ABSTRACT
BACKGROUND AND PURPOSE: Oncocalyxone A (OncoA) has a concentration-dependent anti-platelet activity. The present study aimed to further understand the mechanisms related to this effect. EXPERIMENTAL APPROACH: 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. KEY 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. CONCLUSION AND IMPLICATIONS: 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.
Subject(s)
Anthraquinones/pharmacology , Cyclic AMP/biosynthesis , Platelet Aggregation Inhibitors/pharmacology , Platelet Aggregation/drug effects , Platelet Glycoprotein GPIb-IX Complex/metabolism , Adenosine Diphosphate/pharmacology , Adenosine Triphosphate/metabolism , Adolescent , Adult , Anthraquinones/isolation & purification , Anthraquinones/metabolism , Blood Platelets/drug effects , Blood Platelets/metabolism , Cyclic AMP/blood , Cyclic GMP/blood , Cyclic Nucleotide Phosphodiesterases, Type 5/blood , Cyclic Nucleotide Phosphodiesterases, Type 5/metabolism , Female , Flow Cytometry , Guanylate Cyclase/blood , Guanylate Cyclase/metabolism , Humans , In Vitro Techniques , Male , Middle Aged , Nitric Oxide/metabolism , Platelet Aggregation Inhibitors/metabolism , Protein Binding , Thromboxane A2/physiologyABSTRACT
In the present work we studied the antinociceptive and antiedematogenic effects of a quinone fraction (QF) isolated from the heartwood of Auxemma oncocalyx Taub. The major constituent of QF, which represented around 80% of this fraction, was a terpenoid quinone named oncocalyxone A (1). Results show that QF (10 and 30 mg/kg body wt., i.p.) significantly inhibited paw edema induced by carrageenan at the second, third, and fourth hours. The effect was dose-dependent and long lasting, and QF was less effective orally. An antiedematogenic effect was also demonstrated in the dextran-induced paw edema. In this model, however, QF was somewhat less potent. QF (1 and 5 mg/kg body wt., i.p.) inhibited acetic acid-induced abdominal contractions in mice in a dose-dependent manner. In addition, QF (5 and 10 mg/kg body wt., i.p.) inhibited only the second phase (inflammatory) in the formalin test, and showed no effect in the hot-plate test in mice. The antinociceptive activity of QF was predominantly peripheral and independent of the opioid system. The observed effects of QF are, at least in part, probably due to the presence of oncocalyxone A (1).
Subject(s)
Analgesics, Non-Narcotic/pharmacology , Anthraquinones/pharmacology , Anti-Inflammatory Agents/pharmacology , Boraginaceae , Edema/prevention & control , Pain/prevention & control , Phytotherapy , Acetic Acid , Analgesics, Non-Narcotic/administration & dosage , Analgesics, Non-Narcotic/therapeutic use , Animals , Anthraquinones/administration & dosage , Anthraquinones/therapeutic use , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/therapeutic use , Carrageenan , Dose-Response Relationship, Drug , Edema/chemically induced , Formaldehyde , Injections, Intraperitoneal , Male , Pain/chemically induced , Plant Extracts/administration & dosage , Plant Extracts/pharmacology , Plant Extracts/therapeutic use , Rats , Rats, WistarABSTRACT
Auxemma oncocalyx Taub. belongs to the Boraginaceae family and is native to the Brazilian northeast where it is known as "pau-branco". We investigated the ability of the water soluble fraction isolated from the heartwood of A. oncocalyx to inhibit sea urchin egg development. This fraction contains about 80% oncocalyxone A (quinone fraction), a compound known to possess strong cytotoxic and antitumor activities. In fact, the quinone fraction inhibited cleavage in a dose-dependent manner [IC50 of 18.4 (12.4-27.2) microg/ml, N = 6], and destroyed the embryos in the blastula stage [IC50 of 16.2 (13.7-19.2) microg/ml, N = 6]. We suggest that this activity is due to the presence of oncocalyxone A. In fact, these quinones present in A. oncocalyx extract have strong toxicity related to their antimitotic activity.
Subject(s)
Anthraquinones/toxicity , Boraginaceae/chemistry , Ovum/drug effects , Quinones/toxicity , Animals , Anthraquinones/isolation & purification , Antineoplastic Agents/toxicity , DNA Damage , Plant Extracts/toxicity , Quinones/isolation & purification , Sea UrchinsABSTRACT
Auxemma oncocalyx Taub. belongs to the Boraginaceae family and is native to the Brazilian northeast where it is known as "pau-branco". We investigated the ability of the water soluble fraction isolated from the heartwood of A. oncocalyx to inhibit sea urchin egg development. This fraction contains about 80 percent oncocalyxone A (quinone fraction), a compound known to possess strong cytotoxic and antitumor activities. In fact, the quinone fraction inhibited cleavage in a dose-dependent manner [IC50 of 18.4 (12.4-27.2) æg/ml, N = 6], and destroyed the embryos in the blastula stage [IC50 of 16.2 (13.7-19.2) æg/ml, N = 6]. We suggest that this activity is due to the presence of oncocalyxone A. In fact, these quinones present in A. oncocalyx extract have strong toxicity related to their antimitotic activity
