Abstract 5441: Anticancer effects of 3,3′-diindolylmethane (DIM) in multiple T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) cell lines

Abstract

Abstract Previously, we reported that in utero exposure to the bioactive food chemical indole-3-carbinol (I3C) via the maternal diet reduced risk of T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) in a mouse model of transplacental chemical carcinogenesis. Subsequent in vitro experiments in human CCRF-CEM cells, a T-ALL cell line originating from precursor T-cells, showed that the I3C derivative compound 3,3′-diindolylmethane (DIM) was likely responsible for the anticancer effect of the parent chemical. Specifically, DIM treatment markedly reduced CCRF-CEM cell viability, blocked cell proliferation, increased the rate of apoptosis and induced a G1 cell cycle arrest in vitro at low micromolar concentrations, whereas I3C was only effective at high, supraphysiological concentrations. T-ALL is a heterogeneous disease resulting from the developmental arrest and abnormal proliferation of T-cells at different stages of maturation. Thus, the objective of the present study was to determine whether the anticancer effects observed for DIM in CCRF-CEM cells (CD3-/CD4+/CD8-) are consistent in other T-ALL cell lines, including CCRF-HSB2 (pre-T; CD3-/CD4-/CD8-), SUP-T1 (cortical T; CD3-/CD4+/CD8+) and Jurkat cells (mature T; CD3+/CD4+/CD8-). Each cell line was treated with 0 to 60 μM DIM (BioResponse formulation), 0 to 500 μM I3C or a 0.1% DMSO vehicle control for up to 48 hours, at which time cell viability, proliferation and apoptosis were determined by flow cytometry. In vitro treatment with DIM effectively reduced proliferation of CCRF-HSB2, SUP-T1 and Jurkat cells with calculated IC50 values of 7.5, 13 and 9.1 μM, respectively, whereas I3C was much less effective in these cell lines (IC50 values of 86, 284 and 228 μM, respectively). Cell viability was similarly impacted by DIM (IC50 values of 7.2, 14 and 15 μM for CCRF-HSB2, SUP-T1 and Jurkat cells, respectively) and I3C (IC50 values of 83, 262 and 222 μM, respectively). Interestingly, treatment with 15 μM DIM caused a significant increase in apoptosis in CCRF-HSB2 (52% apoptotic cells, DIM; 9.3%, control; p = 0.02) and SUP-T1 cells (29%, DIM; 8%, control; p < 0.001), but not in Jurkat cells (9.7%, DIM; 3%, control; p = 0.08). Overall, these observations are similar to those we previously reported for CCRF-CEM cells, particularly with respect to the large difference in effectiveness of DIM compared to I3C in vitro. Also of special interest is the finding that both DIM and I3C appear most effective in blocking the growth of CCRF-HSB2 cells, a cell line representing T-ALL derived from pre-T cells. Collectively, these data suggest that DIM (via dietary I3C) could be an effective anticancer agent against T-ALL cancers originating from T cells at different stages of maturation at concentrations that can be reasonably achieved in vivo in humans and in animal models. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5441. doi:1538-7445.AM2012-5441