ST1926, an orally active synthetic retinoid, induces apoptosis in chronic myeloid leukemia cells and prolongs survival in a murine model

Abstract

The tyrosine kinase inhibitor, imatinib, is the first line of treatment for chronic myeloid leukemia (CML) patients. Unfortunately, patients develop resistance and relapse due to bcr-abl point mutations and the persistence of leukemia initiating cells (LIC). Retinoids regulate vital biological processes such as cellular proliferation, apoptosis, and differentiation, in particular of hematopoietic progenitor cells. The clinical usage of natural retinoids is hindered by acquired resistance and undesirable side effects. However, bioavailable and less toxic synthetic retinoids, such as the atypical adamantyl retinoid ST1926, have been developed and tested in cancer clinical trials. We investigated the preclinical efficacy of the synthetic retinoid ST1926 using human CML cell lines and the murine bone marrow transduction/transplantation CML model. In vitro, ST1926 induced irreversible growth inhibition, cell cycle arrest and apoptosis through the dissipation of the mitochondrial membrane potential and caspase activation. Furthermore, ST1926 induced DNA damage and downregulated BCR-ABL. Most importantly, oral treatment with ST1926 significantly prolonged the longevity of primary CML mice, and reduced tumor burden. However, ST1926 did not eradicate LIC, evident by the ability of splenocytes isolated from treated primary mice to develop CML in untreated secondary recipients. These results support a potential therapeutic use of ST1926 in CML targeted therapy.