , Animais , Doenças Autoimunes/etiologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Dermatite/etiologia , Dermatite/metabolismo , Dermatite/patologia , Gerenciamento Clínico , Suscetibilidade a Doenças , Vesículas Extracelulares/metabolismo , Humanos , Melanoma/etiologia , Melanoma/metabolismo , Melanoma/patologia , Dermatopatias/diagnóstico , Dermatopatias/etiologia , Dermatopatias/terapiaRESUMO
The constitutive activation of Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signal transduction is well elucidated in STAT3-mediated oncogenesis related to thyroid cancer and is considered to be a plausible therapeutic target. Hence, we investigated whether curcumin, a natural compound, can target the JAK/STAT3 signaling pathway to induce cytotoxic effects in papillary thyroid cancer (PTC) cell lines (BCPAP and TPC-1) and derived thyroid cancer stem-like cells (thyrospheres). Curcumin suppressed PTC cell survival in a dose-dependent manner via the induction of caspase-mediated apoptosis and caused the attenuation of constitutively active STAT3 (the dephosphorylation of Tyr705-STAT3) without affecting STAT3. Gene silencing with STAT3-specific siRNA showed the modulation of genes associated with cell growth and proliferation. The cotreatment of PTC cell lines with curcumin and cisplatin synergistically potentiated cytotoxic effects via the suppression of JAK/STAT3 activity along with the inhibition of antiapoptotic genes and the induction of proapoptotic genes, and it also suppressed the migration of PTC cells by downregulating matrix metalloproteinases and the inhibition of colony formation. Finally, thyrospheres treated with curcumin and cisplatin showed suppressed STAT3 phosphorylation, a reduced formation of thyrospheres, and the downregulated expression of stemness markers, in addition to apoptosis. The current study's findings suggest that curcumin synergistically enhances the anticancer activity of cisplatin in PTC cells as well as in cancer stem-like cells by targeting STAT3, which suggests that curcumin combined with chemotherapeutic agents may provide better therapeutic outcomes.
Assuntos
Apoptose/efeitos dos fármacos , Curcumina/farmacologia , Janus Quinases/metabolismo , Células-Tronco Neoplásicas/patologia , Fator de Transcrição STAT3/metabolismo , Câncer Papilífero da Tireoide/metabolismo , Câncer Papilífero da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Sinergismo Farmacológico , Humanos , Interleucina-6/metabolismo , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias da Glândula Tireoide/metabolismo , Regulação para Cima/efeitos dos fármacosRESUMO
Sanguinarine (SNG), a natural compound with an array of pharmacological activities, has promising therapeutic potential against a number of pathological conditions, including malignancies. In the present study, we have investigated the antiproliferative potential of SNG against two well-characterized papillary thyroid cancer (PTC) cell lines, BCPAP and TPC-1. SNG significantly inhibited cell proliferation of PTC cells in a dose and time-dependent manner. Western blot analysis revealed that SNG markedly attenuated deregulated expression of p-STAT3, without affecting total STAT3, and inhibited growth of PTC via activation of apoptotic and autophagy signaling cascade, as SNG treatment of PTC cells led to the activation of caspase-3 and caspase-8; cleavage of PARP and activation of autophagy markers. Further, SNG-mediated anticancer effects in PTC cells involved the generation of reactive oxygen species (ROS) as N-acetyl cysteine (NAC), an inhibitor of ROS, prevented SNG-mediated antiproliferative, apoptosis and autophagy inducing action. Interestingly, SNG also sensitized PTC cells to chemotherapeutic drug cisplatin, which was inhibited by NAC. Finally, SNG suppressed the growth of PTC thyrospheres and downregulated stemness markers ALDH2 and SOX2. Altogether, the findings of the current study suggest that SNG has anticancer potential against PTC cells as well its derived cancer stem-like cells, most likely via inactivation of STAT3 and its associated signaling molecules.
Assuntos
Apoptose/efeitos dos fármacos , Benzofenantridinas/farmacologia , Proliferação de Células/efeitos dos fármacos , Isoquinolinas/farmacologia , Câncer Papilífero da Tireoide/tratamento farmacológico , Autofagia/efeitos dos fármacos , Caspase 3/genética , Caspase 8/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células-Tronco Neoplásicas , Espécies Reativas de Oxigênio/metabolismo , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos dos fármacos , Câncer Papilífero da Tireoide/genéticaRESUMO
Tyrosine kinases belong to a family of enzymes that mediate the movement of the phosphate group to tyrosine residues of target protein, thus transmitting signals from the cell surface to cytoplasmic proteins and the nucleus to regulate physiological processes. Non-receptor tyrosine kinases (NRTK) are a sub-group of tyrosine kinases, which can relay intracellular signals originating from extracellular receptor. NRTKs can regulate a huge array of cellular functions such as cell survival, division/propagation and adhesion, gene expression, immune response, etc. NRTKs exhibit considerable variability in their structural make up, having a shared kinase domain and commonly possessing many other domains such as SH2, SH3 which are protein-protein interacting domains. Recent studies show that NRTKs are mutated in several hematological malignancies, including lymphomas, leukemias and myelomas, leading to aberrant activation. It can be due to point mutations which are intragenic changes or by fusion of genes leading to chromosome translocation. Mutations that lead to constitutive kinase activity result in the formation of oncogenes, such as Abl, Fes, Src, etc. Therefore, specific kinase inhibitors have been sought after to target mutated kinases. A number of compounds have since been discovered, which have shown to inhibit the activity of NRTKs, which are remarkably well tolerated. This review covers the role of various NRTKs in the development of hematological cancers, including their deregulation, genetic alterations, aberrant activation and associated mutations. In addition, it also looks at the recent advances in the development of novel natural compounds that can target NRTKs and perhaps in combination with other forms of therapy can show great promise for the treatment of hematological malignancies.
Assuntos
Produtos Biológicos/uso terapêutico , Neoplasias Hematológicas/tratamento farmacológico , Neoplasias Hematológicas/metabolismo , Proteínas Tirosina Quinases/metabolismo , Animais , Neoplasias Hematológicas/enzimologia , Humanos , Transdução de Sinais/efeitos dos fármacosRESUMO
BACKGROUND: The advantages of Enhanced Recovery (ER) programmes are well known, in terms of improved overall experience of the patients, which associates with low morbidity and reduced length of stay. As a result, the pattern of morbidity is changing and some patients may develop complications after discharge. Aim of this work was to evaluate the impact of morbidity and related outcomes such as unplanned readmission and reoperation rate on an ER programme in colorectal surgery. METHODS: Prospectively collected clinical data of patients who underwent colorectal resection have been retrospectively analysed. Endpoints were: 90-day mortality and morbidity, length of hospital stay (LOS) and rate of unplanned readmissions and reoperations. RESULTS: Mortality and morbidity did not change in the analysed period, but LOS reduced significantly. Main determinant of postoperative LOS was the type of surgical approach, laparoscopy being associated with earlier discharge. LOS was longer in patients who developed complications. Morbidity and reoperation rate were significantly higher in patients discharged after day 4. Majority of complications happened in patients who were still in the hospital. However, the few patients who developed complications after discharge did not have a worse outcome if compared to those who had complications in hospital. CONCLUSIONS: ER protocols must become integral part of the perioperative management of colorectal patients. ER and laparoscopy have a synergic effect to improve the postoperative recovery and reduce morbidity. Early discharge of patients does not affect the outcome of postoperative complications.
Assuntos
Laparoscopia/métodos , Complicações Pós-Operatórias/epidemiologia , Idoso , Procedimentos Cirúrgicos do Sistema Digestório/efeitos adversos , Procedimentos Cirúrgicos do Sistema Digestório/métodos , Feminino , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Morbidade , Alta do Paciente , Complicações Pós-Operatórias/etiologia , Período Pós-Operatório , Reoperação , Estudos RetrospectivosRESUMO
BACKGROUND: Alopecia areata (AA) is an autoimmune pathology manifested by loss of hair. OBJECTIVE: To evaluate and compare the efficacy and safety of tofacitinib and azathioprine in patients with AA and variants. METHODS: In this double-blind randomized controlled trail (RCT) carried out at the Department of Dermatology, Medical Teaching Institute-Lady Reading Hospital (MTI-LRH), Peshawar, Pakistan, patients aged ≥ 12 years diagnosed with AA, alopecia totalis (AT) or alopecia universalis (AU) with minimum 50% scalp hair loss for a period ≥ 06 years were included. Patients were randomly assigned to receive oral tofacitinib 5 mg twice daily (Group I) or oral azathioprine 2 mg/kg body weight once daily (Group II). The primary endpoint was Severity of Alopecia Tool (SALT) score, evaluated at baseline and 06 months follow-up. Safety was consistently assessed during the study. RESULTS: A total of 104 patients underwent random allocation into either the tofacitinib group (n = 52) or the azathioprine group (n = 52). The mean (SD) age of patients was 20.23 (7.14) years and 22.26 (8.07) years, while the mean (SD) disease duration was 6.59 (4.01) years and 7.98 (4.40) years in in Group I and II, respectively. Overall, 40 (38.5%) patients were adolescents while 70 (67.3%) were male. 52 (50%) had AA, 37 (35.5%) had AT and 15 (14.5%) had AU. Mean baseline SALT score in tofacitinib group was 91.02 ± 10.21 and azathioprine group was 91.02 ± 10.63, which at 06 months follow-up improved to 14.1 ± 24.6 and 63.9 ± 33.9, respectively (difference, 11.5 points; 95% confidence interval, 38.3-61.3, p < 0.0001). Overall, no major adverse effects and no difference among the minor adverse effects in the two groups (04 adverse events for tofacitinib group and 08 for azathioprine group: p = 0.23) was observed. CONCLUSIONS: Efficacy of tofacitinib was significantly higher than azathioprine, whilst both drugs were well-tolerated in patients with AA and variants.
Assuntos
Alopecia em Áreas , Alopecia , Azatioprina , Piperidinas , Pirimidinas , Humanos , Pirimidinas/administração & dosagem , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Piperidinas/uso terapêutico , Masculino , Alopecia em Áreas/tratamento farmacológico , Alopecia em Áreas/diagnóstico , Método Duplo-Cego , Feminino , Azatioprina/administração & dosagem , Azatioprina/efeitos adversos , Azatioprina/uso terapêutico , Adolescente , Adulto , Adulto Jovem , Alopecia/tratamento farmacológico , Resultado do Tratamento , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/uso terapêutico , Administração Oral , Criança , Pirróis/administração & dosagem , Pirróis/efeitos adversos , Índice de Gravidade de Doença , Imunossupressores/efeitos adversos , Imunossupressores/administração & dosagemRESUMO
Cutaneous T-cell lymphomas (CTC) are a heterogeneous group of T-cell lymphoproliferative malignancies of the skin with limited treatment options, increased resistance and remission. Metabolic reprogramming is vital in orchestrating the uncontrolled growth and proliferation of cancer cells. Importantly, deregulated signalling plays a significant role in metabolic reprogramming. Considering the crucial role of metabolic reprogramming in cancer-cell growth and proliferation, target identification and the development of novel and multi-targeting agents are imperative. The present study explores the underlying mechanisms and metabolic signalling pathways associated with Glabridin mediated anti-cancer actions in CTCL. Our results show that Glabridin significantly inhibits the growth of CTCL cells through induction of programmed cell death (PCD) such as apoptosis, autophagy and necrosis. Interestingly, results further show that Glabridin induces PCD in CTCL cells by targeting MAPK signalling pathways, particularly the activation of ERK. Further, Glabridin also sensitized CTCL cells to the anti-cancer drug, bortezomib. Importantly, LC-MS-based metabolomics analyses further showed that Glabridin targeted multiple metabolites and metabolic pathways intricately involved in cancer cell growth and proliferation in an ERK-dependent fashion. Overall, our findings revealed that Glabridin induces PCD and attenuates the expression of regulatory proteins and metabolites involved in orchestrating the uncontrolled proliferation of CTCL cells through ERK activation. Therefore, Glabridin possesses important features of an ideal anti-cancer agent.
RESUMO
BACKGROUND: The benzophenanthridine Sanguinarine (Sng) is one of the most abundant root alkaloids with a long history of investigation and pharmaceutical applications. The cytotoxicity of Sng against various tumor cells is well-established; however, its antiproliferative and apoptotic potential against the cutaneous squamous cell carcinoma (cSCC) cells remains unknown. In the present study, we investigated the anti-cancer potential of Sng against cSCC cells and elucidated the underlying mechanisms relevant to the drug action. METHODS: The inhibitory effect of Sng on cSCC cells was evaluated by analyzing cell viability, colony-forming ability and multi-caspase activity. Apoptosis was quantified through Annexin-V/Propidium iodide flow cytometric assay and antagonized by pan-caspase inhibitor z-VAD-FMK. Mitochondrial membrane potential (ΔΨm) dysfunction was analyzed by JC-1 staining, whereas reactive oxygen species (ROS) generation was confirmed by pretreatment with N-acetylcysteine (NAC) and fluorogenic probe-based flow cytometric detection. The expression of cell cycle regulatory proteins, apoptotic proteins and MAPK signaling molecules was determined by Western blotting. Involvement of JNK, p38-MAPK and MEK/ERK in ROS-mediated apoptosis was investigated by pretreatment with SP600125 (JNK inhibitor), SB203580 (p38 inhibitor) and U0126 (ERK1/2 inhibitor), respectively. The stemness-targeting potential of Sng was assessed in tumor cell-derived spheroids. RESULTS: Treatment with Sng decreased cell viability and colony formation in primary (A431) and metastatic (A388) cSCC cells in a time- and dose-dependent manner. Sng significantly inhibited cell proliferation by inducing sub-G0/G1 cell-cycle arrest and apoptosis in cSCC cells. Sng evoked ROS generation, intracellular glutathione (GSH) depletion, ΔΨm depolarization and the activation of JNK pathway as well as that of caspase-3, -8, -9, and PARP. Antioxidant NAC inhibited ROS production, replenished GSH levels, and abolished apoptosis induced by Sng by downregulating JNK. Pretreatment with z-VAD-FMK inhibited Sng-mediated apoptosis. The pharmacological inhibition of JNK by SP600125 mitigated Sng-induced apoptosis in metastatic cSCC cells. Finally, Sng ablated the stemness of metastatic cSCC cell-derived spheroids. CONCLUSION: Our results indicate that Sng exerts a potent cytotoxic effect against cSCC cells that is underscored by a mechanism involving multiple levels of cooperation, including cell-cycle sub-G0/G1 arrest and apoptosis induction through ROS-dependent activation of the JNK signaling pathway. This study provides insight into the potential therapeutic application of Sng targeting cSCC.
Assuntos
Antracenos , Carcinoma de Células Escamosas , Isoquinolinas , Neoplasias Cutâneas , Humanos , Espécies Reativas de Oxigênio/metabolismo , Benzofenantridinas/farmacologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Cutâneas/tratamento farmacológico , Transdução de Sinais , Apoptose , Sistema de Sinalização das MAP Quinases , Linhagem Celular TumoralRESUMO
S-phase kinase-associated protein 2 (Skp2) is an F-box protein overexpressed in human cancers and linked with poor prognosis. It triggers cancer pathogenesis, including stemness and drug resistance. In this study, we have explored the potential role of Skp2 targeting in restoring the expression of tumor suppressors in human cutaneous squamous cell carcinoma (cSCC) cells. Our results showed that genetic and pharmacological Skp2 targeting markedly suppressed cSCC cell proliferation, colony growth, spheroid formation, and enhanced sensitization to chemotherapeutic drugs. Further, western blot results demonstrated restoration of tumor suppressor (KLF4) and CDKI (p21) and suppression of vimentin and survivin in Skp2-knocked-down cSCC cells. Importantly, we also explored that Skp2 targeting potentiates apoptosis of cSCC cells through MAPK signaling. Moreover, co-targeting of Skp2 and PI3K/AKT resulted in increased cancer cell death. Interestingly, curcumin, a well-known naturally derived anticancer agent, also inhibits Skp2 expression with concomitant CDKI upregulation. In line, curcumin suppressed cSCC cell growth through ROS-mediated apoptosis, while the use of N-acetyl cysteine (NAC) reversed curcumin-induced cell death. Curcumin treatment also sensitized cSCC cells to conventional anticancer drugs, such as cisplatin and doxorubicin. Altogether, these data suggest that Skp2 targeting restores the functioning of tumor suppressors, inhibits the expression of genes associated with cell proliferation and stemness, and sensitizes cancer cells to anticancer drugs. Thus, genetic, and pharmacological ablation of Skp2 can be an important strategy for attenuating cancer pathogenesis and associated complications in skin squamous cell carcinoma.
Assuntos
Apoptose , Carcinoma de Células Escamosas , Fator 4 Semelhante a Kruppel , Proteínas Quinases Associadas a Fase S , Neoplasias Cutâneas , Humanos , Proteínas Quinases Associadas a Fase S/metabolismo , Proteínas Quinases Associadas a Fase S/genética , Apoptose/efeitos dos fármacos , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Linhagem Celular Tumoral , Fator 4 Semelhante a Kruppel/metabolismo , Proliferação de Células/efeitos dos fármacos , Curcumina/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacosRESUMO
Total hip arthroplasty (THA) is considered the preferred treatment for displaced proximal femoral neck fractures. However, in many countries this option is economically unviable. To improve outcomes in financially disadvantaged populations, we studied the technique of concomitant valgus hip osteotomy and operative fixation (VOOF). This prospective serial study compares two treatment groups: VOOF versus operative fixation alone with cannulated compression screws (CCSs). In the first series, 98 hip fixation procedures were performed using CCS. After fluoroscopic reduction of the fracture, three CCSs were placed. In the second series, 105 VOOF procedures were performed using a closing wedge intertrochanteric osteotomy with a compression lag screw and lateral femoral plate. The alignment goal was to create a modified Pauwel's fracture angle of 30°. After fluoroscopic reduction of fracture, lag screw was placed to achieve the calculated correction angle, followed by inter-trochanteric osteotomy and placement of barrel plate. Patients were followed for a minimum of two years. Mean follow-up was 4.6 years (4.1 to 5.0) in the CCS group and 5.5 years (5.25 to 5.75) in the VOOF group. The mean Harris Hip Score at two-year follow-up was 83.85 in the CCS group versus 88.00 in the VOOF group (p < 0.001). At the latest follow-up, all-cause failure rate was 29.1% in the CCS group and 11.7% in the VOOF group (p = 0.003). The total cost of the VOOF technique was 7.2% of a THA, and total cost of the CCS technique was 6.3% of a THA. The VOOF technique decreased all-cause failure rate compared to CCS. The total cost of VOOF was 13.5% greater than CCS, but 92.8% less than a THA. Increased cost of VOOF was considered acceptable to all patients in this series. VOOF technique provides a reasonable alternative to THA in patients who cannot afford a THA procedure.