Inhibition of serine/threonine phosphatase PP2A enhances cancer chemotherapy by blocking DNA damage induced defense mechanisms

Proc Natl Acad Sci U S A. 2009 Jul 14;106(28):11697-702. doi: 10.1073/pnas.0905930106. Epub 2009 Jun 29.

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Alkylating / therapeutic use
  • Blotting, Western
  • Cell Cycle Proteins / metabolism
  • DNA Damage*
  • Dacarbazine / analogs & derivatives
  • Dacarbazine / therapeutic use
  • Enzyme Inhibitors / pharmacology
  • Enzyme Inhibitors / therapeutic use*
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Enzymologic / drug effects*
  • Glioblastoma / drug therapy*
  • Mice
  • Mice, SCID
  • Neuroblastoma / drug therapy*
  • Protein Phosphatase 2 / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Temozolomide

Substances

  • Antineoplastic Agents, Alkylating
  • Cell Cycle Proteins
  • Enzyme Inhibitors
  • Proto-Oncogene Proteins
  • Dacarbazine
  • Akt1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • polo-like kinase 1
  • Protein Phosphatase 2
  • Temozolomide