adenanthin and Precursor-B-Cell-Lymphoblastic-Leukemia-Lymphoma

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a genetically heterogeneous blood cancer characterized by abnormal expansion of immature B cells. Although intensive chemotherapy provides high cure rates in a majority of patients, subtypes harboring certain genetic lesions, such as MLL rearrangements or BCR-ABL1 fusion, remain clinically challenging, necessitating a search for other therapeutic approaches. Herein, we aimed to validate antioxidant enzymes of the thioredoxin system as potential therapeutic targets in BCP-ALL. We observed oxidative stress along with aberrant expression of the enzymes associated with the activity of thioredoxin antioxidant system in BCP-ALL cells. Moreover, we found that auranofin and adenanthin, inhibitors of the thioredoxin system antioxidant enzymes, effectively kill BCP-ALL cell lines and pediatric and adult BCP-ALL primary cells, including primary cells cocultured with bone marrow-derived stem cells. Furthermore, auranofin delayed the progression of leukemia in MLL-rearranged patient-derived xenograft model and prolonged the survival of leukemic NSG mice. Our results unveil the thioredoxin system as a novel target for BCP-ALL therapy, and indicate that further studies assessing the anticancer efficacy of combinations of thioredoxin system inhibitors with conventional anti-BCP-ALL drugs should be continued.

Topics: Animals; Auranofin; Cell Line, Tumor; Diterpenes, Kaurane; Drug Delivery Systems; Female; Fusion Proteins, bcr-abl; Gene Rearrangement; Histone-Lysine N-Methyltransferase; Humans; Male; Mice; Mice, Inbred NOD; Myeloid-Lymphoid Leukemia Protein; Neoplasm Proteins; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; Thioredoxins; Xenograft Model Antitumor Assays