Abstract
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 G1 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.
Highlights
Acute lymphoblastic leukemia (ALL), the most frequently diagnosed cancer in children ages 0 to 19 years [1], comprises a diverse population of malignant lymphoid progenitors undergoing clonal proliferation at various stages of differentiation [2]
More than half of T-cell acute lymphoblastic leukemia (T-ALL) cases are characterized by a gain-of-function mutation in the Notch1 receptor, which leads to constitutive activation of Notch-mediated cell proliferation and survival [5,6,7]
Subpopulations of T-ALL patients and cell lines are insensitive to gamma secretase inhibitors (GSIs) therapy, presumably due to mutations that result in constitutive intracellular Notch (ICN) expression or additional mutations in genes downstream [8] such as phosphatase and tensin homolog (PTEN), a tumor suppressor and negative regulator of the PI3K/AKT/ mTOR signaling pathway [11]
Summary
Acute lymphoblastic leukemia (ALL), the most frequently diagnosed cancer in children ages 0 to 19 years [1], comprises a diverse population of malignant lymphoid progenitors undergoing clonal proliferation at various stages of differentiation [2]. Cases of T-cell origin (T-ALL) comprise 15% of ALL patients. Therapeutic gamma secretase inhibitors (GSIs) prevent cleavage of the intracellular Notch (ICN) domain and subsequent transcriptional activation of Notch target genes [8,9,10]. Subpopulations of T-ALL patients and cell lines (including CEM, SUP-T1, and Jurkat cells) are insensitive to GSI therapy, presumably due to mutations that result in constitutive ICN expression or additional mutations in genes downstream [8] such as phosphatase and tensin homolog (PTEN), a tumor suppressor and negative regulator of the PI3K/AKT/ mTOR signaling pathway [11]. Due to the complexity and diversity of T-ALL signaling pathways, therapeutic efficacy and safety may be improved through the use of natural products that target multiple cancer signaling pathways, either alone or adjuvant to systemic or directed chemotherapy [12,13]
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