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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 106; no. 28; pp. 11697 - 11702
• Main Authors: Lu, Jie, Kovach, John S, Johnson, Francis, Chiang, Jeffrey, Hodes, Richard, Lonser, Russell, Zhuang, Zhengping
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 14-07-2009; National Acad Sciences
• Subjects: Amino acids; Animals; Antineoplastic Agents, Alkylating - therapeutic use; Biological Sciences; Blotting, Western; Cancer; Cell cycle; Cell Cycle Proteins - metabolism; Cell lines; Cell nucleus; Chemotherapy; Cultured cells; Dacarbazine - analogs & derivatives; Dacarbazine - therapeutic use; DNA Damage; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Flow Cytometry; Fluorescent Antibody Technique; Gene Expression Regulation, Enzymologic - drug effects; Genomics; Glioblastoma - drug therapy; Heterologous transplantation; Mice; Mice, SCID; Neuroblastoma - drug therapy; Neurons; Phosphatases; Polo-Like Kinase 1; Protein Phosphatase 2 - antagonists & inhibitors; Protein Serine-Threonine Kinases - metabolism; Proteins; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt - metabolism; Temozolomide; Tumors; Vehicles
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0905930106

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.