RESUMEN
Radiotherapy (RT) and immunotherapy (IT) are the powerful tools for cancer treatment which act through the stimulation of immune response, and evidence suggest that combinatorial actions of these therapies may augment each other's beneficial effect through complex synergistic mechanisms. These molecular strategies are designed to target rapidly dividing cancer cells by either directly or indirectly inducing DNA damage. However, when cells detect DNA damage, they activate a range of signalling pathways known as the DNA damage response (DDR) to repair. Strategies are being developed to interfere with the DDR pathways in cancer cells to ensure their damage-induced degeneration. The stability of a cell's genetic material is largely dependent on the efficacy of DNA repair and therefore, an in-depth understanding of DNA damages and repair mechanism(s) in cancer cells is important to develop a promising therapeutic strategies for ensuring the efficacy of damage-induced tumor cell death. In recent years, a wide range of small molecule drugs have been developed which are currently being employed to combat the DNA repair deficiencies associated with tumor cells. Sequential or concurrent use of these two modalities significantly enhances the anti-tumor response, however with a concurrent probability of increased incidence of symptomatic adverse effects. With advent of newer IT agents, and administration of higher doses of radiation per fraction, such effects are more difficult to predict owing to the paucity of randomized trial data. It is well established that anti cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4), anti- Programmed cell death protein 1(PD-1), anti-Programmed cell death one ligand 1 (PD-L1) can be safely administered with RT and many studies have demonstrated survival benefit with such combination for patients with metastatic malignancy. However, the biology of radioimmunotherapy (RT/IT) is still an open area where research need to be focused to determine optimum dosage specially the interaction of the RT/IT pathways to determine optimum dosing schedule. In the current article we have summarised the possible intracellular immunological events that might be triggered when RT and IT modalities are combined with the DDR antagonists and highlighted present clinical practices, outcome, and toxicity profile of this novel treatment strategy.
RESUMEN
Cervical cancer is still the leading cause of cancer mortality worldwide even after introduction of vaccine against Human papillomavirus (HPV), due to low vaccine coverage, especially in the developing world. Cervical cancer is primarily treated by Chemo/Radiotherapy, depending on the disease stage, with Carboplatin/Cisplatin-based drug regime. These drugs being non-specific, target rapidly dividing cells, including normal cells, so safer options are needed for lower off-target toxicity. Natural products offer an attractive option compared to synthetic drugs due to their well-established safety profile and capacity to target multiple oncogenic hallmarks of cancer like inflammation, angiogenesis, etc. In the current study, we investigated the effect of Bergenin (C-glycoside of 4-O-methylgallic acid), a natural polyphenol compound that is isolated from medicinal plants such as Bergenia crassifolia, Caesalpinia digyna, and Flueggea leucopyrus. Bergenin has been shown to have anti-inflammatory, anti-ulcerogenic, and wound healing properties but its anticancer potential has been realized only recently. We performed a proteomic analysis of cervical carcinoma cells treated with bergenin and found it to influence multiple hallmarks of cancers, including apoptosis, angiogenesis, and tumor suppressor proteins. It was also involved in many different cellular processes unrelated to cancer, as shown by our proteomic analysis. Further analysis showed bergenin to be a potent-angiogenic agent by reducing key angiogenic proteins like Galectin 3 and MMP-9 (Matrix Metalloprotease 9) in cervical carcinoma cells. Further understanding of this interaction was carried out using molecular docking analysis, which indicated MMP-9 has more affinity for bergenin as compared to Galectin-3. Cumulatively, our data provide novel insight into the anti-angiogenic mechanism of bergenin in cervical carcinoma cells by modulation of multiple angiogenic proteins like Galectin-3 and MMP-9 which warrant its further development as an anticancer agent in cervical cancer.
Asunto(s)
Benzopiranos , Proliferación Celular , Galectina 3 , Metaloproteinasa 9 de la Matriz , Neoplasias del Cuello Uterino , Humanos , Metaloproteinasa 9 de la Matriz/metabolismo , Benzopiranos/farmacología , Femenino , Neoplasias del Cuello Uterino/tratamiento farmacológico , Neoplasias del Cuello Uterino/metabolismo , Neoplasias del Cuello Uterino/patología , Galectina 3/metabolismo , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Simulación del Acoplamiento Molecular , Galectinas/metabolismo , Galectinas/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Apoptosis/efectos de los fármacos , Células HeLa , Proteínas SanguíneasRESUMEN
Esophageal cancer (EC) is significantly influenced by the tumor microenvironment (TME) and altered signaling pathways. Downregulating these pathways in EC is essential for suppressing tumor development, preventing metastasis, and enhancing therapeutic outcomes. This approach can increase tumor sensitivity to treatments, enhance patient outcomes, and inhibit cancer cell proliferation and spread. The TME, comprising cellular and non-cellular elements surrounding the tumor, significantly influences EC's development, course, and treatment responsiveness. Understanding the complex relationships within the TME is crucial for developing successful EC treatments. Immunotherapy is a vital TME treatment for EC. However, the heterogeneity within the TME limits the application of anticancer drugs outside clinical settings. Therefore, identifying reliable microenvironmental biomarkers that can detect therapeutic responses before initiating therapy is crucial. Combining approaches focusing on EC signaling pathways with TME can enhance treatment outcomes. This integrated strategy aims to interfere with essential signaling pathways promoting cancer spread while disrupting factors encouraging tumor development. Unraveling aberrant signaling pathways and TME components can lead to more focused and efficient treatment approaches, identifying specific cellular targets for treatments. Targeting the TME and signaling pathways may reduce metastasis risk by interfering with mechanisms facilitating cancer cell invasion and dissemination. In conclusion, this integrative strategy has significant potential for improving patient outcomes and advancing EC research and therapy. This review discusses the altered signaling pathways and TME in EC, focusing on potential future therapeutics.
Asunto(s)
Neoplasias Esofágicas , Transducción de Señal , Microambiente Tumoral , Humanos , Neoplasias Esofágicas/patología , Animales , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Inmunoterapia/métodosRESUMEN
Obesity stands as a formidable global health challenge, predisposing individuals to a plethora of chronic illnesses such as cardiovascular disease, diabetes, and cancer. A confluence of genetic polymorphisms, suboptimal dietary choices, and sedentary lifestyles significantly contribute to the elevated incidence of obesity. This multifaceted health issue profoundly disrupts homeostatic equilibrium at both organismal and cellular levels, with marked alterations in gut permeability as a salient consequence. The intricate mechanisms underlying these alterations have yet to be fully elucidated. Still, evidence suggests that heightened inflammatory cytokine levels and the remodeling of tight junction (TJ) proteins, particularly claudins, play a pivotal role in the manifestation of epithelial barrier dysfunction in obesity. Strategic targeting of proteins implicated in these pathways and metabolites such as short-chain fatty acids presents a promising intervention for restoring barrier functionality among individuals with obesity. Nonetheless, recognizing the heterogeneity among affected individuals is paramount; personalized medical interventions or dietary regimens tailored to specific genetic backgrounds and allergy profiles may prove indispensable. This comprehensive review delves into the nexus of obesity, tight junction remodeling, and barrier dysfunction, offering a critical appraisal of potential therapeutic interventions.
Asunto(s)
Obesidad , Uniones Estrechas , Humanos , Mucosa Intestinal/metabolismo , AnimalesRESUMEN
Non-melanoma skin cancer (NMSC), encompassing basal and squamous cell carcinoma, is the most prevalent cancer in the United States. While surgical removal remains the conventional therapy with a 95% 5-year cure rate, there is a growing interest in exploring alternative treatment strategies. In this study, we investigated the role of Bortezomib (BTZ), a proteasome inhibitor, in NMSC. Using two NMSC cell lines (A431 and A388), we examined the effects of BTZ treatment. Our results demonstrated that 48 h of BTZ treatment led to downregulating Skp2 expression in both A431 and A388 cells while upregulating p53 expression, specifically in A388 cells. These alterations resulted in impaired cellular growth and caspase-dependent cell death. Silencing Skp2 in A388 cells with siRNA confirmed the upregulation of p53 as a direct target. Furthermore, BTZ treatment increased the Bax to Bcl-2 ratio, promoting mitochondrial permeability and the subsequent release of cytochrome C, thereby activating caspases. We also found that BTZ exerted its antitumor effects by generating reactive oxygen species (ROS), as blocking ROS production significantly reduced BTZ-induced apoptotic cell death. Interestingly, BTZ treatment induced autophagy, which is evident from the increased expression of microtubule-associated proteins nucleoporin p62 and LC-3A/B. In addition to cell lines, we assessed the impact of BTZ in an in vivo setting using Caenorhabditis elegans (C. elegans). Our findings demonstrated that BTZ induced germline apoptosis in worms even at low concentrations. Notably, this increased apoptosis was mediated through the activity of CEP-1, the worm's counterpart to mammalian p53. In summary, our study elucidated the molecular mechanism underlying BTZ-induced apoptosis in NMSC cell lines and C. elegans. By targeting the skp2/p53 axis, inducing mitochondrial permeability, generating ROS, and promoting autophagy, BTZ demonstrates promising anti-cancer activity in NMSC. These findings provide novel insights into potential therapeutic strategies for controlling the unregulated growth of NMSC.
RESUMEN
The growing global burden of malignant tumors with increasing incidence and mortality rates underscores the urgent need for more effective and less toxic therapeutic options. Herbal compounds are being increasingly studied for their potential to meet these needs due to their reduced side effects and significant efficacy. Pristimerin (PS), a triterpenoid from the quinone formamide class derived from the Celastraceae and Hippocrateaceae families, has emerged as a potent anticancer agent. It exhibits broad-spectrum anti-tumor activity across various cancers such as breast, pancreatic, prostate, glioblastoma, colorectal, cervical, and lung cancers. PS modulates several key cellular processes, including apoptosis, autophagy, cell migration and invasion, angiogenesis, and resistance to chemotherapy, targeting crucial signaling pathways such as those involving NF-κB, p53, and STAT3, among others. The main objective of this review is to provide a comprehensive synthesis of the current literature on PS, emphasizing its mechanisms of action and molecular targets with the utmost clarity. It discusses the comparative advantages of PS over current cancer therapies and explores the implications for future research and clinical applications. By delineating the specific pathways and targets affected by PS, this review seeks to offer valuable insights and directions for future research in this field. The information gathered in this review could pave the way for the successful development of PS into a clinically applicable anticancer therapy.
RESUMEN
Cancer is caused by a complex interaction of factors that interrupt the normal growth and division of cells. At the center of this process is the intricate relationship between DNA damage and the cellular mechanisms responsible for maintaining genomic stability. When DNA damage is not repaired, it can cause genetic mutations that contribute to the initiation and progression of cancer. On the other hand, the DNA damage response system, which involves the phosphorylation of the histone variant H2AX (γH2AX), is crucial in preserving genomic integrity by signaling and facilitating the repair of DNA double-strand breaks. This review provides an explanation of the molecular dynamics of H2AX in the context of DNA damage response. It emphasizes the crucial role of H2AX in recruiting and localizing repair machinery at sites of chromatin damage. The review explains how H2AX phosphorylation, facilitated by the master kinases ATM and ATR, acts as a signal for DNA damage, triggering downstream pathways that govern cell cycle checkpoints, apoptosis, and the cellular fate decision between repair and cell death. The phosphorylation of H2AX is a critical regulatory point, ensuring cell survival by promoting repair or steering cells towards apoptosis in cases of catastrophic genomic damage. Moreover, we explore the therapeutic potential of targeting H2AX in cancer treatment, leveraging its dual function as a biomarker of DNA integrity and a therapeutic target. By delineating the pathways that lead to H2AX phosphorylation and its roles in apoptosis and cell cycle control, we highlight the significance of H2AX as both a prognostic tool and a focal point for therapeutic intervention, offering insights into its utility in enhancing the efficacy of cancer treatments.
Asunto(s)
Daño del ADN , Reparación del ADN , Histonas , Neoplasias , Humanos , Histonas/metabolismo , Neoplasias/genética , Neoplasias/patología , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Animales , Fosforilación , Transducción de Señal , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Terapia Molecular DirigidaRESUMEN
Esophageal cancer (EC) remains a significant health challenge globally, with increasing incidence and high mortality rates. Despite advances in treatment, there remains a need for improved diagnostic methods and understanding of disease progression. This study addresses the significant challenges in the automatic classification of EC, particularly in distinguishing its primary subtypes: adenocarcinoma and squamous cell carcinoma, using histopathology images. Traditional histopathological diagnosis, while being the gold standard, is subject to subjectivity and human error and imposes a substantial burden on pathologists. This study proposes a binary class classification system for detecting EC subtypes in response to these challenges. The system leverages deep learning techniques and tissue-level labels for enhanced accuracy. We utilized 59 high-resolution histopathological images from The Cancer Genome Atlas (TCGA) Esophageal Carcinoma dataset (TCGA-ESCA). These images were preprocessed, segmented into patches, and analyzed using a pre-trained ResNet101 model for feature extraction. For classification, we employed five machine learning classifiers: Support Vector Classifier (SVC), Logistic Regression (LR), Decision Tree (DT), AdaBoost (AD), Random Forest (RF), and a Feed-Forward Neural Network (FFNN). The classifiers were evaluated based on their prediction accuracy on the test dataset, yielding results of 0.88 (SVC and LR), 0.64 (DT and AD), 0.82 (RF), and 0.94 (FFNN). Notably, the FFNN classifier achieved the highest Area Under the Curve (AUC) score of 0.92, indicating its superior performance, followed closely by SVC and LR, with a score of 0.87. This suggested approach holds promising potential as a decision-support tool for pathologists, particularly in regions with limited resources and expertise. The timely and precise detection of EC subtypes through this system can substantially enhance the likelihood of successful treatment, ultimately leading to reduced mortality rates in patients with this aggressive cancer.
RESUMEN
Extracellular vesicles (EVs) are nano-sized, membranous structures secreted into the extracellular space. They exhibit diverse sizes, contents, and surface markers and are ubiquitously released from cells under normal and pathological conditions. Human serum is a rich source of these EVs, though their isolation from serum proteins and non-EV lipid particles poses challenges. These vesicles transport various cellular components such as proteins, mRNAs, miRNAs, DNA, and lipids across distances, influencing numerous physiological and pathological events, including those within the tumor microenvironment (TME). Their pivotal roles in cellular communication make EVs promising candidates for therapeutic agents, drug delivery systems, and disease biomarkers. Especially in cancer diagnostics, EV detection can pave the way for early identification and offers potential as diagnostic biomarkers. Moreover, various EV subtypes are emerging as targeted drug delivery tools, highlighting their potential clinical significance. The need for non-invasive biomarkers to monitor biological processes for diagnostic and therapeutic purposes remains unfulfilled. Tapping into the unique composition of EVs could unlock advanced diagnostic and therapeutic avenues in the future. In this review, we discuss in detail the roles of EVs across various conditions, including cancers (encompassing head and neck, lung, gastric, breast, and hepatocellular carcinoma), neurodegenerative disorders, diabetes, viral infections, autoimmune and renal diseases, emphasizing the potential advancements in molecular diagnostics and drug delivery.
Asunto(s)
Vesículas Extracelulares , MicroARNs , Neoplasias , Virosis , Humanos , Vesículas Extracelulares/genética , Vesículas Extracelulares/metabolismo , MicroARNs/metabolismo , Biomarcadores , Neoplasias/diagnóstico , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Microambiente TumoralRESUMEN
Cancer is a complex disease displaying a variety of cell states and phenotypes. This diversity, known as cancer cell plasticity, confers cancer cells the ability to change in response to their environment, leading to increased tumor diversity and drug resistance. This review explores the intricate landscape of cancer cell plasticity, offering a deep dive into the cellular, molecular, and genetic mechanisms that underlie this phenomenon. Cancer cell plasticity is intertwined with processes such as epithelial-mesenchymal transition and the acquisition of stem cell-like features. These processes are pivotal in the development and progression of tumors, contributing to the multifaceted nature of cancer and the challenges associated with its treatment. Despite significant advancements in targeted therapies, cancer cell adaptability and subsequent therapy-induced resistance remain persistent obstacles in achieving consistent, successful cancer treatment outcomes. Our review delves into the array of mechanisms cancer cells exploit to maintain plasticity, including epigenetic modifications, alterations in signaling pathways, and environmental interactions. We discuss strategies to counteract cancer cell plasticity, such as targeting specific cellular pathways and employing combination therapies. These strategies promise to enhance the efficacy of cancer treatments and mitigate therapy resistance. In conclusion, this review offers a holistic, detailed exploration of cancer cell plasticity, aiming to bolster the understanding and approach toward tackling the challenges posed by tumor heterogeneity and drug resistance. As articulated in this review, the delineation of cellular, molecular, and genetic mechanisms underlying tumor heterogeneity and drug resistance seeks to contribute substantially to the progress in cancer therapeutics and the advancement of precision medicine, ultimately enhancing the prospects for effective cancer treatment and patient outcomes.
Asunto(s)
Plasticidad de la Célula , Neoplasias , Humanos , Plasticidad de la Célula/genética , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Neoplasias/patología , Resistencia a Antineoplásicos/genética , Transición Epitelial-Mesenquimal/genética , Transducción de SeñalRESUMEN
Breast cancer remains a major global health challenge. Its rising incidence is attributed to factors such as delayed diagnosis, the complexity of its subtypes, and increasing drug resistance, all contributing to less-than-ideal patient outcomes. Central to the progression of breast cancer are epigenetic aberrations, which significantly contribute to drug resistance and the emergence of cancer stem cell traits. These include alterations in DNA methylation, histone modifications, and the expression of non-coding RNAs. Understanding these epigenetic changes is crucial for developing advanced breast cancer management strategies despite their complexity. Investigating these epigenetic modifications offers the potential for novel diagnostic markers, more accurate prognostic indicators, and the identification of reliable predictors of treatment response. This could lead to the development of new targeted therapies. However, this requires sustained, focused research efforts to navigate the challenges of understanding breast cancer carcinogenesis and its epigenetic underpinnings. A deeper understanding of epigenetic mechanisms in breast cancer can revolutionize personalized medicine. This could lead to significant improvements in patient care, including early detection, precise disease stratification, and more effective treatment options.
Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/genética , Metilación de ADN/genética , Epigénesis Genética , Carcinogénesis/genética , EpigenómicaRESUMEN
Neosetophomone B (NSP-B) is a unique meroterpenoid fungal secondary metabolite that has previously demonstrated promising anti-cancer properties against various cancer cell lines in vitro. However, its in vivo anti-cancer potential remaines unexplored. To fill this gap in our knowledge, we tested NSP-B's in vivo anti-cancer activity using a zebrafish model, an organism that has gained significant traction in biomedical research due to its genetic similarities with humans and its transparent nature, allowing real-time tumor growth observation. For our experiments, we employed the K562-injected zebrafish xenograft model. Upon treating these zebrafish with NSP-B, we observed a marked reduction in the size and number of tumor xenografts. Delving deeper, our analyses indicated that NSP-B curtailed tumor growth and proliferation of leukemic grafted xenograft within the zebrafish. These results show that NSP-B possesses potent in vivo anti-cancer properties, making it a potential novel therapeutic agent for addressing hematological malignancies.
Asunto(s)
Neoplasias , Pez Cebra , Animales , Humanos , Pez Cebra/metabolismo , Xenoinjertos , Modelos Animales de Enfermedad , Línea Celular Tumoral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
The tumor microenvironment (TME) exerts a profound influence on the oncogenesis and progression of various cancers, notably those instigated by the human papillomavirus (HPV) and the Epstein-Barr virus (EBV). The etiology of HPV and EBV-associated malignancies is rooted in intricate interactions that intertwine viral infections, genetic predispositions, and distinct TME dynamics. These interactions foster a milieu that can either support or hinder tumorigenic progression. Gaining in-depth knowledge of the TME's unique features, including its cellular composition, cytokine profiles, and metabolic alterations specific to HPV and EBV-associated cancers, is fundamental to innovating more efficacious therapeutic strategies. This review delineates the intricate roles of HPV and EBV in shaping the TME and expounds upon the unique TME characteristics specific to HPV and EBV-driven cancers. Additionally, we spotlight innovative approaches to remodel the TME, aiming to augment therapeutic efficacy in combatting HPV and EBV-associated neoplasms.
Asunto(s)
Infecciones por Virus de Epstein-Barr , Neoplasias , Infecciones por Papillomavirus , Humanos , Herpesvirus Humano 4 , Infecciones por Virus de Epstein-Barr/complicaciones , Infecciones por Papillomavirus/complicaciones , Virus del Papiloma Humano , Microambiente Tumoral , Carcinogénesis , Papillomaviridae/genéticaRESUMEN
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.
Asunto(s)
Antracenos , Carcinoma de Células Escamosas , Isoquinolinas , Neoplasias Cutáneas , Humanos , Especies Reactivas de Oxígeno/metabolismo , Benzofenantridinas/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos/metabolismo , Carcinoma de Células Escamosas/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Transducción de Señal , Apoptosis , Sistema de Señalización de MAP Quinasas , Línea Celular TumoralRESUMEN
Multiple myeloma (MM) is a hematologic malignancy associated with malignant plasma cell proliferation in the bone marrow. Despite the available treatments, drug resistance and adverse side effects pose significant challenges, underscoring the need for alternative therapeutic strategies. Natural products, like the fungal metabolite neosetophomone B (NSP-B), have emerged as potential therapeutic agents due to their bioactive properties. Our study investigated NSP-B's antitumor effects on MM cell lines (U266 and RPMI8226) and the involved molecular mechanisms. NSP-B demonstrated significant growth inhibition and apoptotic induction, triggered by reduced AKT activation and downregulation of the inhibitors of apoptotic proteins and S-phase kinase protein. This was accompanied by an upregulation of p21Kip1 and p27Cip1 and an elevated Bax/BCL2 ratio, culminating in caspase-dependent apoptosis. Interestingly, NSP-B also enhanced the cytotoxicity of bortezomib (BTZ), an existing MM treatment. Overall, our findings demonstrated that NSP-B induces caspase-dependent apoptosis, increases cell damage, and suppresses MM cell proliferation while improving the cytotoxic impact of BTZ. These findings suggest that NSP-B can be used alone or in combination with other medicines to treat MM, highlighting its importance as a promising phytoconstituent in cancer therapy.
Asunto(s)
Antineoplásicos , Mieloma Múltiple , Humanos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Mieloma Múltiple/metabolismo , Línea Celular Tumoral , Apoptosis , Transducción de Señal , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Bortezomib/farmacología , Proliferación CelularRESUMEN
Significant progress has been achieved in the realm of therapeutic interventions for multiple myeloma (MM), leading to transformative shifts in its clinical management. While conventional modalities such as surgery, radiotherapy, and chemotherapy have improved the clinical outcomes, the overarching challenge of effecting a comprehensive cure for patients afflicted with relapsed and refractory MM (RRMM) endures. Notably, adoptive cellular therapy, especially chimeric antigen receptor T-cell (CAR-T) therapy, has exhibited efficacy in patients with refractory or resistant B-cell malignancies and is now also being tested in patients with MM. Within this context, the B-cell maturation antigen (BCMA) has emerged as a promising candidate for CAR-T-cell antigen targeting in MM. Alternative targets include SLAMF7, CD38, CD19, the signaling lymphocyte activation molecule CS1, NKG2D, and CD138. Numerous clinical studies have demonstrated the clinical efficacy of these CAR-T-cell therapies, although longitudinal follow-up reveals some degree of antigenic escape. The widespread implementation of CAR-T-cell therapy is encumbered by several barriers, including antigenic evasion, uneven intratumoral infiltration in solid cancers, cytokine release syndrome, neurotoxicity, logistical implementation, and financial burden. This article provides an overview of CAR-T-cell therapy in MM and the utilization of BCMA as the target antigen, as well as an overview of other potential target moieties.
RESUMEN
The interaction of visual exploration and auditory processing is central to early cognitive development, supporting object discrimination, categorization, and word learning. Research has shown visual-auditory interactions to be complex, created from multiple processes and changing over multiple timescales. To better understand these interactions, we generalize a formal neural process model of early word learning to two studies examining how words impact 9- to 22-month-olds' attention to novelty. These simulations clarify the origin and nature of previously demonstrated effects of labels on visual exploration and the basis of mutual exclusivity effects in word learning. We use our findings to discuss key questions for this special section: what makes a good theory and how should formal theories interface with empirical paradigms and findings?
Asunto(s)
Cognición , Aprendizaje Verbal , Humanos , Lactante , Percepción Auditiva , Desarrollo del LenguajeRESUMEN
Obesity and asthma are two common health issues that have shown increased prevalence in recent years and have become a significant socioeconomic burden worldwide. Obesity increases asthma incidence and severity. Obese asthmatic individuals often experience increased exacerbation rates, enhanced airway remodeling, and reduced response to standard corticosteroid therapy. Recent studies indicate that obesity-associated non-T2 factors such as mechanical stress, hyperinsulinemia, systemic inflammation, adipose tissue mediators, metabolic dysregulation, microbiome dysbiosis, and high-fat-diet are responsible for increased asthma symptoms and reduced therapeutic response in obese asthmatic individuals. This manuscript reviews the recent findings highlighting the role of obesity-associated factors that contribute to airway hyper-reactivity, airway inflammation and remodeling, and immune cell dysfunction, consequently contributing to worsening asthma symptoms. Furthermore, the review also discusses the possible future therapies that might play a role in reducing asthma symptoms by diminishing the impact of obesity-associated non-T2 factors.
RESUMEN
BACKGROUND: Cutaneous T cell lymphoma (CTCL) is a T cell-derived non-Hodgkin lymphoma primarily affecting the skin, with treatment posing a significant challenge and low survival rates. OBJECTIVE: In this study, we investigated the anti-cancer potential of Neosetophomone B (NSP-B), a fungal-derived secondary metabolite, on CTCL cell lines H9 and HH. METHODS: Cell viability was measured using Cell counting Kit-8 (CCK8) assays. Apoptosis was measured by annexin V/PI dual staining. Immunoblotting was performed to examine the expression of proteins. Applied Biosystems' high-resolution Human Transcriptome Array 2.0 was used to examine gene expression. RESULTS: NSP-B induced apoptosis in CTCL cells by activating mitochondrial signaling pathways and caspases. We observed downregulated expression of BUB1B, Aurora Kinases A and B, cyclin-dependent kinases (CDKs) 4 and 6, and polo-like kinase 1 (PLK1) in NSP-B treated cells, which was further corroborated by Western blot analysis. Notably, higher expression levels of these genes showed reduced overall and progression-free survival in the CTCL patient cohort. FOXM1 and BUB1B expression exhibited a dose-dependent reduction in NSP-B-treated CTCL cells.FOXM1 silencing decreased cell viability and increased apoptosis via BUB1B downregulation. Moreover, NSP-B suppressed FOXM1-regulated genes, such as Aurora Kinases A and B, CDKs 4 and 6, and PLK1. The combined treatment of Bortezomib and NSP-B showed greater efficacy in reducing CTCL cell viability and promoting apoptosis compared to either treatment alone. CONCLUSION: Our findings suggest that targeting the FOXM1 pathway may provide a promising therapeutic strategy for CTCL management, with NSP-B offering significant potential as a novel treatment option.
Asunto(s)
Linfoma Cutáneo de Células T , Neoplasias Cutáneas , Humanos , Apoptosis , Aurora Quinasa A/metabolismo , Aurora Quinasa A/uso terapéutico , Línea Celular Tumoral , Proteína Forkhead Box M1/efectos de los fármacos , Proteína Forkhead Box M1/metabolismo , Linfoma Cutáneo de Células T/tratamiento farmacológico , Linfoma Cutáneo de Células T/patología , Transducción de Señal/efectos de los fármacos , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/patología , Terpenos/farmacología , Terpenos/uso terapéuticoRESUMEN
BACKGROUND: Telomeres are repetitive DNA sequences located at the ends of chromosomes, playing a vital role in maintaining chromosomal integrity and stability. Dysregulation of telomeres has been implicated in the development of various cancers, including non-small cell lung cancer (NSCLC), which is the most common type of lung cancer. Genetic variations within telomere maintenance genes may influence the risk of developing NSCLC. The present study aimed to evaluate the genetic associations of select variants within telomere maintenance genes in a population from Jammu and Kashmir, North India, and to investigate the relationship between telomere length and NSCLC risk. METHODS: We employed the cost-effective and high-throughput MassARRAY MALDI-TOF platform to assess the genetic associations of select variants within telomere maintenance genes in a population from Jammu and Kashmir, North India. Additionally, we used TaqMan genotyping to validate our results. Furthermore, we investigated telomere length variation and its relation to NSCLC risk in the same population using dual-labeled fluorescence-based qPCR. RESULTS: Our findings revealed significant associations of TERT rs10069690 and POT1 rs10228682 with NSCLC risk (adjusted p-values = 0.019 and 0.002, respectively), while TERF2 rs251796 and rs2975843 showed no significant associations. The TaqMan genotyping validation further substantiated the associations of TERT rs10069690 and rs2242652 with NSCLC risk (adjusted p-values = 0.02 and 0.003, respectively). Our results also demonstrated significantly shorter telomere lengths in NSCLC patients compared to controls (p = 0.0004). CONCLUSION: This study highlights the crucial interplay between genetic variation in telomere maintenance genes, telomere attrition, and NSCLC risk in the Jammu and Kashmir population of North India. Our findings suggest that TERT and POT1 gene variants, along with telomere length, may serve as potential biomarkers and therapeutic targets for NSCLC in this population. Further research is warranted to elucidate the underlying mechanisms and to explore the potential clinical applications of these findings.