Arsenic trioxide-mediated antiplatelet activity: pivotal role of the phospholipase C gamma 2-protein kinase C-p38 MAPK cascade.
Arsenic trioxide produces high rates of complete clinical remission in patients with relapsed/refractory acute promyelocytic leukemia. Platelet activation is relevant in a variety of acute thrombotic events and coronary heart diseases. Few studies have examined the effects of arsenic trioxide on platelets, and the mechanisms underlying the signaling pathways remain obscure. The aim of this study was to examine systematically the detailed mechanisms of arsenic trioxide in preventing platelet activation. Arsenic trioxide (5 micromol/L) exhibited more potent activity at inhibiting collagen (1 microg/mL)-induced platelet aggregation than other agonists. Arsenic trioxide (15 and 25 micromol/L) inhibited collagen-induced platelet activation accompanied by [Ca(+2)]i mobilization, thromboxane A(2) (TxA(2)) formation, phospholipase C (PLC)gamma 2 phosphorylation, and protein kinase C (PKC) activation. Arsenic trioxide (15 and 25 micromol/L) did not significantly affect cyclic nucleotide-induced vasodilator-stimulated phosphoprotein phosphorylation. Moreover, arsenic trioxide markedly inhibited p38 mitogen-activated protein kinase (MAPK) but not JNK1/2 or ERK2 phosphorylation in washed platelets. Arsenic trioxide also markedly reduced hydroxyl radical (OH(.)) formation in the erythrocyte sedimentation rate (ESR) study. The most important findings of this study suggest that the inhibitory effect of arsenic trioxide possibly involves inhibition of the PLC gamma 2-PKC-p38 MAPK cascade, thereby leading to inhibition of [Ca(+2)]i or free radical formation, and finally the inhibition of platelet aggregation.
Graduate Institute of Medical Sciences, Department of Pharmacology, Taipei Medical University, Taipei, Taiwan.
Kuan H
KH
Lin
Yi F
YF
Chang
Chiao Y
CY
Fan
Thanasekaran
T
Jayakumar
Jie J
JJ
Lee
Duen S
DS
Chou
George
G
Hsiao
Joen-Rong
JR
Sheu
D000970:Antineoplastic Agents / Q000494:pharmacology; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects* / Q000201:enzymology*; D015815:Cell Adhesion Molecules / Q000378:metabolism; D003094:Collagen / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D017665:Hydroxyl Radical / Q000378:metabolism; D066298:In Vitro Techniques; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008840:Microfilament Proteins / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D051966:Phospholipase C gamma / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D015539:Platelet Activation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011493:Protein Kinase C / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000098662:Vasodilator-Stimulated Phosphoprotein
D000970:Antineoplastic Agents; D001152:Arsenicals; D015815:Cell Adhesion Molecules; D008840:Microfilament Proteins; D010087:Oxides; D010750:Phosphoproteins; D010975:Platelet Aggregation Inhibitors; D000098662:Vasodilator-Stimulated Phosphoprotein; D017665:Hydroxyl Radical; D003094:Collagen; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; D051966:Phospholipase C gamma; D000077237:Arsenic Trioxide