abt-199 and acadesine

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.

Topics: Adenine; Aminoimidazole Carboxamide; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Drug Synergism; Female; Gene Expression Regulation, Neoplastic; Humans; Hydrocarbons, Fluorinated; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Piperidines; Prohibitins; Proto-Oncogene Proteins c-bcl-2; Pyrazoles; Pyrimidines; Repressor Proteins; Ribonucleosides; Sulfonamides; Thiazolidines; Tumor Cells, Cultured; Up-Regulation

Acadesine is a nucleoside analogue with known activity against B-cell malignancies. Herein, we showed that in mantle cell lymphoma (MCL) cells acadesine induced caspase-dependent apoptosis through turning on the mitochondrial apoptotic machinery. At the molecular level, the compound triggered the activation of the AMPK pathway, consequently modulating known downstream targets, such as mTOR and the cell motility-related vasodilator-stimulated phosphoprotein (VASP). VASP phosphorylation by acadesine was concomitant with a blockade of CXCL12-induced migration. The inhibition of the mTOR cascade by acadesine, committed MCL cells to enter in apoptosis by a translational downregulation of the antiapoptotic Mcl-1 protein. In contrast, Bcl-2 protein levels were unaffected by acadesine and MCL samples expressing high levels of Bcl-2 tended to have a reduced response to the drug. Targeting Bcl-2 with the selective BH3-mimetic agent ABT-199 sensitized Bcl-2high MCL cells to acadesine. This effect was validated in vivo, where the combination of both agents displayed a more marked inhibition of tumor outgrowth than each drug alone. These findings support the notions that antiapoptotic proteins of the Bcl-2 family regulate MCL cell sensitivity to acadesine and that the combination of this agent with Bcl-2 inhibitors might be an interesting therapeutic option to treat MCL patients.

Topics: Actins; Aminoimidazole Carboxamide; Animals; Apoptosis; Bridged Bicyclo Compounds, Heterocyclic; Cell Adhesion Molecules; Cell Line, Tumor; Cell Movement; Chemokine CXCL12; Chemotaxis; Down-Regulation; Drug Resistance, Neoplasm; Drug Synergism; Female; Flow Cytometry; Gene Expression Regulation, Neoplastic; Humans; Lymphoma, Mantle-Cell; Mice; Mice, SCID; Microfilament Proteins; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Transplantation; Phosphoproteins; Proto-Oncogene Proteins c-bcl-2; Ribonucleosides; Sulfonamides