Inhibitors of phosphatidylinositide 3-kinase

Effects on reactive oxygen species and platelet aggregation

Sheikh Arshad Saeed, John Dennis Connor, Imran, Javeria Quadri, Shumaila Tasneem, Sagheer Ahmed, Osman Mesaik Mohammed Ahmed Hassan, Muhammad Iqbal Choudhary

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Phosphoinositide 3-kinase (PI3-kinase) exists in cells as a family of isoforms. The enzymes are important regulators of fundamental metabolic processes, such as energy utilization, growth, cell proliferation, and survival. They are activated by cell surface receptors for hormones, and by G-protein coupled receptors. Enzyme p110 gamma. in particular, catalyzes production of second messengers from inositol phospholipids, including phosphoinositide (3,4,5) triphosphate or PtdIns (3,4,5) P3, PtdIns (3,4) P2 and Ptdins (3) P. The objective of this study was to corroborate the role of PI 3 kinase in ROS generation and in platelet aggregation through the use of four chemically unrelated inhibitor of PI 3 kinase: wortmannin, LY-294002, resveratrol and quercetin. In this study, we describe the effects of four PI 3 -kinase inhibitors on the production of reactive oxygen species (ROS) and platelet aggregation induced by a diversity of agonists. Neutrophils and platelets were obtained from human blood and macrophages from mouse peritoneal cavity, ROS production was measured by a luminol-enhanced chemiluminescense assay; aggregation was measured in platelet rich plasma (PRP) with a Chronolog Dual Channel Lumi-Aggregometer. Effects of graded concentrations of four enzyme inhibitors (wortmannin, LY-294002, resveratrol and quercetin) were evaluated. All inhibitors caused concentration-dependent depression of ROS generation and human platelet aggregation. They differed only in their potencies as revealed by concentration-response data. Moreover, inhibitors blocked activity of three chemically unrelated stimulants of aggregation: ADP, collagen and epinephrine. We conclude that inhibition of PI 3-kinase would appear to be a useful therapeutic goal in those conditions where the activites of platelets and/or phagocytes become aberrant.

Original languageEnglish
Pages (from-to)238-243
Number of pages6
JournalPharmacological Reports
Volume59
Issue number2
Publication statusPublished - 2007
Externally publishedYes

Fingerprint

Phosphatidylinositol 3-Kinases
Platelet Aggregation
Reactive Oxygen Species
Phosphotransferases
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Quercetin
Phosphatidylinositols
Blood Platelets
Luminol
Platelet-Rich Plasma
1-Phosphatidylinositol 4-Kinase
Peritoneal Cavity
Cell Surface Receptors
Second Messenger Systems
Enzyme Inhibitors
Enzymes
Phagocytes
G-Protein-Coupled Receptors
Adenosine Diphosphate
Epinephrine

Keywords

  • Luminol-enhanced chemiluminescence assay
  • LY 294002
  • Phosphatidylinositide 3-kinase
  • Platelet aggregation
  • Quercetin
  • Resveratrol
  • Wortmannin

ASJC Scopus subject areas

  • Pharmacology

Cite this

Saeed, S. A., Connor, J. D., Imran, Quadri, J., Tasneem, S., Ahmed, S., ... Choudhary, M. I. (2007). Inhibitors of phosphatidylinositide 3-kinase: Effects on reactive oxygen species and platelet aggregation. Pharmacological Reports, 59(2), 238-243.

Inhibitors of phosphatidylinositide 3-kinase : Effects on reactive oxygen species and platelet aggregation. / Saeed, Sheikh Arshad; Connor, John Dennis; Imran; Quadri, Javeria; Tasneem, Shumaila; Ahmed, Sagheer; Mohammed Ahmed Hassan, Osman Mesaik; Choudhary, Muhammad Iqbal.

In: Pharmacological Reports, Vol. 59, No. 2, 2007, p. 238-243.

Research output: Contribution to journalArticle

Saeed, SA, Connor, JD, Imran, Quadri, J, Tasneem, S, Ahmed, S, Mohammed Ahmed Hassan, OM & Choudhary, MI 2007, 'Inhibitors of phosphatidylinositide 3-kinase: Effects on reactive oxygen species and platelet aggregation', Pharmacological Reports, vol. 59, no. 2, pp. 238-243.
Saeed SA, Connor JD, Imran, Quadri J, Tasneem S, Ahmed S et al. Inhibitors of phosphatidylinositide 3-kinase: Effects on reactive oxygen species and platelet aggregation. Pharmacological Reports. 2007;59(2):238-243.
Saeed, Sheikh Arshad ; Connor, John Dennis ; Imran ; Quadri, Javeria ; Tasneem, Shumaila ; Ahmed, Sagheer ; Mohammed Ahmed Hassan, Osman Mesaik ; Choudhary, Muhammad Iqbal. / Inhibitors of phosphatidylinositide 3-kinase : Effects on reactive oxygen species and platelet aggregation. In: Pharmacological Reports. 2007 ; Vol. 59, No. 2. pp. 238-243.
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