1. Academic Validation
  2. Evidence that activation of nuclear factor-kappaB is essential for the cytotoxic effects of doxorubicin and its analogues

Evidence that activation of nuclear factor-kappaB is essential for the cytotoxic effects of doxorubicin and its analogues

  • Biochem Pharmacol. 2004 Jan 15;67(2):353-64. doi: 10.1016/j.bcp.2003.08.039.
Kazuhiro Ashikawa 1 Shishir Shishodia Izabel Fokt Waldemar Priebe Bharat B Aggarwal
Affiliations

Affiliation

  • 1 Cytokine Research Laboratory, Department of Bioimmunotherapy, M.D. Anderson Cancer Center, The University of Texas, 1515 Holcombe Boulevard, Box 143, Houston, TX 77030, USA.
Abstract

Several reports within the last 5 years have suggested that nuclear factor (NF)-kappaB activation suppresses Apoptosis through expression of anti-apoptotic genes. In the present report, we provide evidence from four independent lines that NF-kappaB activation is required for the cytotoxic effects of doxorubicin. We used doxorubicin and its structural analogues WP631 and WP744, to demonstrate that anthracyclines activate NF-kappaB, and this activation is essential for Apoptosis in myeloid (KBM-5) and lymphoid (Jurkat) cells. All three anthracyclines had cytotoxic effects against KBM-5 cells; analogue WP744, was most potent, with an IC(50) of 0.5 microM, and doxorubicin was least active, with an IC(50) of 2 microM. We observed maximum NF-kappaB activation at 1 microM with WP744 and at 50 microM with doxorubicin and WP631, and this activation correlated with the IkappaBalpha degradation. Because the anthracycline analogue (WP744), most active as a cytotoxic agent, was also most active in inducing NF-kappaB activation and the latter preceded the cytotoxic effects, suggests that NF-kappaB activation may mediate cytotoxicity. Second, receptor-interacting protein-deficient cells, which did not respond to doxorubicin-induced NF-kappaB activation, were also protected from the cytotoxic effects of all the three anthracyclines. Third, suppression of NF-kappaB activation by pyrrolidine dithiocarbamate, also suppressed the cytotoxic effects of anthracyclines. Fourth, suppression of NF-kappaB activation by NEMO-binding domain peptide, also suppressed the cytotoxic effects of the drug. Overall our results clearly demonstrate that NF-kappaB activation and IkappaBalpha degradation are early events activated by doxorubicin and its analogues and that they play a critical pro-apoptotic role.

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