RESUMEN
A method to identify anticancer compounds in plants was proposed based on the hypothesis that these compounds are primarily present in plants to provide them with an ecological advantage over neighboring plants and other competitors. According to this view, identifying plants that contain compounds that inhibit or interfere with the development of other plant species may facilitate the discovery of novel anticancer agents. The method was developed and tested using Magnolia grandiflora, Gynoxys verrucosa, Picradeniopsis oppositifolia, and Hedyosmum racemosum, which are plant species known to possess compounds with cytotoxic activities. Plant extracts were screened for growth inhibitory activity, and then a thin-layer chromatography bioautography assay was conducted. This located the major antileukemic compounds 1, 2, 4, and 5 in the extracts. Once the active compounds were located, they were extracted and purified, and their structures were determined. The growth inhibitory activity of the purified compounds showed a significant correlation with their antileukemic activity. The proposed approach is rapid, inexpensive, and can easily be implemented in areas of the world with high biodiversity but with less access to advanced facilities and biological assays.
Asunto(s)
Asteraceae , Asteraceae/química , Cromatografía en Capa Delgada , Extractos Vegetales/química , Extractos Vegetales/farmacología , PlantasRESUMEN
Dehydroleucodine is a bioactive sesquiterpene lactone. Herein, four dehydroleucodine amino derivatives were synthesized using the amines proline, piperidine, morpholine, and tyramine, and spectroscopic methods and single-crystal X-ray diffraction unambiguously established their structures. The cytotoxic activity of these compounds was evaluated against eight acute myeloid leukemia cell lines, and their toxicity to peripheral blood mononuclear cells was also determined. The proline adduct was the most active compound, it showed anti-leukemic activity, upregulated heme oxygenase 1 (HMOX1) and the primary stress-inducible isoform of the heath shock 70 kDa protein 1 (HSPA1A), and downregulated NFkB1 transcription, it was also found to be about 270 times more water soluble than dehydroleucodine.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Lactonas/química , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucocitos Mononucleares/efectos de los fármacos , Sesquiterpenos/química , Línea Celular Tumoral , Cristalografía por Rayos X , Regulación Leucémica de la Expresión Génica/efectos de los fármacos , Proteínas HSP70 de Choque Térmico/genética , Hemo-Oxigenasa 1/genética , Humanos , Lactonas/síntesis química , Lactonas/farmacología , Leucemia Mieloide Aguda/genética , Leucemia Mieloide Aguda/patología , Morfolinas/química , Subunidad p50 de NF-kappa B/genética , Piperidinas/química , Sesquiterpenos/síntesis química , Sesquiterpenos/farmacología , Tiramina/químicaRESUMEN
We have previously demonstrated that cystatin E/M (CST6), which is elevated in a subset of patients with multiple myeloma (MM) lacking osteolytic lesions (OLs), suppresses MM bone disease by blocking osteoclast differentiation and function. CST6 is a secreted type 2 cystatin, a cysteine protease inhibitor that regulates lysosomal cysteine proteases and the asparaginyl endopeptidase legumain. Here, we developed B cell maturation antigen (BCMA) CST6 chimeric antigen receptor T cells (CAR-T cells), which lysed MM cells and released CST6 proteins. Our in vitro studies show that these CAR-T cells suppressed the differentiation and formation of tartrate-resistant acid phosphatase-positive (TRAP+) osteoclasts. Using xenografted MM mice, bioluminescence images showed that both BCMA-CAR-T and BCMA-CST6-CAR-T cells inhibited MM growth to a similar extent. Reconstructed micro-computed tomography images revealed that BCMA-CST6-CAR-T cells, but not BCMA-CAR-T cells, prevented MM-induced bone damage and decreased osteoclast numbers. Our results provide a CAR-T strategy that targets tumor cells directly and delivers an inhibitor of bone resorption.
Asunto(s)
Mieloma Múltiple , Receptores Quiméricos de Antígenos , Humanos , Animales , Ratones , Mieloma Múltiple/patología , Inmunoterapia Adoptiva/métodos , Antígeno de Maduración de Linfocitos B , Linfocitos T , Microtomografía por Rayos X , Cistatina MRESUMEN
The Second Revision of the International Staging System (R2-ISS) was published in 2022 and has been validated in several cohorts of patients with multiple myeloma (MM). In this study, we investigated a total of 860 patients with MM who received an upfront autologous stem cell transplantation between 2001 and 2021. The median age of the patients was 60 years, with a median overall survival (OS) of 123 months and median progression-free survival (PFS) of 70 months. We collected the variables included in the ISS, R-ISS, and R2-ISS systems as well as additional standard variables. Our analyses demonstrated that all 3 ISS series systems (ISS, R-ISS, and R2-ISS) exhibited robust discrimination in terms of both OS and PFS among our study cohort. The ISS system effectively stratified patients into 3 risk groups, whereas the R-ISS system accurately identified patients at extremely high or low risk. The R2-ISS system further refined risk stratification by dividing patients into 4 more balanced risk groups. Furthermore, we specifically focused on identifying variables that distinguished patients with OS < 3 years and OS > 10 years within the low-risk R2-ISS stages (I and II) and high-risk R2-ISS stages (III and IV). Our findings revealed that age, hemoglobin, and 1p deletion significantly influenced the classification of patients in the low-risk R2-ISS stage. Additionally, serum light chain, platelet count, age, and the presence of the t(14;16) translocation were found to affect high-risk classification.