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Indole-3-Carbinol Suppresses Nf-Κb Activity and Stimulates the P53 Pathway in Pre-B Acute Lymphoblastic Leukemia Cells Publisher Pubmed



Safa M1, 2 ; Tavasoli B2 ; Manafi R3 ; Kiani F3 ; Kashiri M3 ; Ebrahimi S3 ; Kazemi A1, 2
Authors
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Authors Affiliations
  1. 1. Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
  2. 2. Department of Hematology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
  3. 3. Department of Hematology, School of Allied Medical Sciences, Tehran University of Medical Sciences, Tehran, Iran

Source: Tumor Biology Published:2015


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. © 2015, International Society of Oncology and BioMarkers (ISOBM).