Bryostatin-1 and 1α,25-dihydroxyvitamin D₃ synergistically stimulate the differentiation of NB4 acute promyelocytic leukemia cells

Abstract

One of the objectives of treatment for patients with acute promyelocytic leukemia (APL) is to induce tumor cell differentiation and block cell proliferation. Acute promyelocytic leukemia cells (NB4) responded to the combination treatment of 1α,25-dihydroxyvitamin D₃ [1α,25(OH)₂D₃] plus phorbol 12-myristate 13-acetate (PMA) and differentiated into monocyte/macrophage-like cells, as well as expressed strong alkaline phosphatase (ALP) activities. Since PMA has limited clinical application due to its tumor–promoting effect, another protein kinase C activator, bryostatin-1, was currently tested for its interaction with 1α,25(OH)₂D₃ to induce NB4 cell differentiation and block cell proliferation. Bryostatin-1 alone, but not 1α,25(OH)₂D₃ alone, significantly inhibited cell proliferation and induced NB4 cell differentiation into monocyte/macrophages; however neither bryostatin-1 nor 1α,25(OH)₂D₃ alone induced ALP expression. Like PMA, bryostatin-1 synergistically interacted with 1α,25(OH)₂D₃ to stimulate ALP expression 30-fold over the control (P < 0.001) and further promote appearance of monocyte/macrophage-like cells. the alp stimulation was both time- and dose-dependent. thus, we demonstrate for the first time that the combination of bryostatin-1 and 1α,25(oh)₂D₃ strongly affect NB4 cell differentiation and proliferation. Therefore, this proposed combination treatment may be an alternatively potential therapeutic regimen for APL patients and assay of ALP may be a more sensitive and facile way to monitor the possible remission of APL patients.