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Towards the Small and the Beautiful: A Small Dibromotyrosine Derivative from Pseudoceratina sp. Sponge Exhibits Potent Apoptotic Effect through Targeting IKK/NFκB Signaling Pathway
National Museum of Marine Biology & Aquarium, Pingtung 944, Taiwan
Graduate Institute of Marine Biotechnology, National Dong Hwa University, Pingtung 944, Taiwan
Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan
Department of Pharmacognosy and Natural Products Chemistry, Faculty of Pharmacy, Ain-Shams University, Organization of African Unity Street, Abassia, Cairo 11566, Egypt
Institute of Marine Biology, National Sun Yat-sen University, Kaohsiung, Taiwan
Department of Marine Biotechnology and Resources and Asia-Pacific Ocean Research Center, National Sun Yat-sen University, Kaohsiung 804, Taiwan
Department of Chemistry, National Sun Yat-sen University, Kaohsiung 804, Taiwan
Department of Medical Laboratory Sciences and Biotechnology, Fooyin University, Kaohsiung 831, Taiwan
These authors contributed equally to this work.
* Author to whom correspondence should be addressed.
Received: 14 May 2013; in revised form: 9 August 2013 / Accepted: 9 August 2013 / Published: 26 August 2013
Abstract: 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.
Keywords: apoptosis; dibromotyrosine; mitochondrial dysfunction; oxidative stress; topoisomerase
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Su, J.-H.; Chen, Y.-C.; El-Shazly, M.; Du, Y.-C.; Su, C.-W.; Tsao, C.-W.; Liu, L.-L.; Chou, Y.; Chang, W.-B.; Su, Y.-D.; Chiang, M.Y.; Yeh, Y.-T.; Lu, M.-C. Towards the Small and the Beautiful: A Small Dibromotyrosine Derivative from Pseudoceratina sp. Sponge Exhibits Potent Apoptotic Effect through Targeting IKK/NFκB Signaling Pathway. Mar. Drugs 2013, 11, 3168-3185.
Su J-H, Chen Y-C, El-Shazly M, Du Y-C, Su C-W, Tsao C-W, Liu L-L, Chou Y, Chang W-B, Su Y-D, Chiang MY, Yeh Y-T, Lu M-C. 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. 2013; 11(9):3168-3185.
Su, Jui-Hsin; Chen, Yu-Cheng; El-Shazly, Mohamed; Du, Ying-Chi; Su, Chiang-Wen; Tsao, Chia-Wei; Liu, Li-Lian; Chou, Yalan; Chang, Wen-Been; Su, Yin-Di; Chiang, Michael Y.; Yeh, Yao-Tsung; Lu, Mei-Chin. 2013. "Towards the Small and the Beautiful: A Small Dibromotyrosine Derivative from Pseudoceratina sp. Sponge Exhibits Potent Apoptotic Effect through Targeting IKK/NFκB Signaling Pathway." Mar. Drugs 11, no. 9: 3168-3185.