ABSTRACT
Fluorizoline is a new synthetic molecule that induces apoptosis by selectively targeting prohibitins. In this study, we have assessed the pro-apoptotic effect of fluorizoline in 3 different multiple myeloma cell lines and 12 primary samples obtained from treatment-naïve multiple myeloma patients. Fluorizoline induced apoptosis in both multiple myeloma cell lines and primary samples at concentrations in the low micromolar range. All primary samples were sensitive to fluorizoline. Moreover, fluorizoline increased the mRNA and protein levels of the pro-apoptotic BCL-2 family member NOXA both in cell lines and primary samples analyzed. Finally, NOXA-depletion by CRISPR/Cas9 in cells that do not express BIM conferred resistance to fluorizoline-induced apoptosis in multiple myeloma cells. These results suggest that targeting prohibitins could be a new therapeutic strategy for myeloma multiple.
Subject(s)
Antineoplastic Agents/metabolism , Apoptosis/physiology , Bcl-2-Like Protein 11/metabolism , Multiple Myeloma/metabolism , Proto-Oncogene Proteins c-bcl-2/metabolism , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Cell Line, Tumor , Cells, Cultured , Dose-Response Relationship, Drug , Female , HEK293 Cells , Humans , Male , Middle Aged , Multiple Myeloma/drug therapy , Multiple Myeloma/pathology , Prohibitins , Protein Binding/physiology , Repressor Proteins/antagonists & inhibitors , Repressor Proteins/metabolismABSTRACT
Fluorizoline is a new synthetic molecule that induces apoptosis by selectively targeting prohibitins. In the study herein, the pro-apoptotic effect of fluorizoline was assessed in 34 primary samples from patients with chronic lymphocytic leukemia. Fluorizoline induced apoptosis in chronic lymphocytic leukemia cells at concentrations in the low micromolar range. All primary samples were sensitive to fluorizoline irrespective of patients' clinical or genetic features, whereas normal T lymphocytes were less sensitive. Fluorizoline increased the protein levels of the pro-apoptotic B-cell lymphoma 2 family member NOXA in chronic lymphocytic leukemia cells. Furthermore, fluorizoline synergized with ibrutinib, 5-aminoimidazole-4-carboxamide riboside or venetoclax to induce apoptosis. These results suggest that targeting prohibitins could be a new therapeutic strategy for chronic lymphocytic leukemia.
Subject(s)
Aminoimidazole Carboxamide/analogs & derivatives , Apoptosis/drug effects , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Gene Expression Regulation, Neoplastic/drug effects , Hydrocarbons, Fluorinated/pharmacology , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Pyrazoles/pharmacology , Pyrimidines/pharmacology , Repressor Proteins/metabolism , Ribonucleosides/pharmacology , Sulfonamides/pharmacology , Thiazolidines/pharmacology , Up-Regulation/drug effects , Adenine/analogs & derivatives , Aminoimidazole Carboxamide/agonists , Aminoimidazole Carboxamide/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/agonists , Drug Synergism , Female , Humans , Hydrocarbons, Fluorinated/agonists , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Male , Piperidines , Prohibitins , Pyrazoles/agonists , Pyrimidines/agonists , Ribonucleosides/agonists , Sulfonamides/agonists , Thiazolidines/agonists , Tumor Cells, CulturedABSTRACT
Fluorizoline is a new synthetic molecule that induces apoptosis by selectively targeting prohibitins (PHBs). In this study, the pro-apoptotic effect of fluorizoline was assessed in two cell lines and 21 primary samples from patients with debut of acute myeloid leukemia (AML). Fluorizoline induced apoptosis in AML cells at concentrations in the low micromolar range. All primary samples were sensitive to fluorizoline irrespectively of patients' clinical or genetic features. In addition, fluorizoline inhibited the clonogenic capacity and induced differentiation of AML cells. Fluorizoline increased the mRNA and protein levels of the pro-apoptotic BCL-2 family member NOXA both in cell lines and primary samples analyzed. These results suggest that targeting PHBs could be a new therapeutic strategy for AML.
Subject(s)
Antineoplastic Agents/pharmacology , Benzothiazoles/pharmacology , Leukemia, Myeloid, Acute/drug therapy , Proto-Oncogene Proteins c-bcl-2/metabolism , Repressor Proteins/antagonists & inhibitors , Apoptosis , Benzothiazoles/chemistry , Cell Differentiation , Cell Line, Tumor , Humans , Molecular Targeted Therapy , Prohibitins , Proto-Oncogene Proteins c-bcl-2/genetics , Repressor Proteins/metabolism , Tumor Cells, Cultured , Up-RegulationABSTRACT
AIMS: Here we report two cases of follicular lymphoma that transformed to CD30 positive diffuse large B cell lymphoma and review the literature on this topic. RESULTS: The first case represents an example of early transformation of conventional low-grade follicular lymphoma to CD30-positive large B cell lymphoma. Immunoglobulin (Ig)H and cytogenetic identity was demonstrated between both components. High-dose and auto-stem cell transplant (SCT) was applied and complete response was achieved. The second case represents an example of d'emblee transformation of intrafollicular neoplasia to CD30-positive large B cell lymphoma. Immunoglobulin K deleting element (IgKde) and cytogenetic identity between both phases was demonstrated. The patient was in partial response after four cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). CONCLUSIONS: CD30 expression was found to be associated in these cases to the transformation event and could be considered a therapeutic target to add to conventional immunochemotherapeutic regimens, even in combination with auto-SCT. We suggest looking for CD30 expression in transformed follicular lymphoma cases.
