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Methotrexate Promotes Platelet Apoptosis via JNK-Mediated Mitochondrial Damage: Alleviation by N-Acetylcysteine and N-Acetylcysteine Amide

Paul, Manoj and Hemshekhar, Mahadevappa and Thushara, Ram M and Sundaram, Mahalingam S and NaveenKumar, Somanathapura K and Naveen, Shivanna and Devaraja, Sannaningaiah and Somyajit, Kumar and West, Robert and Basappa, * and Nayaka, Siddaiah C and Zakai, Uzma I and Nagaraju, Ganesh and Rangappa, Kanchugarakoppal S and Kemparaju, Kempaiah and Girish, Kesturu S (2015) Methotrexate Promotes Platelet Apoptosis via JNK-Mediated Mitochondrial Damage: Alleviation by N-Acetylcysteine and N-Acetylcysteine Amide. In: PLOS ONE, 10 (6).

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Official URL: http://dx.doi.org/10.1371/journal.pone.0127558

Abstract

Thrombocytopenia in methotrexate (MTX)-treated cancer and rheumatoid arthritis (RA) patients connotes the interference of MTX with platelets. Hence, it seemed appealing to appraise the effect of MTX on platelets. Thereby, the mechanism of action of MTX on platelets was dissected. MTX (10 mu M) induced activation of pro-apoptotic proteins Bid, Bax and Bad through JNK phosphorylation leading Delta psi m dissipation, cytochrome c release and caspase activation, culminating in apoptosis. The use of specific inhibitor for JNK abrogates the MTX-induced activation of pro-apoptotic proteins and downstream events confirming JNK phosphorylation by MTX as a key event. We also demonstrate that platelet mitochondria as prime sources of ROS which plays a central role in MTX-induced apoptosis. Further, MTX induces oxidative stress by altering the levels of ROS and glutathione cycle. In parallel, the clinically approved thiol antioxidant N-acetylcysteine (NAC) and its derivative N-acetylcysteine amide (NACA) proficiently alleviate MTX-induced platelet apoptosis and oxidative damage. These findings underpin the dearth of research on interference of therapeutic drugs with platelets, despite their importance in human health and disease. Therefore, the use of antioxidants as supplementary therapy seems to be a safe bet in pathologies associated with altered platelet functions.

Item Type: Journal Article
Additional Information: Copy right for this article belongs to the PUBLIC LIBRARY SCIENCE, 1160 BATTERY STREET, STE 100, SAN FRANCISCO, CA 94111 USA
Department/Centre: Division of Biological Sciences > Biochemistry
Depositing User: Id for Latest eprints
Date Deposited: 31 Jul 2015 15:08
Last Modified: 31 Jul 2015 15:08
URI: http://eprints.iisc.ac.in/id/eprint/51998

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