Anti-tumor activities and mechanism of action of the synthetic retinoid ST1926 in chronic myeloid leukemia

Abstract

Chronic Myeloid Leukemia (CML) is a clonal hematopoietic myeloproliferative disorder caused by the Philadelphia chromosome. The Philadelphia chromosome occurs due to a reciprocal translocation between chromosomes 9 and 22. This translocation generates the BCR-ABL oncogene that encodes for the constitutively active tyrosine kinase BCR-ABL. Tyrosine kinase inhibitors (TKIs) are the current treatment option for CML patients worldwide. The most commonly used TKI, imatinib, results in complete hematological and cytogenetic responses and prolongs the longevity of CML patients. Unfortunately, CML patients develop resistance to imatinib. Retinoids are major regulators of cell proliferation and differentiation, in particular hematopoietic cells. The use of natural retinoids as anti-cancer agents was hindered by their toxicity and resistance. Therefore, synthetic retinoids were developed with reduced toxicity, increased specificity, and that can work through retinoid receptor independent mechanisms. The novel adamantyl retinoid, ST1926, can be administered orally and is currently in phase I clinical trials. Based on these data, we were interested in investigating the anti-leukemic properties and mechanism of action of ST1926 in the well-characterized CML cell lines, AR230, K562, and LAMA. First we characterized the response of the different CML cell lines to the natural retinoid all-trans retinoic acid (ATRA) and the two synthetic retinoids that are currently in clinical trials, HPR and ST1926. We found that in general the CML cell lines are resistant to ATRA and HPR; however, they were all sensitive to clinically achievable micromolar concentrations of ST1926. In fact, ST1926 induced cell growth inhibition and apoptosis in all CML cells, while no effect was detected on normal resting and activated lymphocytes. ST1926-induced cell death was through apoptosis, as it is evident through cell accumulation in the pre G1 region of the cell cycle and TUNEL positivity. Most importantly, ST1926 induces the downregu