Oncocalyxone A inhibits human platelet aggregation by increasing cGMP and by binding to GP Ibalpha glycoprotein.
OBJECTIVE
Oncocalyxone A (OncoA) has a concentration-dependent anti-platelet activity. The present study aimed to further understand the mechanisms related to this effect.


METHODS
Human platelet aggregation was measured by means of a turbidimetric method. OncoA (32-256 microM) was tested against several platelet-aggregating agents, such as adenosine diphosphate (ADP), collagen, arachidonic acid (AA), ristocetin and thrombin.


RESULTS
OncoA completely inhibited platelet aggregation with a calculated mean inhibitory concentration (IC50-microM) of 122 for ADP, 161 for collagen, 159 for AA, 169 for ristocetin and 85 for thrombin. The anti-aggregatory activity of OncoA was not inhibited by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). OncoA, at a concentration that caused no significant anti-aggregatory activity, potentiated sodium nitroprusside (SNP) anti-aggregatory activity (18.8+/-2.9%-SNP vs 85.0+/-8.2%-SNP+OncoA). The levels of nitric oxide (NO) or cAMP were not altered by OncoA while cGMP levels were increased more than 10-fold by OncoA in resting or ADP-activated platelets. Flow cytometry revealed that OncoA does not interact with receptors for fibrinogen, collagen or P-selectin. Nevertheless, OncoA decreased the binding of antibodies to GP Ibalpha, a glycoprotein that is related both to von Willebrand factor and to thrombin-induced platelet aggregation.


CONCLUSIONS
OncoA showed anti-aggregatory activity in platelets that was associated with increased cGMP levels, not dependent on NO and with blocking GP Ibalpha glycoprotein. This new mechanism has the prospect of leading to new anti-thrombotic drugs.
Ferreira
M A D
MA
College of Pharmacy, Federal University of Ceará, Fortaleza, Ceará, Brazil. augusta_drago@yahoo.com.br
do Nascimento
N R F
NR
de Sousa
C M
CM
Pessoa
O D L
OD
de Lemos
T L G
TL
Ventura
J S
JS
Schattner
M
M
Chudzinski-Tavassi
A M
AM
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D000880:Anthraquinones / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000096:biosynthesis* / Q000097:blood; D006152:Cyclic GMP / Q000097:blood; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000097:blood / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006162:Guanylate Cyclase / Q000097:blood / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008875:Middle Aged; D009569:Nitric Oxide / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism*; D011485:Protein Binding; D013928:Thromboxane A2 / Q000502:physiology
D000880:Anthraquinones; D010975:Platelet Aggregation Inhibitors; D019038:Platelet Glycoprotein GPIb-IX Complex; C408504:oncocalyxone A; D009569:Nitric Oxide; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D000242:Cyclic AMP; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006162:Guanylate Cyclase; D006152:Cyclic GMP