RESUMEN
Myeloid leukemia is a hematologic neoplasia characterized by a clonal proliferation of hematopoietic stem cell progenitors. Patient prognosis varies depending on the subtype of leukemia as well as eligibility for intensive treatment regimens and allogeneic stem cell transplantation. Although significant progress has been made in the therapy of patients including novel targeted treatment approaches, there is still an urgent need to optimize treatment outcome. The most common therapy is based on the use of chemotherapeutics cytarabine and anthrayclines. Here, we studied the effect of the recently synthesized marine alkaloid 3,10-dibromofascaplysin (DBF) in myeloid leukemia cells. Unsubstituted fascaplysin was early found to affect cell cycle via inhibiting CDK4/6, thus we compared the activity of DBF and other brominated derivatives with known CDK4/6 inhibitor palbociclib, which was earlier shown to be a promising candidate to treat leukemia. Unexpectedly, the effect DBF on cell cycle differs from palbociclib. In fact, DBF induced leukemic cells apoptosis and decreased the expression of genes responsible for cancer cell survival. Simultaneously, DBF was found to activate the E2F1 transcription factor. Using bioinformatical approaches we evaluated the possible molecular mechanisms, which may be associated with DBF-induced activation of E2F1. Finally, we found that DBF synergistically increase the cytotoxic effect of cytarabine in different myeloid leukemia cell lines. In conclusion, DBF is a promising drug candidate, which may be used in combinational therapeutics approaches to reduce leukemia cell growth.
Asunto(s)
Antineoplásicos/farmacología , Citarabina/farmacología , Leucemia Mieloide/tratamiento farmacológico , Oxindoles/farmacología , Línea Celular Tumoral , Fenómenos Fisiológicos Celulares/efectos de los fármacos , Sinergismo Farmacológico , Regulación Neoplásica de la Expresión Génica , Humanos , Leucemia Mieloide/genéticaRESUMEN
Seven new deoxyisoaustamide derivatives (1-7) together with known compounds (8-10) were isolated from the coral-derived fungus Penicillium dimorphosporum KMM 4689. Their structures were established using spectroscopic methods, X-ray diffraction analysis and by comparison with related known compounds. The absolute configurations of some alkaloids were determined based on CD and NOESY data as well as biogenetic considerations. The cytotoxic and neuroprotective activities of some of the isolated compounds were examined and structure-activity relationships were pointed out. New deoxyisoaustamides 4-6 at concentration of 1 µM revealed a statistical increase of PQ(paraquat)-treated Neuro-2a cell viability by 30-39%.
Asunto(s)
Antozoos , Antineoplásicos/aislamiento & purificación , Indoles/aislamiento & purificación , Penicillium/aislamiento & purificación , Animales , Antozoos/química , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Cristalografía por Rayos X/métodos , Humanos , Indoles/química , Indoles/farmacología , Penicillium/químicaRESUMEN
The therapy of advanced (clear-cell) renal cell carcinoma (RCC) has recently experienced tremendous changes. Several new treatments have been developed, with PD-1 immune-checkpoint inhibition being the backbone of therapy. Diverse immunotherapy combinations change current first-line standards. These changes also require new approaches in subsequent lines of therapy. In an expert panel, we discussed the new treatment options and how they change clinical practice. While first-line immunotherapies introduce a new level of response rates, data on second-line therapies remains poor. This scenario poses a challenge for clinicians as guideline recommendations are based on historical patient cohorts and agents may lack the appropriate label for their in guidelines recommended use. Here, we summarize relevant clinical data and consider appropriate treatment strategies.
Asunto(s)
Carcinoma de Células Renales/diagnóstico , Carcinoma de Células Renales/terapia , Neoplasias Renales/diagnóstico , Neoplasias Renales/terapia , Biomarcadores de Tumor , Carcinoma de Células Renales/etiología , Toma de Decisiones Clínicas , Ensayos Clínicos como Asunto , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Humanos , Neoplasias Renales/etiología , Estadificación de Neoplasias , Guías de Práctica Clínica como Asunto , Retratamiento , Resultado del TratamientoRESUMEN
Leptogorgins A-C (1-3), new humulane sesquiterpenoids, and leptogorgoid A (4), a new dihydroxyketosteroid, were isolated from the gorgonian Leptogorgia sp. collected from the South China Sea. The structures were established using MS and NMR data. The absolute configuration of 1 was confirmed by a modification of Mosher's method. Configurations of double bonds followed from NMR data, including NOE correlations. This is the first report of humulane-type sesquiterpenoids from marine invertebrates. Sesquiterpenoids leptogorgins A (1) and B (2) exhibited a moderate cytotoxicity and some selectivity against human drug-resistant prostate cancer cells 22Rv1.
Asunto(s)
Antozoos/química , Sesquiterpenos/química , Animales , Organismos Acuáticos , Agua de Mar , VietnamRESUMEN
The phenomenon of high sugar consumption by tumor cells is known as Warburg effect. It results from a high glycolysis rate, used by tumors as preferred metabolic pathway even in aerobic conditions. Targeting the Warburg effect to specifically deliver sugar conjugated cytotoxic compounds into tumor cells is a promising approach to create new selective drugs. We designed, synthesized, and analyzed a library of novel 6-S-(1,4-naphthoquinone-2-yl)-d-glucose chimera molecules (SABs)-novel sugar conjugates of 1,4-naphthoquinone analogs of the sea urchin pigments spinochromes, which have previously shown anticancer properties. A sulfur linker (thioether bond) was used to prevent potential hydrolysis by human glycoside-unspecific enzymes. The synthesized compounds exhibited a Warburg effect mediated selectivity to human prostate cancer cells (including highly drug-resistant cell lines). Mitochondria were identified as a primary cellular target of SABs. The mechanism of action included mitochondria membrane permeabilization, followed by ROS upregulation and release of cytotoxic mitochondrial proteins (AIF and cytochrome C) to the cytoplasm, which led to the consequent caspase-9 and -3 activation, PARP cleavage, and apoptosis-like cell death. These results enable us to further clinically develop these compounds for effective Warburg effect targeting.
Asunto(s)
Antineoplásicos/farmacología , Pigmentos Biológicos/química , Neoplasias de la Próstata/tratamiento farmacológico , Erizos de Mar/química , Efecto Warburg en Oncología/efectos de los fármacos , Animales , Antineoplásicos/síntesis química , Antineoplásicos/uso terapéutico , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Ensayos de Selección de Medicamentos Antitumorales , Glucosa/síntesis química , Glucosa/farmacología , Humanos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Membranas Mitocondriales/efectos de los fármacos , Naftoquinonas/síntesis química , Naftoquinonas/farmacología , Naftoquinonas/uso terapéutico , Neoplasias de la Próstata/patologíaRESUMEN
A simple approach toward the synthesis of the marine sponge derived pigment fascaplysin was used to obtain the marine alkaloids 3-bromofascaplysin and 3,10-dibromofascaplysin. These compounds were used for first syntheses of the alkaloids 14-bromoreticulatate and 14-bromoreticulatine. Preliminary bioassays showed that 14-bromoreticulatine has a selective antibiotic (to Pseudomonas aeruginosa) activity and reveals cytotoxicity toward human melanoma, colon, and prostate cancer cells. 3,10-Dibromofascaplysin was able to target metabolic activity of the prostate cancer cells, without disrupting cell membrane's integrity and had a wide therapeutic window amongst the fascaplysin alkaloids.
Asunto(s)
Alcaloides/farmacología , Antibacterianos/farmacología , Antineoplásicos/farmacología , Indoles/farmacología , Poríferos/química , Alcaloides/síntesis química , Animales , Antibacterianos/síntesis química , Antineoplásicos/síntesis química , Línea Celular Tumoral , Técnicas de Química Sintética/métodos , Ensayos de Selección de Medicamentos Antitumorales , Halogenación , Humanos , Indoles/síntesis química , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa/efectos de los fármacosRESUMEN
Six new carotane sesquiterpenoids piltunines A-F (1-6) together with known compounds (7-9) were isolated from the marine-derived fungus Penicillium piltunense KMM 4668. Their structures were established using spectroscopic methods. The absolute configurations of 1-7 were determined based on circular dichroism (CD) and nuclear Overhauser spectroscopy (NOESY) data as well as biogenetic considerations. The cytotoxic activity of some of the isolated compounds and their effects on regulation of reactive oxygen species (ROS) and nitric oxide (NO) production in lipopolysaccharide-stimulated macrophages were examined.
Asunto(s)
Antineoplásicos/farmacología , Macrófagos/efectos de los fármacos , Penicillium/química , Sesquiterpenos/farmacología , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Línea Celular Tumoral , Células Cultivadas , Dicroismo Circular , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Macrófagos/metabolismo , Ratones , Ratones Endogámicos BALB C , Óxido Nítrico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Sesquiterpenos/química , Sesquiterpenos/aislamiento & purificaciónRESUMEN
BACKGROUND: For many years, the standard treatment of metastatic, hormone-sensitive prostatic carcinoma (mHSPC) was androgen deprivation therapy (ADT) alone. By lowering the testosterone level into the castration range, ADT deprives the tumor of a key growth factor. METHODS: For this article, we evaluated the treatment recommendations contained in national and international guidelines (German S3 guidelines and those of the European Society for Medical Oncology [ESMO], European Association of Urology [EAU], and National Comprehensive Cancer Network [NCCN]), as well as pertinent publications revealed by a PubMed search and the congress abstracts of the ESMO and of the American Society of Clinical Oncology [ASCO]. RESULTS: The past few years have witnessed fundamental changes in the treatment of mHSPC. Treatment intensification with docetaxel or with the new drugs directed against the androgen receptor signal pathway (abiraterone, apalutamide and enzalutamide) has been found to lower mortality by 19-40% and is now an integral component of first-line therapy. Relevant new findings have also been obtained with threefold combinations of ADT, docetaxel, and abiraterone or darolutamide. For patients with a light tumor burden, local radiotherapy of the primary tumor improves the probability of survival at 3 years by 8% (45.4 versus 49.1 months, difference 3.6 months; 95% confidence interval, 1.0 to 6.2 months). CONCLUSION: The treatment of mHSPC is constantly changing. Phase III trials that are now in the recruitment stage, as well as our continually improving understanding of the underlying molecular-pathological mechanisms, will be altering the treatment landscape still further in the years to come.
Asunto(s)
Carcinoma , Neoplasias de la Próstata , Masculino , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Antagonistas de Andrógenos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Resultado del Tratamiento , Docetaxel/uso terapéutico , Carcinoma/tratamiento farmacológico , Carcinoma/etiología , Hormonas/uso terapéuticoRESUMEN
Expression of the androgen receptor splice variant 7 (ARV7) in circulating tumor cells (CTCs) has been associated with resistance towards novel androgen receptor (AR)-targeting therapies. While a multitude of ARV7 detection approaches have been developed, the simultaneous enumeration of CTCs and assessment of ARV7 status and the integration of validated technologies for CTC enrichment/detection into their workflow render interpretation of the results more difficult and/or require shipment to centralized labs. Here, we describe the establishment and technical validation of a novel ARV7 detection method integrating the CellSearch® technology, the only FDA-cleared CTC-enrichment method for metastatic prostate cancer available so far. A highly sensitive and specific qPCR-based assay was developed, allowing detection of ARV7 and keratin 19 transcripts from as low as a single ARV7+/K19+ cell, even after 24 h of sample storage. Clinical feasibility was demonstrated on blood samples from 26 prostate cancer patients and assay sensitivity and specificity was corroborated. Our novel approach can now be included into prospective clinical trials aimed to assess the predictive values of CTC/ARV7 measurements in prostate cancer.