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Activation of the c-Jun N-terminal Kinase/Activating Transcription Factor 3 (ATF3) Pathway Characterizes Effective Arylated Diazeniumdiolate-Based Nitric Oxide-Releasing Anticancer Prodrugs

  1. Author:
    Maciag, A. E.
    Nandurdikar, R. S.
    Hong, S. Y.
    Chakrapan, H.
    Diwan, B.
    Morris, N. L.
    Shami, P. J.
    Shiao, Y. H.
    Anderson, L. M.
    Keefer, L. K.
    Saavedra, J. E.

  2. Author Address

    [Maciag, AE; Diwan, B; Saavedra, JE] SAIC Frederick Inc, Basic Sci Program, NCI, Frederick, MD 21702 USA. [Nandurdikar, RS; Hong, SY; Shiao, YH; Anderson, LM; Keefer, LK] NCI, Biol Chem Lab, Frederick, MD 21702 USA. [Chakrapan, H] Indian Inst Sci Educ & Res, Dept Chem, Pune 411008, Maharashtra, India. [Morris, NL] SAIC Frederick Inc, Lab Anim Sci Program, NCI, Frederick, MD 21702 USA. [Shami, PJ] Univ Utah, Div Hematol & Hematol Malignancies, Huntsman Canc Inst, Salt Lake City, UT 84112 USA.;Maciag, AE (reprint author), SAIC Frederick Inc, Basic Sci Program, NCI, Frederick, MD 21702 USA;maciaga@mail.nih.gov
    1. Year: 2011
    2. Date: Nov
  2. Journal: Journal of Medicinal Chemistry
    1. 54
    2. 22
    3. Pages: 7751-7758
  4. Type of Article: Article
  5. ISSN: 0022-2623
  1. Abstract:

    Improved therapies are needed for nonsmall cell lung cancer. Diazeniumdiolate-based nitric oxide (NO)-releasing prodrugs are a growing class of promising NO-based therapeutics. Recently, we have shown that O(2)-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate (JS-K, 1) is effective against nonsmall cell lung cancer (NSCLC) cells in culture and in vivo. Here we report mechanistic studies with compound 1 and its homopiperazine analogue and structural modification of these into more stable prodrugs. Compound 1 and its., homopiperazine analogue were potent cytotoxic agents against NSCLC cells in vitro and in vivo, concomitant with activation of the SAPK/JNK stress pathway and upregulation of its downstream effector ATF3. Apoptosis followed these events. An aryl-substituted analogue, despite extended half-life in the presence of glutathione, did not activate JNK or have antitumor activity. The data suggest that rate of reactivity with glutathione and activation of JNK/ATF3 are determinants of cancer cell killing by these prodrugs.

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External Sources

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  2. DOI: 10.1021/jm2004128
  3. View record in Web of Science®
  4. WOS: 000297001600002

Library Notes

  1. Fiscal Year: FY2011-2012
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