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Tumor Biology

, Volume 36, Issue 5, pp 3919–3930 | Cite as

Indole-3-carbinol suppresses NF-κB activity and stimulates the p53 pathway in pre-B acute lymphoblastic leukemia cells

  • Majid Safa
  • Behnaz Tavasoli
  • Rima Manafi
  • Fatemeh Kiani
  • Meysam Kashiri
  • Saber Ebrahimi
  • Ahmad Kazemi
Research Article

Abstract

B cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common type of cancer in children. Dramatic improvements in primary therapy for childhood ALL have led to an overall cure rate of 80 %, providing opportunities for innovative combined-modality strategies that would increase cure rates while reducing the toxic side effects of current intensive regimens. In this study, we report that indole-3-carbinol (I3C), a natural phytochemical found in cruciferous vegetables, had anti-leukemic properties in BCP-ALL NALM-6 cells. I3C induced cell growth inhibition by G1 cell cycle arrest and triggered apoptosis in a dose- and time-dependent manner. p53, p21, and Bax proteins showed increased expression after I3C treatment. Real-time PCR analysis of pro-apoptotic p53 target genes revealed up-regulation of PUMA, NOXA, and Apaf-1. I3C also suppressed constitutive nuclear factor-κB (NF-κB) activation and inhibited the protein expression of NF-kappa B-regulated antiapoptotic (IAP1, Bcl-xL, Bcl-2, XIAP) and proliferative (c-Myc) gene products. Coadministration of I3C with the topoisomerase II inhibitor, doxorubicin, potentiates cytotoxic effects compared with either agent alone. Apoptosis induction by the drug combination was associated with enhanced caspase-9 activation and PARP cleavage. Furthermore, I3C abolished doxorubicin-induced NF-κB activity as evidenced by decreased nuclear accumulation of p65, inhibition of IκBα phosphorylation and its degradation, and decreased NF-κB DNA-binding activity. Western blot analysis revealed that doxorubicin-induced Bcl-2 protein expression was inhibited by I3C. Overall, our results indicated that using nontoxic agents, such as I3C, in combination with anthracyclines might provide a new insight into the development of novel combination therapies in childhood BCP-ALL.

Keywords

Indole-3-carbinol Acute lymphoblastic leukemia NF-κB p53 Doxorubicin 

Notes

Acknowledgments

This study was supported by the grant 16060 from Iran University of Medical Sciences.

Conflicts of interest

None.

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Majid Safa
    • 1
    • 2
  • Behnaz Tavasoli
    • 2
  • Rima Manafi
    • 3
  • Fatemeh Kiani
    • 3
  • Meysam Kashiri
    • 3
  • Saber Ebrahimi
    • 3
  • Ahmad Kazemi
    • 1
    • 2
  1. 1.Cellular and Molecular Research CenterIran University of Medical SciencesTehranIran
  2. 2.Department of Hematology, Faculty of Allied MedicineIran University of Medical SciencesTehranIran
  3. 3.Department of Hematology, School of Allied Medical SciencesTehran University of Medical SciencesTehranIran

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