Induction of differentiation in human myeloid leukemic cells by T-2 toxin and other trichothecenes

Trichothecenes are sesquiterpen mycotoxins characterized by the tetracyclic 12,13-epoxytrichothec-9-ene skeleton. We determined the effect of these mycotoxins on the growth and differentiation of the human acute promyelocytic leukemia (HL-60) cell line. Sixteen natural and semisynthetic trichothecenes were tested at concentrations of 0.2-60,000 ng/ml. The cytotoxicity exerted by these compounds varied: e.g., roridin A was found to be toxic at 1 ng/ml, whereas T-2 palmitate was not toxic even at 1 microgram/ml. These compounds varied also in their potential to induce differentiation: 9,10-epoxy T-2 toxin and T-2 toxin induced differentiation at concentrations of 2-5 ng/ml, while 9,10-dihydro T-2 toxin was effective only at 100 ng/ml. Other trichothecenes (e.g., verrucarin A and verrucarol) did not induce differentiation at either subtoxic or toxic concentrations. Cell differentiation was always associated with cytotoxicity; optimal concentrations for induction of differentiation were usually 30-60% of the toxic concentrations. The HL-60 cell population was found to be heterogenous with respect to the ability to differentiate in response to trichothecenes, while in some clones up to 70% of the cells underwent differentiation, and other clones were completely resistant. The latter clones could, however, be induced to differentiate by other agents such as retinoic acid, dimethyl sulfoxide and 12-O-tetradecanoylphorbol-13-acetate. Some of the inducible clones differentiated into neutrophilic granulocytes while others into mature macrophages. Thus, a single trichothecene could induce differentiation into either cell types, depending on the clone used. This study presents a new group of differentiation inducers. Further investigation is required to evaluate their possible therapeutic application.