Edgardo Becerra , Laura C. Berumen , T. García-Gasca , Jesica Escobar , Ulisses Moreno C , Guadalupe García-Alcocer
{"title":"Antiproliferative and apoptotic interaction between azathioprine and N-acetylcysteine in acute lymphoblastic leukemia Jurkat cells","authors":"Edgardo Becerra , Laura C. Berumen , T. García-Gasca , Jesica Escobar , Ulisses Moreno C , Guadalupe García-Alcocer","doi":"10.1016/j.synres.2019.100061","DOIUrl":null,"url":null,"abstract":"<div><p><span><span><span>T cell acute lymphoblastic leukaemia is a type of cancer that develops from lymphoid progenitors, and chemotherapy is corner stone of the </span>treatment<span>. Thiopurine </span></span>drugs<span><span>, consisting of 6-mercaptopurine, 6-thioguanine, and azathioprine (Aza), can effectively treat this disease. To be activated, Aza must first be biotransformed to 6-mercaptopurine by </span>thiol groups<span> in glutathione<span><span>. However, glutathione is decreased in cancer cells<span><span> due to high levels of reactive oxygen species (ROS). N-acetylcysteine could provide thiol groups for glutathione synthesis to biotransform Aza. Using flow cytometry, the ability of N-acetylcysteine to increase the antiproliferative and apoptotic effects of Aza without increasing ROS was tested in </span>Jurkat cells. Individually, Aza 1.0 and 2.0 μM, as well as N- </span></span>acetylcysteine<span> 3.0 mM, induced apoptosis and cell cycle arrest. Together, Aza + N-acetylcysteine significantly reduced proliferation compared to that obtained with the individual drugs. Combination of N-acetylcysteine 3.0 mM with Aza 1.0 μM was as effective at inducing apoptosis as Aza 2.0 μM alone. The combination of N-acetylcysteine 3.0 mM + Aza 1.0 μM increased cell cycle arrest at the G</span></span></span></span></span><sub>2</sub><span>/M phase. We found that Aza 1.0 or 2.0 μM induced a significant increase in ROS compared to that in untreated cells, while N-acetylcysteine 3.0 mM and N-acetylcysteine 3.0 mM + Aza 1.0 μM kept ROS at control levels; the latter drugpairing represents a favourable combination to reduce oxidative stress in the presence of Aza. In conclusion, N-acetylcysteine augments antiproliferative and apoptotic effects of Aza without increasing ROS </span><em>in vitro.</em></p></div>","PeriodicalId":38079,"journal":{"name":"Synergy","volume":"10 ","pages":"Article 100061"},"PeriodicalIF":0.0000,"publicationDate":"2020-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/j.synres.2019.100061","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Synergy","FirstCategoryId":"1085","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2213713018300385","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"Medicine","Score":null,"Total":0}
引用次数: 0
Abstract
T cell acute lymphoblastic leukaemia is a type of cancer that develops from lymphoid progenitors, and chemotherapy is corner stone of the treatment. Thiopurine drugs, consisting of 6-mercaptopurine, 6-thioguanine, and azathioprine (Aza), can effectively treat this disease. To be activated, Aza must first be biotransformed to 6-mercaptopurine by thiol groups in glutathione. However, glutathione is decreased in cancer cells due to high levels of reactive oxygen species (ROS). N-acetylcysteine could provide thiol groups for glutathione synthesis to biotransform Aza. Using flow cytometry, the ability of N-acetylcysteine to increase the antiproliferative and apoptotic effects of Aza without increasing ROS was tested in Jurkat cells. Individually, Aza 1.0 and 2.0 μM, as well as N- acetylcysteine 3.0 mM, induced apoptosis and cell cycle arrest. Together, Aza + N-acetylcysteine significantly reduced proliferation compared to that obtained with the individual drugs. Combination of N-acetylcysteine 3.0 mM with Aza 1.0 μM was as effective at inducing apoptosis as Aza 2.0 μM alone. The combination of N-acetylcysteine 3.0 mM + Aza 1.0 μM increased cell cycle arrest at the G2/M phase. We found that Aza 1.0 or 2.0 μM induced a significant increase in ROS compared to that in untreated cells, while N-acetylcysteine 3.0 mM and N-acetylcysteine 3.0 mM + Aza 1.0 μM kept ROS at control levels; the latter drugpairing represents a favourable combination to reduce oxidative stress in the presence of Aza. In conclusion, N-acetylcysteine augments antiproliferative and apoptotic effects of Aza without increasing ROS in vitro.