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JS-K, an arylating nitric oxide (NO) donor, has synergistic anti-leukemic activity with cytarabine (ARA-C)

  1. Author:
    Shami, P. J.
    Maciag, A. E.
    Eddington, J. K.
    Udupi, V.
    Kosak, K. M.
    Saavedra, J. E.
    Keefer, L. K.

  2. Author Address

    Shami, Paul J.; Eddington, Jordan K.; Udupi, Vidya, Kosak, Ken M.] Univ Utah, Salt Lake City, UT USA. [Maciag, Anna E.; Saavedra, Joseph E.] SAIC Frederick Inc, Frederick, MD USA. [Keefer, Larry K.] NCI, Comparat Carcinogenesis Lab, Frederick, MD 21701 USA.
    1. Year: 2009
  2. Journal: Leukemia Research
    1. 33
    2. 11
    3. Pages: 1525-1529
  4. Type of Article: Article
  1. Abstract:

    We have designed prodrugs, that release nitric oxide (NO) on metabolism by glutathione S-transferases (GST). This design exploits the upregulation of GST in acute myeloid leukemia (AML) cells. O-2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, a member of this class) has potent anti-leukemic activity. HL-60 myeloid leukemia cells were used for in vitro studies of the combination of JS-K with daunorubicin (DAUNO), cytarabine (ARA-C) or etoposide (ETOP) using the median effect method to determine synergistic, antagonistic, or additive effects. Combinations of JS-K added simultaneously, 2 h before or 2 h after the other compounds were used. JS-K and DAUNO were antagonistic in all three drug sequences. JS-K and ETOP were also antagonistic but to a lesser degree. JS-K and ARA-C showed strong synergy. The combination index at the 50% fraction affected was 0.37 +/- 0.23, 0.24 +/- 0.27, and 0.15 +/- 0.11 for simultaneous,JS-K first and ARA-C first additions, respectively. JS-K by itself induced DNA strand breaks at relatively high concentrations. However, at submicromolar concentrations, it significantly augmented ARA-C-induced DNA strand breaks. NMR spectroscopy revealed no evidence of chemical interaction between JS-K and the other chemotherapeutic agents. We conclude that ARA-C and JS-K have synergistic anti-leukemic activity and warrant further exploration in combination. (C) 2009 Elsevier Ltd. All rights reserved.

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  2. DOI: 10.1016/j.leukres.2009.01.002
  3. PMID: 19193435

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