title: 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: Surgical Neurology Branch, National Institute of Neurologic Disorders and Stroke, National Institutes of Health, 9000 Rockvillle Pike, Bethesda, MD 20892, USA.
authors: Jie
authors: J
authors: Lu
authors: John S
authors: JS
authors: Kovach
authors: Francis
authors: F
authors: Johnson
authors: Jeffrey
authors: J
authors: Chiang
authors: Richard
authors: R
authors: Hodes
authors: Russell
authors: R
authors: Lonser
authors: Zhengping
authors: Z
authors: Zhuang
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000627:therapeutic use; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000378:metabolism; D004249:DNA Damage; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005909:Glioblastoma / Q000188:drug therapy*; D051379:Mice; D016513:Mice, SCID; D009447:Neuroblastoma / Q000188:drug therapy*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D000077204:Temozolomide; D000097869:Polo-Like Kinase 1
chemical_list: D018906:Antineoplastic Agents, Alkylating; D018797:Cell Cycle Proteins; D003606:Dacarbazine; D004791:Enzyme Inhibitors; D054648:Protein Phosphatase 2; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D000077204:Temozolomide; D000097869:Polo-Like Kinase 1; C514862:Akt1 protein, mouse