Towards the Small and the Beautiful: A Small Dibromotyrosine Derivative from Pseudoceratina sp. Sponge Exhibits Potent Apoptotic Effect through Targeting IKK/NFκB Signaling Pathway
A dibromotyrosine derivative, (1′R,5′S,6′S)-2-(3′,5′-dibromo-1′,6′-dihydroxy-4′-oxocyclohex-2′-enyl) acetonitrile (DT), was isolated from the sponge Pseudoceratina sp., and was found to exhibit a significant cytotoxic activity against leukemia K562 cells. Despite the large number of the isolated bro...
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| Format: | Article |
| Language: | English |
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MDPI AG
2013-08-01
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| Series: | Marine Drugs |
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| Online Access: | http://www.mdpi.com/1660-3397/11/9/3168 |
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| author | Michael Y. Chiang Yao-Tsung Yeh Mei-Chin Lu Yin-Di Su Wen-Been Chang Yalan Chou Chia-Wei Tsao Li-Lian Liu Ying-Chi Du Chiang-Wen Su Yu-Cheng Chen Mohamed El-Shazly Jui-Hsin Su |
| author_facet | Michael Y. Chiang Yao-Tsung Yeh Mei-Chin Lu Yin-Di Su Wen-Been Chang Yalan Chou Chia-Wei Tsao Li-Lian Liu Ying-Chi Du Chiang-Wen Su Yu-Cheng Chen Mohamed El-Shazly Jui-Hsin Su |
| author_sort | Michael Y. Chiang |
| collection | DOAJ |
| description | A dibromotyrosine derivative, (1′R,5′S,6′S)-2-(3′,5′-dibromo-1′,6′-dihydroxy-4′-oxocyclohex-2′-enyl) acetonitrile (DT), was isolated from the sponge Pseudoceratina sp., and was found to exhibit a significant cytotoxic activity against leukemia K562 cells. Despite the large number of the isolated bromotyrosine derivatives, studies focusing on their biological mechanism of action are scarce. In the current study we designed a set of experiments to reveal the underlying mechanism of DT cytotoxic activity against K562 cells. First, the results of MTT cytotoxic and the annexin V-FITC/PI apoptotic assays, indicated that the DT cytotoxic activity is mediated through induction of apoptosis. This effect was also supported by caspases-3 and -9 activation as well as PARP cleavage. DT induced generation of reactive oxygen species (ROS) and the disruption of mitochondrial membrane potential (MMP) as indicated by flow cytometric assay. The involvement of ROS generation in the apoptotic activity of DT was further corroborated by the pretreatment of K562 cells with N-acetyl-cysteine (NAC), a ROS scavenger, which prevented apoptosis and the disruption of MMP induced by DT. Results of cell-free system assay suggested that DT can act as a topoisomerase II catalytic inhibitor, unlike the clinical anticancer drug, etoposide, which acts as a topoisomerase poison. Additionally, we found that DT treatment can block IKK/NFκB pathway and activate PI3K/Akt pathway. These findings suggest that the cytotoxic effect of DT is associated with mitochondrial dysfunction-dependent apoptosis which is mediated through oxidative stress. Therefore, DT represents an interesting reference point for the development of new cytotoxic agent targeting IKK/NFκB pathway. |
| first_indexed | 2024-04-13T07:53:22Z |
| format | Article |
| id | doaj.art-4b20928622684ba69d500273aae5bc42 |
| institution | Directory Open Access Journal |
| issn | 1660-3397 |
| language | English |
| last_indexed | 2024-04-13T07:53:22Z |
| publishDate | 2013-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Marine Drugs |
| spelling | doaj.art-4b20928622684ba69d500273aae5bc422022-12-22T02:55:28ZengMDPI AGMarine Drugs1660-33972013-08-011193168318510.3390/md11093168Towards the Small and the Beautiful: A Small Dibromotyrosine Derivative from Pseudoceratina sp. Sponge Exhibits Potent Apoptotic Effect through Targeting IKK/NFκB Signaling PathwayMichael Y. ChiangYao-Tsung YehMei-Chin LuYin-Di SuWen-Been ChangYalan ChouChia-Wei TsaoLi-Lian LiuYing-Chi DuChiang-Wen SuYu-Cheng ChenMohamed El-ShazlyJui-Hsin SuA dibromotyrosine derivative, (1′R,5′S,6′S)-2-(3′,5′-dibromo-1′,6′-dihydroxy-4′-oxocyclohex-2′-enyl) acetonitrile (DT), was isolated from the sponge Pseudoceratina sp., and was found to exhibit a significant cytotoxic activity against leukemia K562 cells. Despite the large number of the isolated bromotyrosine derivatives, studies focusing on their biological mechanism of action are scarce. In the current study we designed a set of experiments to reveal the underlying mechanism of DT cytotoxic activity against K562 cells. First, the results of MTT cytotoxic and the annexin V-FITC/PI apoptotic assays, indicated that the DT cytotoxic activity is mediated through induction of apoptosis. This effect was also supported by caspases-3 and -9 activation as well as PARP cleavage. DT induced generation of reactive oxygen species (ROS) and the disruption of mitochondrial membrane potential (MMP) as indicated by flow cytometric assay. The involvement of ROS generation in the apoptotic activity of DT was further corroborated by the pretreatment of K562 cells with N-acetyl-cysteine (NAC), a ROS scavenger, which prevented apoptosis and the disruption of MMP induced by DT. Results of cell-free system assay suggested that DT can act as a topoisomerase II catalytic inhibitor, unlike the clinical anticancer drug, etoposide, which acts as a topoisomerase poison. Additionally, we found that DT treatment can block IKK/NFκB pathway and activate PI3K/Akt pathway. These findings suggest that the cytotoxic effect of DT is associated with mitochondrial dysfunction-dependent apoptosis which is mediated through oxidative stress. Therefore, DT represents an interesting reference point for the development of new cytotoxic agent targeting IKK/NFκB pathway.http://www.mdpi.com/1660-3397/11/9/3168apoptosisdibromotyrosinemitochondrial dysfunctionoxidative stresstopoisomerase |
| spellingShingle | Michael Y. Chiang Yao-Tsung Yeh Mei-Chin Lu Yin-Di Su Wen-Been Chang Yalan Chou Chia-Wei Tsao Li-Lian Liu Ying-Chi Du Chiang-Wen Su Yu-Cheng Chen Mohamed El-Shazly Jui-Hsin Su Towards the Small and the Beautiful: A Small Dibromotyrosine Derivative from Pseudoceratina sp. Sponge Exhibits Potent Apoptotic Effect through Targeting IKK/NFκB Signaling Pathway Marine Drugs apoptosis dibromotyrosine mitochondrial dysfunction oxidative stress topoisomerase |
| title | Towards the Small and the Beautiful: A Small Dibromotyrosine Derivative from Pseudoceratina sp. Sponge Exhibits Potent Apoptotic Effect through Targeting IKK/NFκB Signaling Pathway |
| title_full | Towards the Small and the Beautiful: A Small Dibromotyrosine Derivative from Pseudoceratina sp. Sponge Exhibits Potent Apoptotic Effect through Targeting IKK/NFκB Signaling Pathway |
| title_fullStr | Towards the Small and the Beautiful: A Small Dibromotyrosine Derivative from Pseudoceratina sp. Sponge Exhibits Potent Apoptotic Effect through Targeting IKK/NFκB Signaling Pathway |
| title_full_unstemmed | Towards the Small and the Beautiful: A Small Dibromotyrosine Derivative from Pseudoceratina sp. Sponge Exhibits Potent Apoptotic Effect through Targeting IKK/NFκB Signaling Pathway |
| title_short | Towards the Small and the Beautiful: A Small Dibromotyrosine Derivative from Pseudoceratina sp. Sponge Exhibits Potent Apoptotic Effect through Targeting IKK/NFκB Signaling Pathway |
| title_sort | towards the small and the beautiful a small dibromotyrosine derivative from pseudoceratina sp sponge exhibits potent apoptotic effect through targeting ikk nfκb signaling pathway |
| topic | apoptosis dibromotyrosine mitochondrial dysfunction oxidative stress topoisomerase |
| url | http://www.mdpi.com/1660-3397/11/9/3168 |
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