Apoptosis Induced by the Curcumin Analogue EF-24 Is Neither Mediated by Oxidative Stress-Related Mechanisms nor Affected by Expression of Main Drug Transporters ABCB1 and ABCG2 in Human Leukemia Cells
The synthetic curcumin analogue, 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone (EF-24), suppresses NF-κB activity and exhibits antiproliferative effects against a variety of cancer cells in vitro. Recently, it was reported that EF-24-induced apoptosis was mediated by a redox-dependent mechanism....
Main Authors: | , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
MDPI AG
2017-10-01
|
Series: | International Journal of Molecular Sciences |
Subjects: | |
Online Access: | https://www.mdpi.com/1422-0067/18/11/2289 |
id |
doaj-1f06a6cf97cf4a2294fd223c30a486dc |
---|---|
record_format |
Article |
spelling |
doaj-1f06a6cf97cf4a2294fd223c30a486dc2020-11-24T21:51:19ZengMDPI AGInternational Journal of Molecular Sciences1422-00672017-10-011811228910.3390/ijms18112289ijms18112289Apoptosis Induced by the Curcumin Analogue EF-24 Is Neither Mediated by Oxidative Stress-Related Mechanisms nor Affected by Expression of Main Drug Transporters ABCB1 and ABCG2 in Human Leukemia CellsNikola Skoupa0Petr Dolezel1Eliska Ruzickova2Petr Mlejnek3Department of Anatomy, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 77515, Czech RepublicDepartment of Anatomy, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 77515, Czech RepublicDepartment of Anatomy, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 77515, Czech RepublicDepartment of Anatomy, Faculty of Medicine and Dentistry, Palacky University Olomouc, Hnevotinska 3, Olomouc 77515, Czech RepublicThe synthetic curcumin analogue, 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone (EF-24), suppresses NF-κB activity and exhibits antiproliferative effects against a variety of cancer cells in vitro. Recently, it was reported that EF-24-induced apoptosis was mediated by a redox-dependent mechanism. Here, we studied the effects of N-acetylcysteine (NAC) on EF-24-induced cell death. We also addressed the question of whether the main drug transporters, ABCB1 and ABCG2, affect the cytotoxic of EF-24. We observed that EF-24 induced cell death with apoptotic hallmarks in human leukemia K562 cells. Importantly, the loss of cell viability was preceded by production of reactive oxygen species (ROS), and by a decrease of reduced glutathione (GSH). However, neither ROS production nor the decrease in GSH predominantly contributed to the EF-24-induced cell death. We found that EF-24 formed an adduct with GSH, which is likely the mechanism contributing to the decrease of GSH. Although NAC abrogated ROS production, decreased GSH and prevented cell death, its protective effect was mainly due to a rapid conversion of intra- and extra-cellular EF-24 into the EF-24-NAC adduct without cytotoxic effects. Furthermore, we found that neither overexpression of ABCB1 nor ABCG2 reduced the antiproliferative effects of EF-24. In conclusion, a redox-dependent-mediated mechanism only marginally contributes to the EF-24-induced apoptosis in K562 cells. The main mechanism of NAC protection against EF-24-induced apoptosis is conversion of cytotoxic EF-24 into the noncytotoxic EF-24-NAC adduct. Neither ABCB1 nor ABCG2 mediated resistance to EF-24.https://www.mdpi.com/1422-0067/18/11/2289NF-κBNrf2EF-24-GSH adductEF-24-NAC adductK562 cells |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Nikola Skoupa Petr Dolezel Eliska Ruzickova Petr Mlejnek |
spellingShingle |
Nikola Skoupa Petr Dolezel Eliska Ruzickova Petr Mlejnek Apoptosis Induced by the Curcumin Analogue EF-24 Is Neither Mediated by Oxidative Stress-Related Mechanisms nor Affected by Expression of Main Drug Transporters ABCB1 and ABCG2 in Human Leukemia Cells International Journal of Molecular Sciences NF-κB Nrf2 EF-24-GSH adduct EF-24-NAC adduct K562 cells |
author_facet |
Nikola Skoupa Petr Dolezel Eliska Ruzickova Petr Mlejnek |
author_sort |
Nikola Skoupa |
title |
Apoptosis Induced by the Curcumin Analogue EF-24 Is Neither Mediated by Oxidative Stress-Related Mechanisms nor Affected by Expression of Main Drug Transporters ABCB1 and ABCG2 in Human Leukemia Cells |
title_short |
Apoptosis Induced by the Curcumin Analogue EF-24 Is Neither Mediated by Oxidative Stress-Related Mechanisms nor Affected by Expression of Main Drug Transporters ABCB1 and ABCG2 in Human Leukemia Cells |
title_full |
Apoptosis Induced by the Curcumin Analogue EF-24 Is Neither Mediated by Oxidative Stress-Related Mechanisms nor Affected by Expression of Main Drug Transporters ABCB1 and ABCG2 in Human Leukemia Cells |
title_fullStr |
Apoptosis Induced by the Curcumin Analogue EF-24 Is Neither Mediated by Oxidative Stress-Related Mechanisms nor Affected by Expression of Main Drug Transporters ABCB1 and ABCG2 in Human Leukemia Cells |
title_full_unstemmed |
Apoptosis Induced by the Curcumin Analogue EF-24 Is Neither Mediated by Oxidative Stress-Related Mechanisms nor Affected by Expression of Main Drug Transporters ABCB1 and ABCG2 in Human Leukemia Cells |
title_sort |
apoptosis induced by the curcumin analogue ef-24 is neither mediated by oxidative stress-related mechanisms nor affected by expression of main drug transporters abcb1 and abcg2 in human leukemia cells |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1422-0067 |
publishDate |
2017-10-01 |
description |
The synthetic curcumin analogue, 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone (EF-24), suppresses NF-κB activity and exhibits antiproliferative effects against a variety of cancer cells in vitro. Recently, it was reported that EF-24-induced apoptosis was mediated by a redox-dependent mechanism. Here, we studied the effects of N-acetylcysteine (NAC) on EF-24-induced cell death. We also addressed the question of whether the main drug transporters, ABCB1 and ABCG2, affect the cytotoxic of EF-24. We observed that EF-24 induced cell death with apoptotic hallmarks in human leukemia K562 cells. Importantly, the loss of cell viability was preceded by production of reactive oxygen species (ROS), and by a decrease of reduced glutathione (GSH). However, neither ROS production nor the decrease in GSH predominantly contributed to the EF-24-induced cell death. We found that EF-24 formed an adduct with GSH, which is likely the mechanism contributing to the decrease of GSH. Although NAC abrogated ROS production, decreased GSH and prevented cell death, its protective effect was mainly due to a rapid conversion of intra- and extra-cellular EF-24 into the EF-24-NAC adduct without cytotoxic effects. Furthermore, we found that neither overexpression of ABCB1 nor ABCG2 reduced the antiproliferative effects of EF-24. In conclusion, a redox-dependent-mediated mechanism only marginally contributes to the EF-24-induced apoptosis in K562 cells. The main mechanism of NAC protection against EF-24-induced apoptosis is conversion of cytotoxic EF-24 into the noncytotoxic EF-24-NAC adduct. Neither ABCB1 nor ABCG2 mediated resistance to EF-24. |
topic |
NF-κB Nrf2 EF-24-GSH adduct EF-24-NAC adduct K562 cells |
url |
https://www.mdpi.com/1422-0067/18/11/2289 |
work_keys_str_mv |
AT nikolaskoupa apoptosisinducedbythecurcuminanalogueef24isneithermediatedbyoxidativestressrelatedmechanismsnoraffectedbyexpressionofmaindrugtransportersabcb1andabcg2inhumanleukemiacells AT petrdolezel apoptosisinducedbythecurcuminanalogueef24isneithermediatedbyoxidativestressrelatedmechanismsnoraffectedbyexpressionofmaindrugtransportersabcb1andabcg2inhumanleukemiacells AT eliskaruzickova apoptosisinducedbythecurcuminanalogueef24isneithermediatedbyoxidativestressrelatedmechanismsnoraffectedbyexpressionofmaindrugtransportersabcb1andabcg2inhumanleukemiacells AT petrmlejnek apoptosisinducedbythecurcuminanalogueef24isneithermediatedbyoxidativestressrelatedmechanismsnoraffectedbyexpressionofmaindrugtransportersabcb1andabcg2inhumanleukemiacells |
_version_ |
1725879145843392512 |