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Importance: Evidence on the association of early intervention services (EISs) with self-harm and suicide among patients with first-episode schizophrenia (FES) at older than 25 years is lacking. Objective: To examine changes in self-harm and suicide rates among patients with FES before and after the implementation of an EIS program. Design, Setting, and Participants: This population-based cohort study conducted among 37â¯040 patients aged 15 to 64 years with FES between January 1, 2001, and March 31, 2020, used electronic medical records from the Hong Kong Clinical Data Analysis and Reporting System. All patients were followed up from the first diagnosis of schizophrenia (the index date) until the date of their death or the end of the study period (March 31, 2021), whichever came first. Statistical analysis was performed from July to November 2023. Exposure: The EIS extended the Early Assessment Service for Young People With Early Psychosis (EASY) program from patients aged 15 to 25 years to those aged 15 to 64 years (EASY Plus). The exposure was the implementation of the EASY Plus program in April 2011. The exposure period was defined as between April 2012 and March 2021 for the 1-year-time-lag analysis. Main Outcomes and Measures: The outcomes were monthly rates of self-harm and suicide among patients with FES before and after the implementation of the EASY Plus program. Interrupted time series analysis was used for the main analysis. Results: This study included 37â¯040 patients with FES (mean [SD] age at onset, 39 [12] years; 82.6% older than 25 years; 53.0% female patients). The 1-year-time-lag analysis found an immediate decrease in self-harm rates among patients aged 26 to 44 years (rate ratio [RR], 0.77 [95% CI, 0.59-1.00]) and 45 to 64 years (RR, 0.70 [95% CI, 0.49-1.00]) and among male patients (RR, 0.71 [95% CI, 0.56-0.91]). A significant long-term decrease in self-harm rates was found for all patients with FES (patients aged 15-25 years: RR, 0.98 [95% CI, 0.97-1.00]; patients aged 26-44 years: RR, 0.98 [95% CI, 0.97-0.99]; patients aged 45-64 years: RR, 0.97 [95% CI, 0.96-0.98]). Suicide rates decreased immediately after the implementation of the EASY Plus program among patients aged 15 to 25 years (RR, 0.33 [95% CI, 0.14-0.77]) and 26 to 44 years (RR, 0.38 [95% CI, 0.20-0.73]). Compared with the counterfactual scenario, the EASY Plus program might have led to 6302 fewer self-harm episodes among patients aged 26 to 44 years. Conclusions and Relevance: This cohort study of the EASY Plus program suggests that the extended EIS was associated with reduced self-harm and suicide rates among all patients with FES, including those older than 25 years. These findings emphasize the importance of developing tailored interventions for patients across all age ranges to maximize the benefits of EISs.
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Esquizofrenia , Conducta Autodestructiva , Suicidio , Humanos , Masculino , Esquizofrenia/epidemiología , Esquizofrenia/terapia , Femenino , Adulto , Conducta Autodestructiva/epidemiología , Conducta Autodestructiva/psicología , Adolescente , Hong Kong/epidemiología , Adulto Joven , Persona de Mediana Edad , Suicidio/estadística & datos numéricos , Suicidio/psicología , Estudios de Cohortes , Intervención Médica Temprana/métodosRESUMEN
Breast cancer brain metastasis (BCBM) is a lethal disease with no effective treatments. Prior work has shown that brain cancers and metastases are densely infiltrated with anti-inflammatory, protumourigenic tumour-associated macrophages, but the role of brain-resident microglia remains controversial because they are challenging to discriminate from other tumour-associated macrophages. Using single-cell RNA sequencing, genetic and humanized mouse models, we specifically identify microglia and find that they play a distinct pro-inflammatory and tumour-suppressive role in BCBM. Animals lacking microglia show increased metastasis, decreased survival and reduced natural killer and T cell responses, showing that microglia are critical to promote anti-tumour immunity to suppress BCBM. We find that the pro-inflammatory response is conserved in human microglia, and markers of their response are associated with better prognosis in patients with BCBM. These findings establish an important role for microglia in anti-tumour immunity and highlight them as a potential immunotherapy target for brain metastasis.
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Neoplasias Encefálicas , Neoplasias de la Mama , Ratones , Animales , Humanos , Femenino , Microglía , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias Encefálicas/patología , Encéfalo/patología , Resultado del TratamientoRESUMEN
Women with germline BRCA1 mutations (BRCA1+/mut) have increased risk for hereditary breast cancer. Cancer initiation in BRCA1+/mut is associated with premalignant changes in breast epithelium; however, the role of the epithelium-associated stromal niche during BRCA1-driven tumor initiation remains unclear. Here we show that the premalignant stromal niche promotes epithelial proliferation and mutant BRCA1-driven tumorigenesis in trans. Using single-cell RNA sequencing analysis of human preneoplastic BRCA1+/mut and noncarrier breast tissues, we show distinct changes in epithelial homeostasis including increased proliferation and expansion of basal-luminal intermediate progenitor cells. Additionally, BRCA1+/mut stromal cells show increased expression of pro-proliferative paracrine signals. In particular, we identify pre-cancer-associated fibroblasts (pre-CAFs) that produce protumorigenic factors including matrix metalloproteinase 3 (MMP3), which promotes BRCA1-driven tumorigenesis in vivo. Together, our findings demonstrate that precancerous stroma in BRCA1+/mut may elevate breast cancer risk through the promotion of epithelial proliferation and an accumulation of luminal progenitor cells with altered differentiation.
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Neoplasias de la Mama , Glándulas Mamarias Humanas , Femenino , Humanos , Mutación , Proteína BRCA1/genética , Neoplasias de la Mama/patología , Transformación Celular Neoplásica/metabolismo , Glándulas Mamarias Humanas/metabolismo , Carcinogénesis/patología , Células del Estroma/patologíaRESUMEN
Metastasis is a fatal disease where research progress has been hindered by a lack of authentic experimental models. Here, we develop a 3D tumor sphere culture-transplant system that facilitates the growth and engineering of patient-derived xenograft (PDX) tumor cells for functional metastasis assays in vivo. Orthotopic transplantation and RNA sequencing (RNA-seq) analyses show that PDX tumor spheres maintain tumorigenic potential, and the molecular marker and global transcriptome signatures of native tumor cells. Tumor spheres display robust capacity for lentiviral engineering and dissemination in spontaneous and experimental metastasis assays in vivo. Inhibition of pathways previously reported to attenuate metastasis also inhibit metastasis after sphere culture, validating our approach for authentic investigations of metastasis. Finally, we demonstrate a new role for the metabolic enzyme NME1 in promoting breast cancer metastasis, providing proof-of-principle that our culture-transplant system can be used for authentic propagation and engineering of patient tumor cells for functional studies of metastasis.
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Neoplasias de la Mama/patología , Xenoinjertos , Metástasis de la Neoplasia , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Modelos Animales de Enfermedad , Femenino , Ratones , Neoplasias Experimentales , Microambiente TumoralRESUMEN
Mitochondria display complex morphology and movements, which complicates their segmentation and tracking in time-lapse images. Here, we introduce Mitometer, an algorithm for fast, unbiased, and automated segmentation and tracking of mitochondria in live-cell two-dimensional and three-dimensional time-lapse images. Mitometer requires only the pixel size and the time between frames to identify mitochondrial motion and morphology, including fusion and fission events. The segmentation algorithm isolates individual mitochondria via a shape- and size-preserving background removal process. The tracking algorithm links mitochondria via differences in morphological features and displacement, followed by a gap-closing scheme. Using Mitometer, we show that mitochondria of triple-negative breast cancer cells are faster, more directional, and more elongated than those in their receptor-positive counterparts. Furthermore, we show that mitochondrial motility and morphology in breast cancer, but not in normal breast epithelia, correlate with metabolic activity. Mitometer is an unbiased and user-friendly tool that will help resolve fundamental questions regarding mitochondrial form and function.
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Neoplasias de la Mama/patología , Imagenología Tridimensional/métodos , Mitocondrias , Programas Informáticos , Imagen de Lapso de Tiempo/métodos , Algoritmos , Neoplasias de la Mama/metabolismo , Células Cultivadas , Femenino , Humanos , Glándulas Mamarias Humanas/citología , Mitocondrias/metabolismo , NAD/metabolismo , Reproducibilidad de los Resultados , Neoplasias de la Mama Triple Negativas/patologíaRESUMEN
Although metastasis remains the cause of most cancer-related mortality, mechanisms governing seeding in distal tissues are poorly understood. Here, we establish a robust method for the identification of global transcriptomic changes in rare metastatic cells during seeding using single-cell RNA sequencing and patient-derived-xenograft models of breast cancer. We find that both primary tumours and micrometastases display transcriptional heterogeneity but micrometastases harbour a distinct transcriptome program conserved across patient-derived-xenograft models that is highly predictive of poor survival of patients. Pathway analysis revealed mitochondrial oxidative phosphorylation as the top pathway upregulated in micrometastases, in contrast to higher levels of glycolytic enzymes in primary tumour cells, which we corroborated by flow cytometric and metabolomic analyses. Pharmacological inhibition of oxidative phosphorylation dramatically attenuated metastatic seeding in the lungs, which demonstrates the functional importance of oxidative phosphorylation in metastasis and highlights its potential as a therapeutic target to prevent metastatic spread in patients with breast cancer.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Transcriptoma , Animales , Neoplasias de la Mama/metabolismo , Metabolismo Energético , Femenino , Humanos , Ratones Endogámicos NOD , Ratones SCID , Mitocondrias/metabolismo , Metástasis de la Neoplasia , Fosforilación Oxidativa , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Transcripción GenéticaRESUMEN
Myeloid-derived suppressor cells (MDSCs) are innate immune cells that acquire the capacity to suppress adaptive immune responses during cancer. It remains elusive how MDSCs differ from their normal myeloid counterparts, which limits our ability to specifically detect and therapeutically target MDSCs during cancer. Here, we sought to determine the molecular features of breast cancer-associated MDSCs using the widely studied mouse model based on the mouse mammary tumor virus (MMTV) promoter-driven expression of the polyomavirus middle T oncoprotein (MMTV-PyMT). To identify MDSCs in an unbiased manner, we used single-cell RNA sequencing to compare MDSC-containing splenic myeloid cells from breast tumor-bearing mice with wild-type controls. Our computational analysis of 14,646 single-cell transcriptomes revealed that MDSCs emerge through an aberrant neutrophil maturation trajectory in the spleen that confers them an immunosuppressive cell state. We establish the MDSC-specific gene signature and identify CD84 as a surface marker for improved detection and enrichment of MDSCs in breast cancers.
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Neoplasias de la Mama/patología , Células Supresoras de Origen Mieloide/patología , Análisis de la Célula Individual , Transcriptoma , Animales , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/inmunología , Neoplasias de la Mama/inmunología , Diferenciación Celular/genética , Femenino , Humanos , Ratones , Ratones Endogámicos , Ratones Transgénicos , Células Supresoras de Origen Mieloide/inmunología , ARN Neoplásico/genética , ARN Neoplásico/inmunología , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genética , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/inmunologíaRESUMEN
Neurons consume the highest amount of oxygen, depend on oxidative metabolism for energy, and survive for the lifetime of an individual. Therefore, neurons are vulnerable to death caused by oxidative-stress, accumulation of damaged and dysfunctional proteins and organelles. There is an exponential increase in the number of patients diagnosed with neurodegenerative diseases such as Alzheimer's (AD) as the number of elderly increases exponentially. Development of AD pathology is a complex phenomenon characterized by neuronal death, accumulation of extracellular amyloid-ß plaques and neurofibrillary tangles, and most importantly loss of memory and cognition. These pathologies are most likely caused by mechanisms including oxidative stress, mitochondrial dysfunction/stress, accumulation of misfolded proteins, and defective organelles due to impaired proteasome and autophagy mechanisms. Currently, there are no effective treatments to halt the progression of this disease. In order to treat this complex disease with multiple biochemical pathways involved, a complex treatment regimen targeting different mechanisms should be investigated. Furthermore, as AD is a progressive disease-causing morbidity over many years, any chemo-modulator for treatment must be used over long period of time. Therefore, treatments must be safe and non-interfering with other processes. Ideally, a treatment like medicinal food or a supplement that can be taken regularly without any side effect capable of reducing oxidative stress, stabilizing mitochondria, activating autophagy or proteasome, and increasing energy levels of neurons would be the best solution. This review summarizes progress in research on different mechanisms of AD development and some of the potential therapeutic development strategies targeting the aforementioned pathologies.
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Enfermedad de Alzheimer/patología , Transducción de Señal/efectos de los fármacos , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Autofagia , Progresión de la Enfermedad , Humanos , Estrés OxidativoRESUMEN
During wound healing in adult mouse skin, hair follicles and then adipocytes regenerate. Adipocytes regenerate from myofibroblasts, a specialized contractile wound fibroblast. Here we study wound fibroblast diversity using single-cell RNA-sequencing. On analysis, wound fibroblasts group into twelve clusters. Pseudotime and RNA velocity analyses reveal that some clusters likely represent consecutive differentiation states toward a contractile phenotype, while others appear to represent distinct fibroblast lineages. One subset of fibroblasts expresses hematopoietic markers, suggesting their myeloid origin. We validate this finding using single-cell western blot and single-cell RNA-sequencing on genetically labeled myofibroblasts. Using bone marrow transplantation and Cre recombinase-based lineage tracing experiments, we rule out cell fusion events and confirm that hematopoietic lineage cells give rise to a subset of myofibroblasts and rare regenerated adipocytes. In conclusion, our study reveals that wounding induces a high degree of heterogeneity among fibroblasts and recruits highly plastic myeloid cells that contribute to adipocyte regeneration.
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Adipocitos/citología , Adipocitos/metabolismo , Fibroblastos/citología , Fibroblastos/metabolismo , Análisis de la Célula Individual/métodos , Piel/citología , Células Madre/citología , Animales , Western Blotting , Células Cultivadas , Femenino , Masculino , Ratones , Análisis de Secuencia de ARN , Células Madre/metabolismo , Cicatrización de Heridas/fisiologíaRESUMEN
Alzheimer's disease (AD) is the most prevalent form of dementia and is associated with loss of memory, amyloid-beta plaque buildup, and neurofibrillary tangles. These features might be a result of neuronal cell death in the cerebral cortex and hippocampal regions of the brain. AD pathologies can be attributed to a variety of biochemical consequences including mitochondrial dysfunction, increased oxidative stress, and autophagy inhibition. Unfortunately, current therapeutics are limited only to symptomatic relief and do not halt the progression of neurodegeneration. Previous in vitro experiments have shown that a water-soluble formulation of coenzyme-Q10, Ubisol-Q10, can stabilize the mitochondria, prevent oxidative stress, and inhibit premature senescence in fibroblasts of AD patients. Since autophagy plays a critical role in maintenance and survival of neurons, we hypothesized that Ubisol-Q10 treatment could result in resumption of autophagy. Indeed, we observed induction of autophagy by Ubisol-Q10 treatment in AD fibroblasts as well as in the brains of transgenic AD mice. We found increased expression of autophagy-related genes beclin-1 and JNK1 following Ubisol-Q10 treatment of AD fibroblasts. These results were confirmed at the protein level by immunofluorescence and Western blotting. Interestingly, despite reduction of oxidative stress in cells due to Ubisol-Q10 treatment, autophagy inhibition leads to resumption of premature senescence in these PS-1 mutated fibroblasts indicating that autophagy is critical to prevent the senescence phenotype. Withdrawal of Ubisol-Q10 treatment also leads to the return of the senescence phenotype in AD fibroblasts indicating that constant supplementation of Ubisol-Q10 is required. Additionally, Ubisol-Q10 supplementation in the drinking water of double transgenic AD mice leads to increased expression of beclin-1 and JNK1 in the cortical region. Thus, the activation of autophagy by Ubisol-Q10 could be the mechanism for its ability to halt the progression of AD pathology in transgenic AD mice shown previously.
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Enfermedad de Alzheimer/tratamiento farmacológico , Corteza Cerebral/metabolismo , Fibroblastos/fisiología , Mutación/genética , Presenilina-1/genética , Ubiquinona/análogos & derivados , Animales , Autofagia , Beclina-1/genética , Beclina-1/metabolismo , Muerte Celular , Senescencia Celular/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Modelos Animales de Enfermedad , Fibroblastos/efectos de los fármacos , Humanos , Ratones , Ratones Transgénicos , Proteína Quinasa 8 Activada por Mitógenos/genética , Proteína Quinasa 8 Activada por Mitógenos/metabolismo , Neuroprotección , Ubiquinona/química , Ubiquinona/uso terapéutico , Regulación hacia ArribaRESUMEN
BACKGROUND: Chronic back disorders (CBD) are prevalent, costly, and among the most common reasons for seeking primary care; however, little is known regarding the comparative use of family physician, chiropractic, and physiotherapy services among people with CBD in Canada. Elucidating these differences may identify potential gaps in access to care and inform the development of strategies to improve access. The research objectives were to investigate patterns of health care use and to profile factors associated with self-reported use of family physicians, chiropractors, and physiotherapists among adult Canadians with CBD. METHODS: The combined 2009 and 2010 Canadian Community Health Surveys conducted by Statistics Canada were used to investigate self-reported health care use among adults with CBD. This complex survey employs population weights and bootstrapping to be representative of the Canadian population. Following descriptive analyses, we used multiple logistic regression to profile self-reported health care use while statistically controlling for possible confounding effects. RESULTS: The majority of adult respondents with CBD sought care only with a family physician (53.8%), with 20.9% and 16.2% seeking care with combined family physician/chiropractor or family physician/physiotherapist, respectively. Few respondents sought care only with a chiropractor (2.5%) or physiotherapist (1.0%). After adjustment, differential patterns of utilization (p < 0.05) were evident between provider groups with respect to age, gender, socioeconomic status, rural/urban residence, functional limitations, and presence of co-morbidities. CONCLUSIONS: This research highlights potential inequities in access to physiotherapists and chiropractors in relation to family physicians among adult Canadians with CBD, particularly among lower socioeconomic status and rural/remote populations.
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Dolor de Espalda/terapia , Quiropráctica/estadística & datos numéricos , Medicina Familiar y Comunitaria/estadística & datos numéricos , Aceptación de la Atención de Salud/estadística & datos numéricos , Modalidades de Fisioterapia/estadística & datos numéricos , Adolescente , Adulto , Distribución por Edad , Anciano , Dolor de Espalda/epidemiología , Canadá/epidemiología , Dolor Crónico/epidemiología , Servicios de Salud Comunitaria/estadística & datos numéricos , Comorbilidad , Utilización de Instalaciones y Servicios , Femenino , Encuestas Epidemiológicas , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Fisioterapeutas/estadística & datos numéricos , Médicos de Familia/estadística & datos numéricos , Prevalencia , Salud Rural/estadística & datos numéricos , Autoinforme , Encuestas y Cuestionarios , Adulto JovenRESUMEN
This corrects the article DOI: 10.1038/srep42957.
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Breast cancer arises from breast epithelial cells that acquire genetic alterations leading to subsequent loss of tissue homeostasis. Several distinct epithelial subpopulations have been proposed, but complete understanding of the spectrum of heterogeneity and differentiation hierarchy in the human breast remains elusive. Here, we use single-cell mRNA sequencing (scRNAseq) to profile the transcriptomes of 25,790 primary human breast epithelial cells isolated from reduction mammoplasties of seven individuals. Unbiased clustering analysis reveals the existence of three distinct epithelial cell populations, one basal and two luminal cell types, which we identify as secretory L1- and hormone-responsive L2-type cells. Pseudotemporal reconstruction of differentiation trajectories produces one continuous lineage hierarchy that closely connects the basal lineage to the two differentiated luminal branches. Our comprehensive cell atlas provides insights into the cellular blueprint of the human breast epithelium and will form the foundation to understand how the system goes awry during breast cancer.
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Neoplasias de la Mama/genética , Mama/citología , Células Epiteliales/fisiología , Perfilación de la Expresión Génica/métodos , Transcriptoma/genética , Adulto , Biomarcadores de Tumor/genética , Mama/patología , Neoplasias de la Mama/patología , Diferenciación Celular/genética , Linaje de la Célula/genética , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Análisis por Conglomerados , Femenino , Humanos , Análisis de Secuencia de ARN/métodos , Análisis de la Célula Individual/métodosRESUMEN
Harsh adverse effects as a result of nonspecific targeting of chemotherapeutics currently pose obstacles in cancer therapy; thus, it would be invaluable to devise novel approaches to specifically target cancer cells. The natural compound pancratistatin (PST) has been shown to preferentially induce apoptosis in a variety of cancer cell types. Recently, several analogs of PST were shown to be efficacious in inducing apoptosis in a variety of aggressive cancer cell types via cancer cell mitochondrial targeting; it caused dissipation of mitochondrial membrane potential and decreased oxygen consumption, and with isolated mitochondria, it induced the release of apoptogenic factors. The natural compound piperlongumine has been shown to target the stress response to reactive oxygen species in cancer cells. We explored the combinatorial potential of two small molecules (SVTH-6 and piperlongumine) that target these vulnerabilities in cancer cells. Interestingly, when combined with the PST analog, SVTH-6, an increase in mitochondrial dysfunction was observed, leading to an enhanced cytotoxic effect against several human cancer cell types. Additionally, this combination treatment was effective in reducing cancer cell growth in physiologically more relevant 3-dimensional spheroid cell cultures. This enhanced effect was found to be dependent on reactive oxygen species generation because an antioxidant could rescue cancer cells from this combination treatment. Importantly, noncancerous cells were markedly less sensitive to this combination treatment. Thus, targeting mitochondrial and oxidative stress vulnerabilities of cancer cells could be an effective strategy for cancer therapy.-Ma, D., Gilbert, T., Pignanelli, C., Tarade, D., Noel, M., Mansour, F., Gupta, M., Ma, S., Ropat, J., Curran, C., Vshyvenko, S., Hudlicky, T., Pandey. S. Exploiting mitochondrial and oxidative vulnerabilities with a synthetic analog of pancratistatin in combination with piperlongumine for cancer therapy.
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Alcaloides de Amaryllidaceae/administración & dosificación , Dioxolanos/administración & dosificación , Isoquinolinas/administración & dosificación , Neoplasias/tratamiento farmacológico , Alcaloides de Amaryllidaceae/química , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Sinergismo Farmacológico , Células HCT116 , Células HT29 , Humanos , Isoquinolinas/química , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Neoplasias/metabolismo , Neoplasias/patología , Estrés Oxidativo/efectos de los fármacos , Células U937RESUMEN
Recently, research has focused on targeting the oxidative and metabolic vulnerabilities in cancer cells. Natural compounds like curcumin that target such susceptibilities have failed further clinical advancements due to the poor stability and bioavailability as well as the need of high effective doses. We have synthesized and evaluated the anti-cancer activity of several monocarbonyl analogs of curcumin. Interestingly, two novel analogs (Compound A and I) in comparison to curcumin, have increased chemical stability and have greater anti-cancer activity in a variety of human cancer cells, including triple-negative, inflammatory breast cancer cells. In particular, the generation of reactive oxygen species was selective to cancer cells and occurred upstream of mitochondrial collapse and execution of apoptosis. Furthermore, Compound A in combination with another cancer-selective/pro-oxidant, piperlongumine, caused an enhanced anti-cancer effect. Most importantly, Compound A was well tolerated by mice and was effective in inhibiting the growth of human triple-negative breast cancer and leukemia xenografts in vivo when administered intraperitoneally. Thus, exploiting oxidative vulnerabilities in cancer cells could be a selective and efficacious means to eradicate malignant cells as demonstrated by the curcumin analogs presented in this report with high therapeutic potential.
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Antineoplásicos/farmacología , Curcumina/análogos & derivados , Curcumina/farmacología , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/síntesis química , Neoplasias de la Mama/tratamiento farmacológico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Curcumina/administración & dosificación , Curcumina/síntesis química , Modelos Animales de Enfermedad , Humanos , Leucemia/tratamiento farmacológico , Ratones , Trasplante de Neoplasias , Especies Reactivas de Oxígeno/análisis , Especies Reactivas de Oxígeno/toxicidad , Resultado del TratamientoRESUMEN
The cis-stilbene, combretastatin A4 (CA4), is a potent microtubule targeting and vascular damaging agent. Despite promising results at the pre-clinical level and extensive clinical evaluation, CA4 has yet to be approved for therapeutic use. One impediment to the development of CA4 is an inherent conformational instability about the ethylene linker, which joins two aromatic rings. We have previously published preliminary data regarding structurally simplified biphenyl derivatives of CA4, lacking an ethylene linker, which retain anti-proliferative and pro-apoptotic activity, albeit at higher doses. Our current study provides a more comprehensive evaluation regarding the anti-proliferative and pro-apoptotic properties of biphenyl CA4 derivatives in both 2D and 3D cancerous and non-cancerous cell models. Computational analysis has revealed that cytotoxicity of CA4 and biphenyl analogues correlates with predicted tubulin affinity. Additional mechanistic evaluation of the biphenyl derivatives found that their anti-cancer activity is dependent on prolonged mitotic arrest, in a similar manner to CA4. Lastly, we have shown that cancer cells deficient in the extrinsic pathway of apoptosis experience delayed cell death following treatment with CA4 or analogues. Biphenyl derivatives of CA4 represent structurally simplified analogues of CA4, which retain a similar mechanism of action. The biphenyl analogues warrant in vivo examination to evaluate their potential as vascular damaging agents.
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Antineoplásicos/química , Antineoplásicos/farmacología , Compuestos de Bifenilo/química , Puntos de Control del Ciclo Celular/efectos de los fármacos , Mitosis/efectos de los fármacos , Estilbenos/química , Estilbenos/farmacología , Antineoplásicos/metabolismo , Apoptosis/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Daño del ADN , Humanos , Células Jurkat , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Modelos Moleculares , Conformación Proteica , Estilbenos/metabolismo , Tubulina (Proteína)/química , Tubulina (Proteína)/metabolismoRESUMEN
Enhanced mitochondrial stability and decreased dependence on oxidative phosphorylation confer an acquired resistance to apoptosis in cancer cells, but may present opportunities for therapeutic intervention. The compound pancratistatin (PST) has been shown to selectively induce apoptosis in cancer cells. However, its low availability in nature has hindered its clinical advancement. We synthesized PST analogs and a medium-throughput screen was completed. Analogs SVTH-7, -6, and -5 demonstrated potent anti-cancer activity greater than PST and several standard chemotherapeutics. They disrupted mitochondrial function, activated the intrinsic apoptotic pathway, and reduced growth of tumor xenografts in vivo. Interestingly, the pro-apoptotic effects of SVTH-7 on cancer cells and mitochondria were abrogated with the inhibition of mitochondrial complex II and III, suggesting mitochondrial or metabolic vulnerabilities may be exploited by this analog. This work provides a scaffold for characterizing distinct mitochondrial and metabolic features of cancer cells and reveals several lead compounds with high therapeutic potential.
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Alcaloides de Amaryllidaceae/farmacología , Antineoplásicos/farmacología , Complejo III de Transporte de Electrones/metabolismo , Complejo II de Transporte de Electrones/metabolismo , Isoquinolinas/farmacología , Mitocondrias/efectos de los fármacos , Alcaloides de Amaryllidaceae/química , Alcaloides de Amaryllidaceae/uso terapéutico , Animales , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Caspasas/metabolismo , Técnicas de Cultivo de Célula , Línea Celular Tumoral , Complejo II de Transporte de Electrones/antagonistas & inhibidores , Complejo III de Transporte de Electrones/antagonistas & inhibidores , Humanos , Isoquinolinas/química , Isoquinolinas/uso terapéutico , Ratones , Ratones Desnudos , Mitocondrias/metabolismo , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Especies Reactivas de Oxígeno/metabolismo , Esferoides Celulares/efectos de los fármacos , Esferoides Celulares/patología , Trasplante HeterólogoRESUMEN
Cancer cells are reported to have elevated levels of reactive oxygen species (ROS) and are highly dependent on cellular defense mechanisms against oxidative stress. Numerous nutraceuticals and natural polyphenolic compounds have a wide range of abilities to alter cellular redox states with potential implications in various diseases. Furthermore, therapeutic options for cancers are mostly nonselective treatments including genotoxic or tubulin-targeting compounds. Some of the natural extracts, containing multiple bioactive compounds, could target multiple pathways in cancer cells to selectively induce cell death. Cymbopogon citratus (lemongrass) and Camellia sinensis (white tea) extracts have been shown to have medicinal properties, however, their activity against lymphoma and leukemia, as well as mechanistic details, have not been fully characterized. Herein, we report potent anti-cancer properties in dose and time-dependent manners of ethanolic lemongrass and hot water white tea extracts in lymphoma and leukemia models. Both extracts were able to effectively induce apoptosis selectively in these human cancer cell types. Interestingly, ethanolic lemongrass extract induces apoptosis primarily by the extrinsic pathway and was found to be dependent on the generation of ROS. Conversely, apoptotic induction by hot water white tea extract was independent of ROS. Furthermore, both of these extracts caused mitochondrial depolarization and decreased rates of oxygen consumption in lymphoma and leukemia cells, leading to cell death. Most importantly, both these extracts were effective in reducing tumor growth in human lymphoma xenograft models when administered orally. Thus, these natural extracts could have potential for being nontoxic alternatives for the treatment of cancer.