ABSTRACT
Chronic lymphocytic leukemia (CLL) is the most common leukemia in western societies, recognized by clinical and molecular heterogeneity. Despite the success of targeted therapies, acquired resistance remains a challenge for relapsed and refractory CLL, as a consequence of mutations in the target or the upregulation of other survival pathways leading to the progression of the disease. Research on proteins that can trigger such pathways may define novel therapies for a successful outcome in CLL such as the receptor tyrosine kinase-like orphan receptor 1 (ROR1). ROR1 is a signaling receptor for Wnt5a, with an important role during embryogenesis. The aberrant expression on CLL cells and several types of tumors, is involved in cell proliferation, survival, migration as well as drug resistance. Antibody-based immunotherapies and small-molecule compounds emerged to target ROR1 in preclinical and clinical studies. Efforts have been made to identify new prognostic markers having predictive value to refine and increase the detection and management of CLL. ROR1 can be considered as an attractive target for CLL diagnosis, prognosis, and treatment. It can be clinically effective alone and/or in combination with current approved agents. In this review, we summarize the scientific achievements in targeting ROR1 for CLL diagnosis, prognosis, and treatment.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Receptor Tyrosine Kinase-like Orphan Receptors , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Humans , Receptor Tyrosine Kinase-like Orphan Receptors/metabolism , Prognosis , Molecular Targeted Therapy , Animals , Biomarkers, Tumor/metabolismABSTRACT
Introduction: In classical Hodgkin lymphoma (cHL), the survival of neoplastic cells is mediated by the activation of NF-κB, JAK/STAT and PI3K/Akt signaling pathways. CK2 is a highly conserved serine/threonine kinase, consisting of two catalytic (α) and two regulatory (ß) subunits, which is involved in several cellular processes and both subunits were found overexpressed in solid tumors and hematologic malignancies. Methods and results: Biochemical analyses and in vitro assays showed an impaired expression of CK2 subunits in cHL, with CK2α being overexpressed and a decreased expression of CK2ß compared to normal B lymphocytes. Mechanistically, CK2ß was found to be ubiquitinated in all HL cell lines and consequently degraded by the proteasome pathway. Furthermore, at basal condition STAT3, NF-kB and AKT are phosphorylated in CK2-related targets, resulting in constitutive pathways activation. The inhibition of CK2 with CX-4945/silmitasertib triggered the de-phosphorylation of NF-κB-S529, STAT3-S727, AKT-S129 and -S473, leading to cHL cell lines apoptosis. Moreover, CX-4945/silmitasertib was able to decrease the expression of the immuno-checkpoint CD274/PD-L1 but not of CD30, and to synergize with monomethyl auristatin E (MMAE), the microtubule inhibitor of brentuximab vedotin. Conclusions: Our data point out a pivotal role of CK2 in the survival and the activation of key signaling pathways in cHL. The skewed expression between CK2α and CK2ß has never been reported in other lymphomas and might be specific for cHL. The effects of CK2 inhibition on PD-L1 expression and the synergistic combination of CX-4945/silmitasertib with MMAE pinpoints CK2 as a high-impact target for the development of new therapies for cHL.
Subject(s)
B7-H1 Antigen , Casein Kinase II , Hodgkin Disease , Signal Transduction , Humans , Hodgkin Disease/metabolism , Hodgkin Disease/drug therapy , Hodgkin Disease/genetics , Hodgkin Disease/pathology , Casein Kinase II/metabolism , Casein Kinase II/antagonists & inhibitors , Casein Kinase II/genetics , B7-H1 Antigen/metabolism , B7-H1 Antigen/genetics , Cell Line, Tumor , Phenazines , Naphthyridines/pharmacology , Apoptosis , Gene Expression Regulation, Neoplastic , PhosphorylationABSTRACT
Signalling events downstream the B-cell receptor (BCR) are central for the survival and progression of chronic lymphocytic leukaemia (CLL) cells. Focal adhesion kinase (FAK), regulated through calpain, interacts with molecules of BCR signalling, cytoskeletal modelling and disease progression, such as Src/Lyn, cortactin and HS1. Hypothesizing that FAK might play a key role in CLL pathogenesis, we observed a down-modulation of FAK whole form, associated with FAK cleavage due to calpain activity upon BCR stimulation. Patients, whose cells were able to release Ca++ after BCR stimulation, had less amount of full-length FAK, which translated into a higher presence of cleaved/activated form of the protein phosphorylated at Y397, these features being mostly shown by immunoglobulin heavy chain (IGHV)-unmutated poor-prognosis patients. Moreover, we found that cortactin and HS1 proteins were overexpressed in those cells, suggesting a possible interplay with FAK. Treatment with the FAK inhibitor Defactinib was able to induce apoptosis in CLL cells. In conclusion, the malignant phenotype in unfavourable-prognosis patients seems to be encouraged by the overexpression of cortactin and HS1, that, together with FAK, may be involved in a druggable pathogenetic pathway in CLL.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Focal Adhesion Protein-Tyrosine Kinases/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Calpain/metabolism , Cortactin/metabolism , Calcium/metabolism , Phosphorylation , Receptors, Antigen, B-Cell/metabolismABSTRACT
The search for molecules to be targeted that are involved in apoptosis resistance/increased survival and pathogenesis of onco-hematological malignancies is ongoing since these diseases are still not completely understood. Over the years, a good candidate has been identified in the Heat Shock Protein of 70kDa (HSP70), a molecule defined as "the most cytoprotective protein ever been described". HSP70 is induced in response to a wide variety of physiological and environmental insults, allowing cells to survive lethal conditions. This molecular chaperone has been detected and studied in almost all the onco-hematological diseases and is also correlated to poor prognosis and resistance to therapy. In this review, we give an overview of the discoveries that have led us to consider HSP70 as a therapeutic target for mono- or combination-therapies in acute and chronic leukemias, multiple myeloma and different types of lymphomas. In this excursus, we will also consider HSP70 partners, such as its transcription factor HSF1 or its co-chaperones whose druggability could indirectly affect HSP70. Finally, we will try to answer the question asked in the title of this review considering that, despite the effort made by research in this field, HSP70 inhibitors never reached the clinic.
Subject(s)
Heat-Shock Proteins , Multiple Myeloma , Humans , Heat-Shock Proteins/metabolism , HSP70 Heat-Shock Proteins/metabolism , Transcription Factors/metabolism , Apoptosis/physiology , Molecular ChaperonesABSTRACT
The Btk inhibitor ibrutinib has significantly changed the management of chronic lymphocytic leukemia (CLL) patients. Despite its clinical efficacy, relapses occur, and outcomes after ibrutinib failure are poor. Although BTK and PLCγ2 mutations have been found to be associated with ibrutinib resistance in a fair percentage of CLL patients, no information on resistance mechanisms is available in patients lacking these mutations. The heat shock protein of 70 kDa (HSP70) and its transcription factor heat shock factor 1 (HSF1) play a role in mediating the survival and progression of CLL, as well as taking part in drug resistance in various cancers. We demonstrated that resveratrol and related phenols were able to induce apoptosis in vitro in leukemic cells from CLL untreated patients by acting on the HSP70/HSF1 axis. The same was achieved in cells recovered from 13 CLL patients failing in vivo ibrutinib treatment. HSP70 and HSF1 levels decreased following in vitro treatment, correlating to apoptosis induction. We suggest an involvement of HSP70/HSF1 axis in controlling resistance to ibrutinib in CLL cells, since their inhibition is effective in inducing in vitro apoptosis in cells from ibrutinib refractory patients. The targeting of HSP70/HSF1 axis could represent a novel rational therapeutic strategy for CLL, also for relapsing patients.
ABSTRACT
New palladacyclopentadienyl complexes with bis-N-heterocyclic carbenes as spectator ligands have been synthesized and exhaustively characterized. The crystal structure of complex 1a has been also determined by X-ray diffraction analysis. Their in vitro cytotoxicity and that of other palladacyclopentadienyl derivatives coordinating different ancillary ligands has been determined against different cancer cell lines. Many complexes have shown an antiproliferative activity toward tumor cells often definitely better than cisplatin, whereas they have resulted practically inactive against the non-cancer MRC-5â¯cell line. The mechanism of action of bis-NHC derivative 1a, particularly active against ovarian cancer cell lines was studied in depth. Through a longitudinally analysis, it is shown that compound 1a induces apoptosis via DNA damage and release of cytochrome C. We propose compound 1a as a powerful and specific drug for the therapy of a deadly disease such as high grade serous ovarian cancer.
Subject(s)
Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , Heterocyclic Compounds/pharmacology , Methane/analogs & derivatives , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line , Cell Proliferation/drug effects , Cell Survival/drug effects , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Heterocyclic Compounds/chemistry , Humans , Ligands , Methane/chemistry , Methane/pharmacology , Models, Molecular , Molecular Structure , Structure-Activity RelationshipABSTRACT
Monoacylglycerol lipase (MAGL) is an attractive therapeutic target for many pathologies, including neurodegenerative diseases, cancer as well as chronic pain and inflammatory pathologies. The identification of reversible MAGL inhibitors, devoid of the side effects associated to prolonged MAGL inactivation, is a hot topic in medicinal chemistry. In this study, a novel phenyl(piperazin-1-yl)methanone inhibitor of MAGL was identified through a virtual screening protocol based on a fingerprint-driven consensus docking (CD) approach. Molecular modeling and preliminary structure-based hit optimization studies allowed the discovery of derivative 4, which showed an efficient reversible MAGL inhibition (IC50 = 6.1 µM) and a promising antiproliferative activity on breast and ovarian cancer cell lines (IC50 of 31-72 µM), thus representing a lead for the development of new and more potent reversible MAGL inhibitors. Moreover, the obtained results confirmed the reliability of the fingerprint-driven CD approach herein developed.
Subject(s)
Computer Simulation , Drug Discovery/methods , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Monoacylglycerol Lipases/antagonists & inhibitors , Piperazines/chemistry , Piperazines/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , High-Throughput Screening Assays , Humans , Inhibitory Concentration 50 , Molecular Dynamics Simulation , Monoacylglycerol Lipases/metabolism , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Fyn tyrosine kinase inhibitors are considered potential therapeutic agents for a variety of human cancers. Furthermore, the involvement of Fyn kinase in signalling pathways that lead to severe pathologies, such as Alzheimer's and Parkinson's diseases, has also been demonstrated. In this study, starting from 3-(benzo[d][1,3]dioxol-5-ylamino)-6-methyl-1,2,4-triazin-5(2H)-one (VS6), a hit compound that showed a micromolar inhibition of Fyn (IC50 = 4.8 µM), we computationally investigated the binding interactions of the 3-amino-1,2,4-triazin-5(2H)-one scaffold and started a preliminary hit to lead optimisation. This analysis led us to confirm the hypothesised binding mode of VS6 and to identify a new derivative that is about 6-fold more active than VS6 (compound 3, IC50 = 0.76 µM).
Subject(s)
Antineoplastic Agents/pharmacology , Cytosine/analogs & derivatives , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-fyn/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Binding Sites/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cytosine/chemical synthesis , Cytosine/chemistry , Cytosine/pharmacology , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-fyn/metabolism , Structure-Activity RelationshipABSTRACT
PIN1 is a member of a family of peptidylprolyl isomerases that bind phosphoproteins and catalyze the rapid cis-trans isomerization of proline peptidyl bonds, resulting in an alteration of protein structure, function, and stability. PIN1 is overexpressed in human cancers, suggesting it promotes tumorigenesis, but depending on the cellular context, it also acts as a tumor suppressor. Here, we review the role of PIN1 in cancer and the regulation of PIN1 expression, and catalog the single nucleotide polymorphisms, and mutations in PIN1 gene associated with cancer. In addition, we provide a 3D model of the protein to localize the mutated residues.