John P Alao

Publications (31) View all

• Source

  Available from: Per Sunnerhagen

  Article: The ATM and ATR inhibitors CGK733 and caffeine suppress cyclin D1 levels and inhibit cell proliferation.

  John P Alao, Per Sunnerhagen
  [show abstract] [hide abstract]
  ABSTRACT: The ataxia telangiectasia mutated (ATM) and the ATM- related (ATR) kinases play a central role in facilitating the resistance of cancer cells to genotoxic treatment regimens. The components of the ATM and ATR regulated signaling pathways thus provide attractive pharmacological targets, since their inhibition enhances cellular sensitivity to chemo- and radiotherapy. Caffeine as well as more specific inhibitors of ATM (KU55933) or ATM and ATR (CGK733) have recently been shown to induce cell death in drug-induced senescent tumor cells. Addition of these agents to cancer cells previously rendered senescent by exposure to genotoxins suppressed the ATM mediated p21 expression required for the survival of these cells. The precise molecular pharmacology of these agents however, is not well characterized. Herein, we report that caffeine, CGK733, and to a lesser extent KU55933, inhibit the proliferation of otherwise untreated human cancer and non-transformed mouse fibroblast cell lines. Exposure of human cancer cell lines to caffeine and CGK733 was associated with a rapid decline in cyclin D1 protein levels and a reduction in the levels of both phosphorylated and total retinoblastoma protein (RB). Our studies suggest that observations based on the effects of these compounds on cell proliferation and survival must be interpreted with caution. The differential effects of caffeine/CGK733 and KU55933 on cyclin D1 protein levels suggest that these agents will exhibit dissimilar molecular pharmacological profiles.
  Radiation Oncology 11/2009; 4:51. · 2.32 Impact Factor
• Article: Antiplasmodial quinones from Pentas longiflora and Pentas lanceolata.

  Milkyas Endale, John Patrick Alao, Hoseah M Akala, Nelson K Rono, Fredrick L Eyase, Solomon Derese, Albert Ndakala, Martin Mbugua, Douglas S Walsh, Per Sunnerhagen, Mate Erdelyi, Abiy Yenesew
  [show abstract] [hide abstract]
  ABSTRACT: The dichloromethane/methanol (1:1) extracts of the roots of Pentas longiflora and Pentas lanceolata showed low micromolar (IC(50) = 0.9-3 µg/mL) IN VITRO antiplasmodial activity against chloroquine-resistant (W2) and chloroquine-sensitive (D6) strains of PLASMODIUM FALCIPARUM. Chromatographic separation of the extract of PENTAS LONGIFLORA led to the isolation of the pyranonaphthoquinones pentalongin (1) and psychorubrin (2) with IC(50) values below 1 µg/mL and the naphthalene derivative mollugin (3), which showed marginal activity. Similar treatment of Pentas lanceolata led to the isolation of eight anthraquinones ( 4-11, IC(50) = 5-31 µg/mL) of which one is new (5,6-dihydroxydamnacanthol, 11), while three--nordamnacanthal (7), lucidin-ω-methyl ether (9), and damnacanthol (10)--are reported here for the first time from the genus Pentas. The compounds were identified by NMR and mass spectroscopic techniques.
  Planta Medica 01/2012; 78(1):31-5. · 2.15 Impact Factor
• Source

  Available from: Per Sunnerhagen

  Article: Design, synthesis, and biological evaluation of chromone-based p38 MAP kinase inhibitors.

  Christine Dyrager, Linda Nilsson Möllers, Linda Karlsson Kjäll, John Patrick Alao, Peter Dinér, Fredrik K Wallner, Per Sunnerhagen, Morten Grøtli
  [show abstract] [hide abstract]
  ABSTRACT: 3-(4-Fluorophenyl)-2-(4-pyridyl)chromone derivatives were synthesized and evaluated as p38 MAP kinase inhibitors. Introduction of an amino group in the 2-position of the pyridyl moiety gave p38α inhibitors with IC(50) in the low nanomolar range (e.g., IC(50) = 17 nm). The inhibitors showed excellent selectivity profiles when tested on a panel of 62 kinases, as well as efficient inhibition of p38 signaling in human breast cancer cells.
  Journal of Medicinal Chemistry 09/2011; 54(20):7427-31. · 4.80 Impact Factor
• Source

  Available from: Per Sunnerhagen

  Article: Hyperosmosis enhances radiation and hydroxyurea resistance of Schizosaccharomyces pombe checkpoint mutants through the spindle checkpoint and delayed cytokinesis.

  John P Alao, Pim J Huis In 't Veld, Frederike Buhse, Per Sunnerhagen
  [show abstract] [hide abstract]
  ABSTRACT: The DNA damage and stress response pathways interact to regulate cellular responses to genotoxins and environmental stresses. How these pathways interact in Schizosaccharomyces pombe is not well understood. We demonstrate that osmotic stress suppresses the DNA damage sensitivity of checkpoint mutants, and that this occurs through three distinct cell cycle delays. A delay in G2/M is dependent on Srk1. Progression through mitosis is halted by the Mad2-dependent spindle checkpoint. Finally, cytokinesis is impaired by modulating Cdc25 expression. These three delays, imposed by osmotic stress, together compensate for the loss of checkpoint signalling.
  Molecular Microbiology 04/2010; 77(1):143-57. · 5.01 Impact Factor
• Article: The regulation of cyclin D1 degradation: roles in cancer development and the potential for therapeutic invention

  John Alao
  [show abstract] [hide abstract]
  ABSTRACT: Abstract Cyclin D1 is an important regulator of cell cycle progression and can function as a transcriptionl co-regulator. The overexpression of cyclin D1 has been linked to the development and progression of cancer. Deregulated cyclin D1 degradation appears to be responsible for the increased levels of cyclin D1 in several cancers. Recent findings have identified novel mechanisms involved in the regulation of cyclin D1 stability. A number of therapeutic agents have been shown to induce cyclin D1 degradation. The therapeutic ablation of cyclin D1 may be useful for the prevention and treatment of cancer. In this review, current knowledge on the regulation of cyclin D1 degradation is discussed. Novel insights into cyclin D1 degradation are also discussed in the context of ablative therapy. A number of unresolved questions regarding the regulation of cellular cyclin D1 levels are also addressed.
  Molecular Cancer. 01/2007;