Low dose leflunomide activates PI3K/Akt signalling in erythroleukemia cells and reduces apoptosis induced by anticancer agents |
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Authors: | D Y Leger B Liagre J L Beneytout |
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Institution: | (1) Laboratoire de Biochimie, UPRES EA 4021, Faculté de Pharmacie, 2 rue du Docteur Marcland, 87025 Limoges Cedex, France |
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Abstract: | Rheumatoid arthritis (RA) is characterized by persistent joint synovial tissue inflammation. Leflunomide is an immunomodulatory
agent that has been approved for treatment of active RA. In the past few years, uses other than RA treatment have appeared.
Leflunomide has been reported to show antitumor potential through inhibition of cancer cell proliferation. We thus tested
the antiproliferative potential of leflunomide on HEL and K562 erythroleukemia cells. The findings summarized in this report
demonstrate for the first time that low dose leflunomide prolonged survival and reduced apoptosis induced by several anticancer
agents in erythroleukemia cells. We showed that in treated cells, leflunomide reduced the signalling pathways involved in
promoting apoptosis by reducing p38 MAPK and JNK basal activity. On the other hand, leflunomide transiently activated the
ERK signalling pathway and induced a sustained activation of Akt. We also showed that leflunomide reduced caspase-3 activity
and DNA fragmentation induced by anticancer agents. By using an inhibitory strategy, we showed that inhibition of Akt activation
but not ERK abolished the protective effect of leflunomide. Thus our findings suggested that leflunomide reduced apoptosis
induced by anticancer agents through PI3K/Akt signalling activation. |
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Keywords: | Leflunomide Erythroleukemia cells Akt MAPK Apoptosis |
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