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

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.

• Authors: Jie Lu, John S Kovach, Francis Johnson, Jeffrey Chiang, Richard Hodes, Russell Lonser, Zhengping Zhuang
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 106 Issue 28 Pg. 11697-702 (Jul 14 2009) ISSN: 1091-6490 [Electronic] United States
• PMID: 19564615 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Animals
• Antineoplastic Agents, Alkylating (therapeutic use)
• Blotting, Western
• Cell Cycle Proteins (metabolism)
• DNA Damage
• Dacarbazine (analogs & derivatives, therapeutic use)
• Enzyme Inhibitors (pharmacology, 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
• Polo-Like Kinase 1