1-methylpropyl-2-imidazolyl-disulfide and Precursor-Cell-Lymphoblastic-Leukemia-Lymphoma

Imbalances in redox homeostasis have been described to be involved in the development, progression and relapse of leukemia. As the thioredoxin (Trx) system, one of the major cellular antioxidant networks, has been implicated in acute lymphoblastic leukemia (ALL), we investigated the therapeutic potential of Trx inhibition in ALL. Here, we show that the Trx inhibitor PX-12 reduced cell viability and induced cell death in a dose- and time-dependent manner in different ALL cell lines. This antileukemic activity was accompanied by an increase in reactive oxygen species (ROS) levels and enhanced PRDX3 dimerization. Pre-treatment with the thiol-containing ROS scavenger N-acetylcysteine (NAC), but not with non-thiol-containing scavengers α-tocopherol (α-Toc) or Mn(III)tetrakis(4-benzoic acid) porphyrin chloride (MnTBAP), significantly rescued PX-12-induced cell death. Furthermore, PX-12 triggered activation of BAK. Importantly, knockdown of BAK reduced PX-12-stimulated ROS production and cell death. Similarly, silencing of NOXA provided significant protection from PX-12-mediated cell death. The relevance of mitochondria-mediated, caspase-dependent apoptosis was further supported by data showing that PX-12 triggered cleavage of caspase-3 and that addition of the broad-range caspase inhibitor carbobenzoxy-valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (zVAD.fmk) potently blocked cell death upon PX-12 treatment. This study provides novel insights into the mechanisms of PX-12-induced cell death in ALL and further highlights the therapeutic potential of redox-active compounds in ALL.

Topics: Antineoplastic Agents; Apoptosis; Cell Survival; Disulfides; Drug Screening Assays, Antitumor; Humans; Imidazoles; Mitochondria; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Reactive Oxygen Species; Tumor Cells, Cultured

Increased expression of intracellular thioredoxin has been implicated in the inhibition of apoptosis and in a decrease in the sensitivity of the malignancies to drug-induced apoptosis. In the present studies, we analyzed expression of thioredoxin in samples from 28 children with T-cell acute lymphoblastic leukemia and analyzed their sensitivity toward inhibition of thioredoxin expression. Thioredoxin was expressed in variable amounts. Higher expression was associated with higher WBC counts. Exogenously added thioredoxin stimulated proliferation of clonogenic cells among the T-cell acute lymphoblastic leukemia samples expressing relatively lower levels of intracellular thioredoxin, whereas there was no effect on the clonogenic cells expressing high levels of thioredoxin. In addition, there was differential sensitivity of the leukemia clonogenic cells toward 1-methylpropyl 2-imidazolyl disulfide, an inhibitor of thioredoxin expression, as compared with normal hematopoietic progenitors. This suggests the possibility of using this approach for treatment. Because overexpression of thioredoxin is associated with resistance to many anticancer drugs, the inhibition of thioredoxin expression may overcome this drug resistance and probably sensitize leukemia cells to other chemotherapeutic agents.

Topics: Antineoplastic Agents; Child; Disulfides; Hematopoietic Stem Cells; Humans; Imidazoles; Leukemia-Lymphoma, Adult T-Cell; Leukocyte Count; Neoplastic Stem Cells; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Thioredoxins