ABSTRACT
Background: Chimeric antigen receptor T (CAR-T) cell therapy has achieved marked therapeutic success in ameliorating hematological malignancies. However, there is an extant void in the clinical guidelines concerning the most effective chemotherapy regimen prior to chimeric antigen receptor T (CAR-T) cell therapy, as well as the optimal timing for CAR-T cell infusion post-chemotherapy. Materials and Methods: We employed cell-derived tumor xenograft (CDX) murine models to delineate the optimal pre-conditioning chemotherapy regimen and timing for CAR-T cell treatment. Furthermore, transcriptome sequencing was implemented to identify the therapeutic targets and elucidate the underlying mechanisms governing the treatment regimen. Results: Our preclinical in vivo evaluation determined that a combination of cyclophosphamide and fludarabine, followed by the infusion of CD19 CAR-T cells five days subsequent to the chemotherapy, exerts the most efficacious therapeutic effect in B-cell hematological malignancies. Concurrently, RNA-seq data indicated that the therapeutic efficacy predominantly perturbs tumor cell metabolism, primarily through the inhibition of key mitochondrial targets, such as C-Jun Kinase enzyme (C-JUN). Conclusion: In summary, the present study offers critical clinical guidance and serves as an authoritative reference for the deployment of CD19 CAR-T cell therapy in the treatment of B-cell hematological malignancies.
Subject(s)
Antigens, CD19 , Cyclophosphamide , Immunotherapy, Adoptive , Receptors, Chimeric Antigen , Vidarabine , Xenograft Model Antitumor Assays , Vidarabine/analogs & derivatives , Vidarabine/pharmacology , Cyclophosphamide/therapeutic use , Cyclophosphamide/pharmacology , Animals , Mice , Humans , Immunotherapy, Adoptive/methods , Antigens, CD19/immunology , Receptors, Chimeric Antigen/immunology , Hematologic Neoplasms/therapy , Hematologic Neoplasms/drug therapy , Cell Line, Tumor , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Combined Modality TherapyABSTRACT
Acute lymphoblastic leukemia (ALL) is a heterogeneous clonal disease originated from B- or T-cell lymphoid precursor cells. ALL is often refractory or relapses after treatment. Novel treatments are anxiously needed in order to achieve a better response and prolonged overall survival in ALL patients. In the present study, we aimed at examining the anti-tumor effect of niclosamide on ALL. We investigated the effects of niclosamide on the proliferation and apoptosis in vitro, the growth of ALL cells in xenografted NCG mice. The results showed that niclosamide treatment potently inhibited the growth of ALL cells and induced apoptosis via elevating the levels of reactive oxygen species (ROS) and activating TP53. These findings suggest that niclosamide may be a promisingly potential agent for ALL therapy.
ABSTRACT
B-cell acute lymphoblastic leukemia (B-ALL) has been confirmed as the most common malignant hematologic neoplasm among children. A novel antitumor mechanism of lycorine was elucidated in this study. As revealed by the result of this study, lycorine significantly inhibited the growth and proliferation of REH and NALM-6 and induced their apoptosis. The result of the RNA-seq analysis suggested that lycorine targeted PSAT1 of serine/glycine metabolism in B-ALL cells. As indicated by the result of the GSEA analysis, the genes enriched in the amino acid metabolic pathways were down-regulated by lycorine. As revealed by the results of ectopic expression, shRNA knockdown assays, and further liquid-phase tandem mass spectrometry (LC-MS) analysis, lycorine reduced serine/glycine metabolites by down-regulating PSAT1, further disrupting carbon metabolism and eliminating B-ALL cells. Furthermore, lycorine showed a synergistic effect with cytarabine in ALL treatments. Lastly, lycorine significantly down-regulated leukemia progression in the cell line-derived xenograft (CDX) model. In brief, this study has suggested for the first time that lycorine is a promising anti-ALL drug, and a novel amino acid metabolism-associated property of lycorine was identified.
Subject(s)
Glycine , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma , Child , Humans , Cell Proliferation , Cell Line, Tumor , Glycine/pharmacology , Serine , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Apoptosis , Metabolic Networks and PathwaysABSTRACT
Ferroptosis is a kind of iron-dependent programmed cell death discovered in recent years. Its main feature is the accumulation of lipid reactive oxygen species in cells, eventually leading to oxidative stress and cell death. It plays a pivotal role in normal physical conditions and the occurrence and development of various diseases. Studies have shown that tumor cells of the blood system, such as leukemia cells and lymphoma cells, are sensitive to the response to ferroptosis. Regulators that modulate the Ferroptosis pathway can accelerate or inhibit tumor disease progression. This article reviews the mechanism of ferroptosis and its research status in hematological malignancies. Understanding the mechanisms of ferroptosis could provide practical guidance for treating and preventing these dreaded diseases.
ABSTRACT
Compared to normal tissues and cells, the metabolic patterns of tumor illnesses are more complex, and there are hallmarks of metabolic reprogramming in energy metabolism, lipid metabolism, and amino acid metabolism. When tumor cells are in a state of fast growth, they are susceptible to food shortage, resulting in growth suppression. Using this metabolic sensitivity of tumor cells to construct amino acid consumption therapy does not harm the function of normal cells, which is the focus of metabolic therapy research at the moment. As a non-essential amino acid, arginine is involved in numerous crucial biological processes, including the signaling system, cell proliferation, and material metabolism. Rapidly dividing tumor cells are more likely to be deficient in arginine; hence, utilizing arginase to consume arginine can suppress tumor growth. Due to the absence of arginine succinate synthase, arginine succinate lyase, and ornithine carbamoyl transferase in some blood tumors, arginases may be employed to treat blood tumors. By investigating the mechanism of arginase treatment and the mechanism of drug resistance in greater depth, arginase treatment becomes more successful in hematological cancers and a new anti-cancer agent in clinical practice.
ABSTRACT
Background: Tyrosyl phosphorylation is carried out by a group of enzymes known as non-receptor protein tyrosine phosphatases (PTPNs). In the current investigation, it is hoped to shed light on the relationships between the expression patterns of PTPN family members and the prognosis of acute myeloid leukemia (AML). Methods: PTPN expression was examined using GEPIA and GEO databases. To investigate the connection between PTPN expression and survival in AML patients, we downloaded data from the Broad TCGA Firehose and Clinical Proteomic Tumor Analysis (CPTAC) of the Cancer Genome Atlas (TCGA). We used quantitative real-time PCR (qRT-PCR) to confirm that essential genes were performed in clinical samples and cell lines. We then used western blot to verify that the genes expressed in the above databases were positive in normal tissues, AML patient samples, and AML cell lines. Next, we investigated associations between genome-wide expression profiles and PTPN6 expression using the GEO datasets. We investigated the interactive exploration of multidimensional cancer genomics using the cBioPortal datasets. Using the DAVID database, a study of gene ontology enrichment was performed. The protein-protein interaction (PPI) network was created using the STRING portal, and the gene-gene interaction network was performed using GeneMANIA. Results: Data from GEO and GEPIA revealed that most PTPN family members were linked to AML. Patients with leukemia have elevated levels of several PTPN members. All of the AML patients' poor overall survival (OS, p < .05) was significantly linked with higher expression of PTPN1, PTPN6, and PTPN7. Additionally, clinical samples showed that the expression of PTPN 6, PTPN 7, PTPN 13, and PTPN 14 was higher than normal in AML patients (p = .0116, p = .0034, p = .0092, and p = .0057, respectively) and AML cell lines (p = .0004, p = .0035, p = .0357, and p = .0177, respectively). Western blotting results showed that the expression of PTPN6 in AML samples and AML cell lines was significantly higher than that in normal control samples. Conclusion: Differentially expressed PTPN family members were found in AML. The prognosis of patients and PTPN gene expression were shown to be correlated. PTPN6 is one of these members and may be used as an AML diagnostic and prognostic marker.