TY - JOUR
T1 - 3,3′-diindolylmethane induces g 1 arrest and apoptosis in human acute t-cell lymphoblastic leukemia cells
AU - Shorey, Lyndsey E.
AU - Hagman, Amanda M.
AU - Williams, David E.
AU - Ho, Emily
AU - Dashwood, Roderick H.
AU - Benninghoff, Abby D.
N1 - Funding Information:
BioResponse Nutrients, LLC donated the DIM formulation used in this study, BioResponse-DIM. The monetary value of this donation is less than $500. BioResponse Nutrients, LLC did not have any involvement in the experiment design, execution, analysis or composition of this manuscript. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials. USANA Health Sciences provided financial support for this research, via its support of the Linus Pauling Institute and associated laboratories. USANA did not have any involvement in the experiment design, execution, analysis or composition of this manuscript. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.
PY - 2012/4/13
Y1 - 2012/4/13
N2 - Certain bioactive food components, including indole-3-carbinol (I3C) and 3,3′-diindolylmethane (DIM) from cruciferous vegetables, have been shown to target cellular pathways regulating carcinogenesis. Previously, our laboratory showed that dietary I3C is an effective transplacental chemopreventive agent in a dibenzo[def,p]chrysene (DBC)-dependent model of murine T-cell lymphoblastic lymphoma. The primary objective of the present study was to extend our chemoprevention studies in mice to an analogous human neoplasm in cell culture. Therefore, we tested the hypothesis that I3C or DIM may be chemotherapeutic in human T-cell acute lymphoblastic leukemia (T-ALL) cells. Treatment of the T-ALL cell lines CCRF-CEM, CCRF-HSB2, SUP-T1 and Jurkat with DIM in vitro significantly reduced cell proliferation and viability at concentrations 8- to 25-fold lower than the parent compound I3C. DIM (7.5 μM) arrested CEM and HSB2 cells at the G 1 phase of the cell cycle and 15 μM DIM significantly increased the percentage of apoptotic cells in all T-ALL lines. In CEM cells, DIM reduced protein expression of cyclin dependent kinases 4 and 6 (CDK4, CDK6) and D-type cyclin 3 (CCND3); DIM also significantly altered expression of eight transcripts related to human apoptosis (BCL2L10, CD40LG, HRK, TNF, TNFRSF1A, TNFRSF25, TNFSF8, TRAF4). Similar anticancer effects of DIM were observed in vivo. Dietary exposure to 100 ppm DIM significantly decreased the rate of growth of human CEM xenografts in immunodeficient SCID mice, reduced final tumor size by 44% and increased the apoptotic index compared to control-fed mice. Taken together, our results demonstrate a potential for therapeutic application of DIM in T-ALL.
AB - Certain bioactive food components, including indole-3-carbinol (I3C) and 3,3′-diindolylmethane (DIM) from cruciferous vegetables, have been shown to target cellular pathways regulating carcinogenesis. Previously, our laboratory showed that dietary I3C is an effective transplacental chemopreventive agent in a dibenzo[def,p]chrysene (DBC)-dependent model of murine T-cell lymphoblastic lymphoma. The primary objective of the present study was to extend our chemoprevention studies in mice to an analogous human neoplasm in cell culture. Therefore, we tested the hypothesis that I3C or DIM may be chemotherapeutic in human T-cell acute lymphoblastic leukemia (T-ALL) cells. Treatment of the T-ALL cell lines CCRF-CEM, CCRF-HSB2, SUP-T1 and Jurkat with DIM in vitro significantly reduced cell proliferation and viability at concentrations 8- to 25-fold lower than the parent compound I3C. DIM (7.5 μM) arrested CEM and HSB2 cells at the G 1 phase of the cell cycle and 15 μM DIM significantly increased the percentage of apoptotic cells in all T-ALL lines. In CEM cells, DIM reduced protein expression of cyclin dependent kinases 4 and 6 (CDK4, CDK6) and D-type cyclin 3 (CCND3); DIM also significantly altered expression of eight transcripts related to human apoptosis (BCL2L10, CD40LG, HRK, TNF, TNFRSF1A, TNFRSF25, TNFSF8, TRAF4). Similar anticancer effects of DIM were observed in vivo. Dietary exposure to 100 ppm DIM significantly decreased the rate of growth of human CEM xenografts in immunodeficient SCID mice, reduced final tumor size by 44% and increased the apoptotic index compared to control-fed mice. Taken together, our results demonstrate a potential for therapeutic application of DIM in T-ALL.
UR - http://www.scopus.com/inward/record.url?scp=84859732024&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84859732024&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0034975
DO - 10.1371/journal.pone.0034975
M3 - Article
C2 - 22514694
AN - SCOPUS:84859732024
SN - 1932-6203
VL - 7
JO - PloS one
JF - PloS one
IS - 4
M1 - e34975
ER -