Access

You are not currently logged in.

Access your personal account or get JSTOR access through your library or other institution:

login

Log in to your personal account or through your institution.

If You Use a Screen Reader

This content is available through Read Online (Free) program, which relies on page scans. Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.

Inhibition of Serine/Threonine Phosphatase PP2A Enhances Cancer Chemotherapy by Blocking DNA Damage Induced Defense Mechanisms

Jie Lu, John S. Kovach, Francis Johnson, Jeffrey Chiang, Richard Hodes, Russell Lonser, Zhengping Zhuang and Roscoe O. Brady
Proceedings of the National Academy of Sciences of the United States of America
Vol. 106, No. 28 (Jul. 14, 2009), pp. 11697-11702
Stable URL: http://www.jstor.org/stable/40484013
Page Count: 6
  • Read Online (Free)
  • Subscribe ($19.50)
  • Cite this Item
Since scans are not currently available to screen readers, please contact JSTOR User Support for access. We'll provide a PDF copy for your screen reader.
Inhibition of Serine/Threonine Phosphatase PP2A Enhances Cancer Chemotherapy by Blocking DNA Damage Induced Defense Mechanisms
Preview not available

Abstract

A variety of mechanisms maintain the integrity of the genome in the face of cell stress. Cancer cell response to chemotherapeutic and radiation-induced DNA damage is mediated by multiple defense mechanisms including polo-like kinase 1 (Plk-1), protein kinase B (Akt-1), and/or p53 pathways leading to either apoptosis or cell cycle arrest. Subsequently, a subpopulation of arrested viable cancer cells may remain and recur despite aggressive and repetitive therapy. Here, we show that modulation (activation of Akt-1 and Plk-1 and repression of p53) of these pathways simultaneously results in paradoxical enhancement of the effectiveness of cytotoxic chemotherapy. We demonstrate that a small molecule inhibitor, LB-1.2, of protein phosphatase 2A (PP2A) activates Plk-1 and Akt-1 and decreases p53 abundance in tumor cells. Combined with temozolomide (TMZ; a DNA-methylating chemotherapeutic drug), LB-1.2 causes complete regression of glioblastoma multiforme (GBM) xenografts without recurrence in 50% of animals (up to 28 weeks) and complete inhibition of growth of neuroblastoma (NB) xenografts. Treatment with either drug alone results in only short-term inhibition/regression with all xenografts resuming rapid growth. Combined with another widely used anticancer drug, Doxorubicin (DOX, a DNA intercalating agent), LB-1.2 also causes marked GBM xenograft regression, whereas DOX alone only slows growth. Inhibition of PP2A by LB-1.2 blocks cell-cycle arrest and increases progression of cell cycle in the presence of TMZ or DOX. Pharmacologic inhibition of PP2A may be a general method for enhancing the effectiveness of cancer treatments that damage DNA or disrupt components of cell replication.

Page Thumbnails

  • Thumbnail: Page 
[11697]
    [11697]
  • Thumbnail: Page 
11698
    11698
  • Thumbnail: Page 
11699
    11699
  • Thumbnail: Page 
11700
    11700
  • Thumbnail: Page 
11701
    11701
  • Thumbnail: Page 
11702
    11702